Volume 100 Number
`
`September
`
`1993
`
`BJOGAS 1009 799886 1993 ISSN 0306-5456
`
`TTL JJJYAL
`AND YN O/1/3
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDICINE
`
`Journal of
`Obstetricsand
`Gynaecology
`
`Edited by Geoffrey Chamberlain
`
`CU
`
`-t
`
`CU
`
`CU
`
`on behalf of the
`Published
`Roya College of Obstetricians and Gynaecologists
`by Blackwell Scientific Publications
`
`PIaintifr xhIbft
`TJ$
`
`PTX 001
`
`WC_LP0404999
`
`Mylan v. Warner Chilcott IPR2015-00682
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`
`

`
`British Journal of Obstetrics and Gynaecology
`Volume 100 No
`
`1993
`
`Scptcmber
`
`CONTENTS
`
`Commentaries
`
`National
`
`perinatal
`
`epidemiology
`
`unita national
`
`assest
`
`Li/ford
`
`The Read clinical
`
`classification
`
`Barron
`
`False
`
`negative cervical
`
`smears
`
`Macgregor
`
`Review
`
`799
`
`800
`
`801
`
`Recent
`
`advances
`
`in the treatment
`
`of carcinoma
`
`of
`
`the ovary
`
`803
`
`Barker
`
`Obstetrics
`
`Plasma protein levels
`
`in normal human fetuses 131041
`
`weeks
`
`gestation
`
`Fryer
`
`Jones
`
`Strange
`
`Hume
`
`Bell
`
`Report of RCOG Meeting 1617 March
`
`Gynaecological
`
`endoscopy
`
`surgery
`
`Manyond
`
`Case Reports
`
`Repair of prolapse by means of
`Johnson
`
`.J Lilford
`
`living ligament
`
`Batche/or
`
`850
`
`856
`
`859
`
`Primary volvulus
`
`of
`
`the small bowel
`
`following normal
`
`delivery
`
`860
`
`Ranjan
`
`Boullon
`
`Unilateral dysmcnorrhoca
`
`due
`
`to an haematometra
`
`in
`
`rudi
`
`Reagent
`
`strip testing of antenatal
`
`urine
`
`specimens
`
`for
`
`infection
`
`806
`
`mcntary horn
`
`862
`
`Etherington
`
`James
`
`Hussain
`
`Smith
`
`Mi/Is
`
`Placental
`
`vartant
`
`ci
`.0
`
`.0
`
`.0
`
`en
`
`as
`
`Low
`
`dose
`
`pregnancy
`
`aspirin
`
`outcome
`
`in hypertensive
`
`pregnant women effect
`balance
`and prostacyclinthromboxane
`
`on
`
`in
`
`bands
`
`Stock
`
`Hamss
`
`of placenta pracvia
`Ghosh
`
`Pong
`
`mother
`
`and newborn
`
`1.
`
`t/iinikka
`
`Hti/e.cmaa
`
`A.-
`Ylikorkala
`
`Hartikainert-Sorri
`
`809
`
`Adverse
`
`cardiovascular
`
`sequelae
`
`of ergonietrine
`
`Lumme
`
`Carey
`
`863
`
`865
`
`Longitudinal
`
`assessment
`
`of amniotic
`
`fluid index
`
`Nwosu
`
`Welch
`
`Munasse
`
`Walkinshaw
`
`An audit
`nancies
`
`services
`
`of
`
`the
`
`obstetric
`
`outcome
`
`of
`
`148 consecutive
`
`preg-
`
`from assisted
`
`conception
`
`implications
`
`for neonatal
`
`816
`
`820
`
`McFau/
`
`Patel
`
`Mills
`
`Persistent mcnorrhagia
`Ewen
`
`.1
`
`despite
`
`Sutton
`
`total absence
`
`of endomelriuns
`
`866
`
`Twin
`
`and
`
`pregnancy
`
`consisting
`
`of
`
`hydatidiforni
`
`mole
`
`fetus genetic origin
`McConnell
`
`Mitt
`
`determined
`
`Ko
`
`complete
`by DNA typing
`Braude
`
`Warfarin
`
`embryopathy patient possibility
`
`pathogenesis
`
`and
`
`prognosis
`
`de Vries
`
`van der Veer
`
`He jmans
`
`867
`
`869
`
`.2
`.i
`
`.2
`
`Fetal
`
`and Neonatal
`
`Medicine
`
`Increased rtsk
`
`of aneuploidy
`
`in women
`
`having
`
`unsuccessful
`
`High
`
`resolution
`
`nancy
`
`combined
`
`ultrasound
`
`in the diagnosis of heterotopic
`transabdonsinal
`
`and
`
`transvaginal
`
`approach
`
`preg
`
`chorionic
`
`villus sampling procedures
`
`826
`
`Pa
`
`Gerscovich
`
`Donnenfeld
`
`Librizzi
`
`Weiner
`
`Bolognese
`
`The effect
`
`of cordocentesis
`
`on umbilical
`
`and middle
`
`cerebral
`
`artery
`
`blood flow
`
`velocity
`
`waveforms
`
`Hecher
`
`Stettner
`
`Sperno/
`
`Harrington
`
`Szaluy
`
`Short Communications
`
`828
`
`Faccal
`
`carrtagc
`
`Gra.t
`
`of listeria during pregnancy
`Pedler
`
`Barrett
`
`Ltnd
`
`Gynaecology
`
`Comparative
`
`profiles
`
`of reliability
`
`cycle
`
`control
`
`and side effects
`
`The effect
`
`of oxytocics
`
`stored at high temperatures
`
`on post-
`
`partum uterine
`Chua
`
`activity
`Arulkumaran
`
`.4daikan
`
`Ratnam
`
`of
`
`gestrel
`
`either
`
`ker/und
`
`two oral contraceptive
`and
`30 pg or 20 pg ethinyl
`Rde
`
`formulations
`
`containing
`
`150 pg deso-
`
`oestradiol
`
`832
`
`Serum screening for Downs syndrome
`Dawson
`Jones
`Matharu
`
`Reynolds
`
`Westerguard
`
`Penney
`
`Creasy
`
`Gregory
`
`871
`
`873
`
`874
`
`875
`
`5-
`
`so
`
`05
`in
`a-
`
`Stereomicroacopic
`
`demonstration
`
`of chorionic villi differentia-
`
`tion
`
`between
`
`miscarriage and eclopic
`
`pregnancy
`
`Kristiansen
`
`Clausepi
`
`Nielsen
`
`Thomsen
`
`The assessment
`
`of clinical
`
`cortipetencc
`cology in two medical schools by an objective
`
`in obstetrics
`
`and gynae-
`structured clinical
`
`examination
`
`McFaul
`
`Taylor
`
`P1
`
`How is
`
`Reproductive
`
`Science
`
`Low levels
`of amniotic
`Downs syndrome
`md
`Macintosh
`
`lIes
`
`Chard
`
`fluid placental
`
`alkaline
`
`phosphatase
`
`tit
`
`Wathen
`
`Murugan
`
`Campbell
`
`839
`
`842
`
`847
`
`John
`
`of oocyte donors
`Hughes
`
`The recruitment
`
`Horns
`
`Lieberman
`
`Matson
`
`Buck
`
`Management
`
`and
`
`outcome
`
`of obstructive
`
`uropathy
`
`in twin
`
`pregnancies
`
`I.ipit
`
`Robson
`
`Ryan
`
`Hocus/er
`
`Rodeck
`
`Dose and
`time dependent
`administration of mifepristone
`Brooks
`
`Thong
`
`rise of
`
`plasma
`
`cortisol
`
`following
`
`in early
`
`pregnancy
`
`Baird
`
`Correspondence
`
`Book Reviews
`
`877
`
`879
`
`88fl
`
`883
`
`886
`
`in
`
`as
`
`Blackwell Scientific
`
`Publications
`OXFORD LONDON EDINBURGH
`
`BOSTON
`
`MELBOURNE
`
`PARIS
`
`BERLIN VIENNA
`
`Printed
`
`in Great Brilain by Headley Brothet-s Ltd
`
`The Invicta
`
`Press Ashtord Kent and London
`
`III
`
`3b-84BbC1939191-G
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`WC_LP 0405000
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`Mylan v. Warner Chilcott IPR2015-00682
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`

`
`British Journal
`
`of Obstetrics
`
`September
`
`1993 Vol
`
`and Gynaecology
`00 pp 832838
`
`GYNAECOLOGY ____
`
`Comparative profiles of reliability cycle control and
`side effects of two oral contraceptive formulations
`containing 150 pg desogestrel and either 30 tg or 20 pg
`ethinyl oestradiol
`
`Associate
`
`Professor ARNE Roe Private Practitioner JEs WESTERCAARD Professor
`Norway he Department
`Lund Sweden Htmana Ac timed Sandeika
`Clinic
`Hospital of Odense Denmark
`
`of Obstetrics
`
`and
`
`AK ISLUN
`The Student Genoecology
`Gynaecology
`
`iniversity
`
`ABSTRACT
`
`two oral contraceptive
`Objective To compare
`Mercilon or 30 tg Marvelon/Desolett
`and side effect profile
`
`pills both containing
`
`150 sg desogestrel but with either 20
`ethinyl ocstradiol EE regarding reliability cycle control
`
`double blind randomised
`Design
`months the women noted tablet
`
`multicentre
`
`intake
`
`three six and
`follow up after
`study over one year with
`designed diary cards
`arid all bleedings on specifically
`
`12
`
`Setting
`University
`Denmark
`
`clinics
`
`central hospitals
`
`and private
`
`gynaecological
`
`practices
`
`in Norway
`
`Sweden and
`
`Subjects
`
`One thousand women aged 18 to 40 years
`
`requesting
`
`oral contraceptive
`
`pills
`
`Main outcome
`
`measures Reliability
`
`cycle
`
`control
`
`side
`
`effects
`
`blood
`
`pressure body
`
`weight
`
`and
`
`baemoglobin
`
`the 30 pg EE dose pill
`total of 4543 cycles with the 20 .tg EE dose pill and 4688 cycles with
`the
`Results
`in
`irregular bleeding break
`to method failure were
`number of pregnancies
`and
`ascribed
`respectively
`two
`combination
`in about
`through bleeding or spotting was signficantly more frequent with the 150/20
`decreased
`the study Mean blood pressure
`distributed
`over the one year of
`randomly
`about mmHg whereas mean body
`combination
`in the group on the 150/20
`slightly particularly
`12 months Hae
`combination
`approximately 05 kg in the group with
`the 150/30
`and mood
`Side effects other than bleeding problems were
`rare but dizziness
`did not change
`moglobin
`Due to side effects more women
`combination
`changes were more frequent
`in the group on the 150/20
`to six month periods
`combination
`discontinued the study during the one to three
`and four
`on the 150/20
`the end of
`also less positive about continuing the study drug at
`the trial
`and women on this
`
`thirds of
`
`the cycles
`
`weight
`
`increased
`
`after
`
`pill were
`
`Conclusions
`
`Both pills have
`
`nation
`
`the cycle control
`
`the
`
`150/20
`
`combination
`
`irregular bleeding
`
`reliability and are well
`high contraceptive
`in view of
`is less effective However
`the potentially
`some additional
`many women can be expected to accept
`
`tolerated but with
`
`increased
`
`the 150/20
`
`combi
`
`safety profile of
`discomfort due
`
`to
`
`Cs
`
`CO
`
`Some epideiniological
`suggested an associ-
`combined
`dose
`between
`ation
`the use of high oestrogen
`contraceptive OC pills and serious
`oral
`complications such as myocardial
`infarction
`Jiek clot
`venous
`thromboembolism
`
`stroke
`
`1978 Stadel
`
`studies
`
`have
`
`cardiovascular
`
`and
`1981
`cancer seems
`
`the risk of developing
`Furthermore
`to be slightly increased
`long use of high oestrogen
`Jones
`women Rushton
`dose pills by young nulliparous
`
`breast
`
`after
`
`Correspondence Dr
`Gvnaecology
`
`University
`
`Akcrtund Department of Obstetrics
`63 Lund Sweden
`S-223
`Hospital
`
`832
`
`1992
`
`the
`
`By reducing
`EE to the
`30 tg dose
`risk of
`cardiovascular
`
`of ethinyl
`dose
`the daily
`in most currently
`
`oestradiol
`
`used
`
`prep-
`complications has
`arations
`et at
`1980 Stampfer
`decreased markedly Bottiger
`reduction in EE
`further
`1990 Thorogood ci
`1991
`below 30 gg per day has only been described with norethi
`this combination
`was reported to have
`sterone However
`poor cycle control Bounds eta 1979 Furthermore
`with
`the
`norethisterone
`or
`as
`levonorgestrel
`progestational
`
`et
`
`agent
`
`in
`
`pill with less
`
`than 30 .mg EE there would be
`
`WC_LP 0405001
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2013, Pg. 3
`
`

`
`risk of adverse effects on lipoprotein
`
`due
`
`to the
`
`patterns
`these progestogens Bergink ef
`
`resulted
`
`in
`
`advantage
`
`of
`androgenic
`properties
`al 1982 Fotherby 1985
`The search
`for more potent progestogens
`of desogestrel
`which exerts
`its biological
`the development
`to 3-keto-desogestrel The main
`effect after conversion
`other
`with
`of 3-keto-desogestrel
`compared
`in OCs is that
`
`used
`
`it displays
`
`high ratio
`
`progestogens
`between
`
`the
`
`desired
`
`progestational
`
`the
`and
`effects
`1985 This has
`undesired
`effects Cullberg
`androgenic
`allowed reduction of the EE dose to 20 pg without
`risk of
`unfavourable
`on lipids and
`liproteins Klooster
`combi
`hoer et al 1987 Tuimala at al 1987
`of 20 .ig EE and
`was studied
`ig desogestrel
`trial and was found to have
`open clinical
`large although
`index of 02 Lam
`and
`control
`an effective
`op ten Berg 1991 We present
`here the results of
`mers
`study of OC pills containing
`double blind comparative
`and 30 tg of EE together with
`150
`ig of desogestrel
`reliability and
`control
`on
`emphasis
`cycle
`special
`and haemoglobin
`effects on blood pressure body weight
`also studied
`as side effects were
`as well
`
`effects
`
`monophasic
`
`nation
`
`150
`
`cycle
`
`Pearl
`
`in
`
`20
`
`with
`The
`
`Subjects
`
`and methods
`
`gynaecological
`
`performed
`
`and
`
`at
`
`final
`
`visit
`
`COMPARATIVE
`
`PROFILES
`
`OF IWO ORAL CONTRACEPTIVES
`
`833
`
`examination
`
`was
`
`performed
`
`examination
`
`and measurement
`
`after
`concen
`
`tration
`
`150/30
`
`secutive
`
`Follow
`
`pressure
`
`the
`
`study the
`
`including
`gynaecological
`of blood pressure
`and haemoglobin
`mm of seated
`rest body weight
`The women were
`allocated
`to the study
`randomly
`medication
`by simple random
`according to
`list computed
`by Oss
`isation and provided
`by Organon International
`The Netherlands
`485 women on the 150/20
`and 497 on the
`combination
`The tablets were
`by Organon
`supplied
`by in standard unmarked 21 day blister packs
`International
`from another OC formulation to the
`Women either changed
`study medication
`switchers or had not used any hormonal
`medication
`for at least
`two months starters
`contraceptive
`The women started to take the study medication
`on the
`first day of menstruation or of withdrawal bleeding after
`previous OC pill use The tablets were
`taken for 21 con
`days followed by
`tablet-free period
`seven-day
`done after
`up visits were
`three six and 12 months
`of OC-treatment
`with recording of blood
`and
`Furthermore
`weight
`body
`throughout
`women noted all vaginal
`bleeding on specifically
`designed
`diary cards on which each tablet
`and all side effects
`intake
`also were
`recorded
`Completed
`lected and new cards
`distributed
`follow
`were
`
`Cu
`
`-o
`
`I-
`
`.9
`
`.0
`
`Cu
`
`Cu
`
`Cu
`
`It
`
`.0
`
`Ii
`
`cu
`
`containing
`
`1.50
`
`that
`
`portions
`
`limit of
`
`between
`
`provided
`Women
`
`asking
`for the study In Norway
`the study six centres all private
`gynaecological
`tices in Sweden 500 woman two university
`two
`clinics
`in Denmark
`one private practice and
`central
`hospitals
`clinic The participating
`200 women one university
`18 to 35 Norway or 18 to 40 years
`women were
`aged
`obtained
`Sweden Denmark
`Informed
`consent was
`from each
`
`and 20
`Oral contraceptives
`ig desogestrel
`or 30.g of EE per tablet Mercilon and Marvelon/Deso
`in 1000 women over
`lett respectively were
`compared
`treatment period of one year The sample size of the study
`it would be
`500 participants was determined
`so that
`to demonstrate
`there was minimal differ
`that
`possible
`ence with respect
`bleeding With
`to presence of
`irregular
`95% con
`500 women in each group the upper
`interval CI for the difference
`the pro
`fidence
`80%
`would be less than 6% with
`the probability
`the two treatments did not differ
`for oral contraception were
`300 women were
`
`recruited
`
`recruited
`
`for
`
`prac
`
`according
`obtained
`
`participant
`
`to the Helsinki
`
`and
`
`the study was
`declaration
`with
`
`from the
`
`ethics
`
`committees
`
`and
`
`performed
`
`permissions
`from the
`
`national
`
`boards for health
`
`Criteria for exclusion
`
`and welfare
`of women from the study were
`smoking 15/day in women over
`the
`age of 35
`heavy
`thromboembolic
`for or history of
`years risk factor
`cesses
`of
`the participant
`
`or
`
`close relative
`
`pro
`hypertension
`
`liver disorders
`
`nosed
`
`vaginal
`
`and breast
`
`completed
`
`undiag
`systemic lupus erythematosus
`bleeding sickle cell anaemia porphyria
`use
`of ceitain
`antibiotics
`hyperlipidaemia
`otosclerosis
`woman started using
`feeding If
`or anticonvulsants or used
`other
`griseofulvin
`for more than 14 days she was excluded from the study
`At the first visit
`inclusion and exclusion
`check
`lists were
`the medical history was recorded and physical
`
`rifampicin
`
`antibiotics
`
`.0
`
`Cu
`
`Cu
`
`Cu
`
`cC
`
`cC
`
`cC
`
`Cu
`
`cC
`cJ
`Cu
`
`Cl
`
`Cu
`
`It
`
`Cu
`.0
`
`were
`col
`cards
`diary
`as new study medication
`as well
`up visits At
`the
`was
`examination
`again
`concentration measured
`haemoglobin
`as normal withdrawal bleeding if it
`Bleeding was defined
`and lasted
`no more
`started within
`the tablet-free
`interval
`than eight
`days Any other bleeding during the tablet-
`period was defined
`as irregular
`bleeding Bleeding
`was further subdivided
`requiring at the most
`into spotting
`one sanitary pad or tampon
`bleed
`day or breakthrough
`requiring more than one sanitary
`tampon
`pad or
`ing
`day The occurrence
`and duration of
`these
`two types of
`calculated Days of break
`bleeding irregularities were
`bleeding and spotting
`the same bleeding
`within
`through
`episode was all counted as breakthrough
`bleeding For the
`information on bleeding and tablet
`intake was
`analysis
`taken directly
`from the diary cards Cycles in which the pill-
`taking period was less than 18 days or greater
`than 33 days
`treatment were not included in the analysis
`nor were
`of
`pill-free period of less than five days or
`those cycles with
`than nine days The same accounts for cycles
`for
`greater
`which no information was obtained
`on the pill-free period
`treatment
`the first
`days of
`Bleeding during the first eight
`cycle was not included in the calculations
`The occurrence of side effects was recorded at each fol
`If these side effects were reasons for drop-out
`low up visit
`from the study this was also noted At the final
`each
`woman was asked whether or not she would
`participating
`liked to continue with the preparation used
`have
`The x2 test was used for the comparison
`of occurrence
`Otherwise
`comparisons
`bleeding
`irregularities
`by Fishers
`between
`the treatment groups were performed
`permutation test Bradley 1968 which includes
`Fishers
`com
`case Fishers test
`exact
`for paired
`as
`special
`for comparisons within
`parisons Bradley 1968 as applied
`tests were
`treatment groups All
`two-sided
`
`taking
`
`all
`
`of
`
`test
`
`visit
`
`Results
`
`The number of women starting
`on oral contraceptives
`to the study drugs from whom data was avail-
`
`switching
`
`or
`
`WC_LP 04050 02
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2013, Pg. 4
`
`

`
`AKERLUND ET AL
`
`834
`
`Table
`
`Number
`
`starting
`
`contraceptives
`
`or switching
`
`to the 150/20 or 150/30
`
`ag desogestrel/ethinyl
`
`oestradiol
`
`of women
`on oral
`total of 18 women agreed
`is shown
`to participate and were
`pill The age distribution at
`the start of the
`
`combination
`
`with their contraceptive
`
`randomised
`
`to one of the treatment
`
`groups but never
`
`started
`
`is also
`
`indicated
`
`study
`
`Cycle
`
`Start
`
`12
`
`-H
`
`CD
`
`150/20
`
`150/30
`
`Starters
`
`Switchers
`
`Total
`
`Starters
`
`Switchers
`
`Total
`
`188
`
`163
`
`161
`
`136
`
`122
`
`110
`
`41
`
`76
`
`297
`
`279
`
`275
`
`252
`
`228
`
`216
`
`51
`
`139
`
`485
`
`442
`
`436
`
`388
`
`350
`
`326
`
`92
`
`215
`
`197
`
`168
`
`163
`
`138
`
`122
`
`119
`
`59
`
`81
`
`298
`
`282
`
`279
`
`258
`
`235
`
`225
`
`59
`
`145
`
`497
`
`452
`
`444
`
`398
`
`359
`
`346
`
`118
`
`228
`
`90
`
`Age distribution
`20
`2024
`2529
`3034
`3539
`39
`
`50
`
`19
`
`59
`
`37
`
`11
`
`109
`
`56
`
`12
`
`34
`
`20
`
`56
`
`33
`
`53
`
`Information about
`
`previous
`
`use of contraceptives
`
`was not obtained
`
`from two women
`
`38-8 in the 150/20
`
`and 398 in the 150/30
`
`treatment groups
`group No difference
`seen
`study groups was
`parity previous OC use
`regarding previous pregnancies
`of menstrual cycles
`smoking use of medication
`index hae
`blood pressure weight
`length body mass
`and findings
`examination
`moglobin
`
`between
`
`pattern
`
`at gynaecological
`
`as well as the distribution
`able for analyses
`in age groups
`for the two preparations are shown in Table
`Data
`on
`the 150/20
`4543 cycles with
`and 4688 cycles with the 150/30
`The decrease in number of
`combination
`
`obtained
`
`were
`
`from start of
`the study to cycle
`subjects
`and receiving
`women electing
`to participate
`but thereafter
`the medication
`not commencing
`The mean age of women on the
`higher P005 than that of
`23.8 years was significantly
`on the pill with the higher EE dose 23.1 years
`subjects
`The percentage of starters did
`not differ between
`the two
`
`was
`
`due
`
`to
`
`study drug
`
`150/20
`
`combination
`
`-C
`
`CD
`
`CD
`
`3-
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`3-
`
`-C
`
`C-
`
`-C
`
`C-
`
`-C
`
`CC
`
`Reliability
`
`Two
`
`Pearl
`
`occurred
`on
`combination
`the
`150/20
`pregnancies
`index 041 95% CI 0.041.5 but neither of
`
`them
`
`ns
`
`fl Plfl
`
`fl
`
`ns
`
`50
`
`40
`
`30
`
`20fl
`
`10
`
`10
`
`11
`
`12
`
`BTB 150/20
`
`BTB 150/30
`
`11111 Spotting
`
`150/20
`
`1111
`
`Spotting 150/30
`
`Fig
`
`Irregular bleeding BTB and/or
`
`spotting
`
`in percentage
`
`of women per
`
`treatment
`
`cycle
`
`WC_LP 0405003
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2013, Pg. 5
`
`

`
`COMPARATIVE
`
`PROFILES
`
`OF TWO ORAL CONTRACEPTIVES
`
`835
`
`to be due to method failure One subject
`was considered
`had prolonged
`the interval
`of two pills
`between
`the taking
`and one had had diarrhoea for three days but did not
`additional
`
`use
`
`protection
`
`Table
`
`Duration
`
`and/or
`
`spotting
`
`of irregular bleeding
`in women using
`combination Results are shown as mean SD calculated
`women having irregular bleeding
`
`breakthrough
`
`the
`
`150/20
`
`and
`
`ci
`
`H05
`
`bleeding
`
`150/30
`
`for
`
`the
`
`Of
`
`the
`
`three
`
`combination
`
`on the 150/30
`pregnancies
`index 06 95% CI 01-16 two were
`ascribed
`to
`Pearl
`index 04 95% CI 0-0415 The
`method failure Pearl
`third pregnancy occurred in
`woman who had prolonged
`between
`two treatment cycles
`from seven
`the interval
`
`to
`
`nine days
`
`Cycle control
`
`spotting
`
`increasing
`
`duration
`
`the
`
`first
`
`with
`
`of
`
`over
`
`not differ regarding
`
`of
`
`randomly
`The incidence
`
`distributed
`
`of
`
`with
`
`Duration
`
`of irregular bleeding days
`
`Cycle
`
`150/20
`
`150/30
`
`5-2 3.7
`4.4 3.1
`38 2.3
`4.3 2.9
`3.3 2.4
`
`64 4.5
`37 2.5
`39 2.6
`38 3.0
`29 1.4
`
`12
`
`ers the percentage of women having irregular bleeding in
`two cycles of use of the 150/30
`pill was half
`the first
`that of
`combination
`the women
`150/20
`to the
`
`This
`
`difference
`
`switching
`was
`
`not
`
`the mean duration of
`reflected
`two groups not shown
`
`in
`
`irregular bleeding in these
`
`Influence
`
`on blood pressure body weight
`haemoglobin
`
`and
`
`levels
`
`were
`
`seen
`
`after
`
`three
`
`and six
`
`at all check-up
`
`decrease was
`
`Compared with pretreatment
`slight decreases
`0.52 mmHg in mean systolic blood pressure
`combination
`in the group on the 150/20
`in mean diastolic
`months
`and
`pressure
`For the 150/30
`combination
`visits Table
`only seen with
`regard to mean systolic
`after six
`pressure
`months Mean body weight
`had decreased about 02 kg in
`the three month
`combination
`the group on the 150/20
`com
`06 kg in the group on the 150/30
`visit and increased
`No significant
`12 months Table
`differ
`of blood pressure and
`groups in magnitude
`from baseline
`was seen Haemoglobin did
`or between
`
`bination
`
`after
`
`ence between
`
`weight
`changes
`not vary within
`
`at
`
`groups during the study
`
`a..
`
`.0
`
`-a
`
`.0
`a-
`
`-o
`
`cu
`
`a..
`
`-c
`
`a-
`.0
`
`C-
`-o
`
`.0
`-J
`
`ci
`
`C-
`
`C-
`
`After the study was completed
`8900 cycles were available
`8573
`as recorded on the.diary
`cards After data validation
`The occurrence of
`cycles could be included in the analysis
`bleeding or spotting is
`bleeding breakthrough
`irregular
`shown in Fig
`The absence
`for all
`the study
`cycles
`in Table
`withdrawal bleeding is tabulated
`for the cycles
`and 12 The duration of irregular bleeding in the
`women having this event
`is shown in Table
`Irregular
`bleeding was more frequent with the lower EE dose pill
`one The difference
`than with
`the higher
`was statistically
`in two-thirds
`of the cycles
`significant
`the study Fig
`over
`the one year of
`and
`bleeding decreased
`breakthrough
`of use of both OCs
`similar
`trend
`of those women who completed
`was seen in subanalysis
`six months
`the study However
`of
`the study
`lower incidence
`period showed
`irregular bleeding in
`the total study population due
`this group compared
`the study There
`to the women having
`dropped out of
`were
`no significant
`between
`the two groups
`differences
`The
`of withdrawal bleeding Table
`regarding absence
`of irregular bleeding did not show any con
`mean duration
`between
`but decreased
`sistent differences
`the two groups
`time in both of them Table
`The two groups did
`the length of thewithdrawal bleeding
`was made between
`women
`comparison
`and women switching
`starting on the two combinations
`to
`the study medication
`from their previous pills It showed
`that for both preparations in the first
`three months irregu
`lar bleeding was more common
`in the group of starters
`the two com
`There was no difference
`between
`two cycles of the starters
`in the first
`in the third
`bleeding was more common
`in this sub
`one irregular
`the lower EE dose pill In the group of switch-
`
`Table
`
`binations
`
`group with
`
`separate
`
`Table
`
`in women using the
`Absence of withdrawal
`bleeding
`of women
`150/20 or 150/30 combination Results are percentages
`per cycle evaluablc
`for cycle analysis There were no statistically
`between
`differences
`
`significant
`
`study groups
`
`Side effects
`
`Side
`effects with
`the
`two preparations
`reported by 15
`women or more in any of
`for which
`the groups or those
`
`of irregular
`bleed/ng
`in women using
`both stsrtcrs
`including
`of women per
`
`Table
`
`and/or
`
`Frequency
`
`spotting
`
`combination
`
`percentages
`
`Cycle
`
`Starters
`
`Absence of withdrawal
`
`bleeding
`
`Cycle
`
`150/20
`
`150/30
`
`Swilchers
`
`406
`
`383
`
`354
`
`331
`
`271
`
`64
`
`52
`
`42
`
`39
`
`TO
`
`415
`
`395
`
`367
`
`347
`
`292
`
`51
`
`3.5
`
`30
`
`32
`
`14
`
`12
`
`5P.zO05
`sp0.0
`P0.0O1
`
`-o
`
`C-
`
`to
`cu
`
`Ci
`
`F-
`
`breakthrough
`
`bleeding
`
`the
`
`150/20
`
`or
`
`150/30
`
`and
`
`switchers
`
`Results
`
`are
`
`cycle
`
`evaluable
`
`for cycle analysis
`
`Irregular bleeding
`
`150/20
`
`150/30
`
`150
`
`148
`
`146
`
`256
`
`252
`
`237
`
`481
`
`284
`
`288
`
`289
`
`222
`219
`
`156
`
`154
`
`149
`
`259
`
`256
`
`246
`
`519
`
`208
`
`18.8
`
`13.9
`12.95
`
`163
`
`WC_LP 04050 04
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2013, Pg. 6
`
`

`
`836
`
`AKERLUND ET AL
`
`Table
`
`Blood pressure and body weight mean change
`combination Significant differences
`are denoted
`by asterisks
`Blood pressure mmHg
`
`from baseline
`
`increase
`
`decrease in women using the 150/20 or 150/30
`
`Systolic
`
`Diastolic
`
`Body weight kg
`
`150/20
`
`j.55
`
`066
`
`150/30
`
`063
`122
`062
`
`150/20
`
`123
`134
`086
`
`150/30
`
`043
`052
`0.01
`
`150/20
`
`023
`002
`021
`
`150/30
`
`004
`025
`
`Cycle
`
`12
`
`P0-01
`P0.00l
`
`found between
`difference
`were
`in reporting
`significant
`More women on the 150/20
`groups are shown in Table
`mood
`than on the 150/30
`combination
`
`reported dizziness
`
`of
`
`case of pulmonary
`
`on the 150/30
`
`in
`
`and irregular
`bleeding
`change
`Diseases diagnosed during the time of
`the study were
`between
`few mainly infections with no differences
`prep
`arations The only serious event emerging during the time
`embolism This hap
`the study was
`combination
`triphasic OC for
`by scintigraphy
`
`three
`
`been
`
`on
`
`low antithrom
`
`for
`
`four
`
`has
`
`no
`
`in the third cycle
`pened
`woman who had
`previously
`years The diagnosis
`was confirmed
`revealed
`and coagulatory investigation
`bin-TI
`treatment
`activity After anticoagulant
`months
`the patient has recovered completely and she
`now gone
`pregnancy with
`an uncomplicated
`through
`disturbance in antithrombin-III
`
`combination
`
`and
`
`396% and
`
`245% for
`
`the
`
`150/30
`
`combination
`
`out of
`Reasons
`the study by 15 or
`for dropping
`given
`the groups are shown in Table
`more women in any of
`Only regarding irregular bleeding and lack of need of con
`seen
`between
`were significant
`differences
`the
`traceptive
`groups Due to side effects
`and 150/30
`combination
`combination
`more women on the 150/20
`had dropped out
`the study during both the one to three P005 and
`to six P001 month periods During
`
`150/20
`
`of
`
`four
`
`the months
`
`seven
`was
`no
`there
`difference
`to twelve
`remaining women in discontinuation
`effects However women on the 150/20
`were
`less positive about continuing with their preparation than
`85.8% vs 910% wishing
`combination
`those on the 150/30
`to continue P0.05
`
`between
`
`the
`
`because
`
`of
`
`side
`
`combination
`
`Discontinuation and svillingness to continue with study
`drug
`
`150/20
`
`and
`
`to 33% with
`combination
`
`the
`
`with
`
`150/30
`
`Discussion
`
`This
`
`of
`
`investigation
`
`of
`
`two OC agents
`per tablet but varying in the
`specific study of
`the importance
`
`both
`
`-I
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`ii
`
`CD
`
`CD
`
`CD
`
`CD
`
`Discontinuation rate amounted in total
`to 30% with the
`about half of
`the drop-outs in the two groups occurring
`of use The incidence
`three months
`of
`
`during the
`
`first
`
`out was not correlated
`dropping
`on OCs than
`more starters
`study
`P0001 The respective
`figures for starters and switch
`41-5% and 273% for
`out were
`ers dropping
`
`to age group whereas
`switchers
`the
`
`left
`
`the 150/20
`
`cycle
`
`attributed
`
`and two on the 150/30
`
`comparative
`containing 150
`tg desogestrel
`content of EE enabled
`in the lower dose
`range for reliability
`the oestrogen
`and adverse effect profile Mercilon was
`control
`designed to reduce the oestrogen
`dose while maintaining
`and acceptability
`contraceptive
`efficacy
`The contraceptive
`the
`reliability of
`was good with no pregnancy
`on the 150/20
`combination
`nation The low pregnancy
`
`two preparations
`to method failure
`combi
`combi
`
`the 150/20
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`CD
`
`C-
`
`CD
`
`CO
`
`CD
`
`.0
`-c
`
`CD
`
`Table
`
`Number
`
`combination
`
`with
`
`reported
`between
`
`by
`
`less
`
`of women using
`over one year of use Symptoms
`side effects
`than 15 women in
`group and not
`are not shown
`woman may have
`reported
`groups
`between
`more than one symptom Significant
`differences
`by asterisks
`groups are indicated
`
`the
`
`150/20
`
`or
`
`150/30
`
`differing
`
`study
`
`Side effects
`
`150/20
`
`150/30
`
`Nausea
`
`Headache
`
`diarrhoea
`
`vomiting
`
`Dizziness
`Mood change
`Painful menstruation
`
`Prolonged
`
`withdrawal
`
`bleeding
`
`Irregular bleeding
`
`Increased weight
`
`22
`
`28
`
`28
`
`17
`
`25
`
`48
`
`15
`
`16
`
`17
`
`i5
`
`12
`
`13
`
`30
`
`rate with
`
`Table
`
`Reasons
`out of the study over one year of
`for dropping
`combination Reasons
`use of women using the 150/20 or 150/30
`given by less than 15 women in
`and not differing between
`group
`women may have
`groups are not shown
`given more than one
`between
`reason
`the study Significant
`leaving
`by asterisks
`study groups are indicated
`
`for
`
`difterences
`
`Mood changes
`
`need
`
`for contraception
`
`Irregular bleeding
`No present
`Other
`reason
`No reason given
`
`social
`
`P005
`P00l
`
`150/20
`
`150/30
`
`15
`
`27
`
`16
`
`37
`
`10
`
`tO
`10
`
`30
`
`39
`
`WC_LP 04
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2013, Pg. 7
`
`

`
`COMPARATIVE
`
`PROFILES
`
`OF TWO ORAL CONTRACEPTIVES
`
`837
`
`nation
`
`was
`
`multicentre
`
`rccent
`
`26 000
`
`with results
`from the
`consistent
`study on this preparation of about
`rate for method failure was
`in which the pregnancy
`cycles
`005 Lammers
`op ten Berg 1991
`Women
`combination
`the
`150/20
`
`using
`
`generally
`
`had
`
`and
`
`150/30
`
`this study Although
`
`overall
`
`pressure
`
`was observed
`
`op
`small
`
`slight decrease in blood
`this finding is probably fortuitous
`an assumption
`by previous findings with these
`supported
`two OCs in larger
`Lammers
`studies Rekers 1988
`ten Berg 1991 The recorded weight
`were
`changes
`they were coincidental
`and divergent which suggests
`that
`Of
`the side effects other than irregular
`statis
`bleeding
`the groups was only
`changes Whether
`he two
`between
`
`tically
`
`significant
`
`difference
`
`seen
`
`regarding dizziness
`
`between
`and mood
`
`these differences
`
`reflect
`
`real difference
`
`C-
`
`C/
`
`.0
`
`.0
`
`-o
`
`-C
`
`.a
`
`.0
`
`CD
`
`-C
`
`Ct
`
`.0
`-J
`
`Ct
`
`CD
`
`the
`
`sig
`
`chance
`
`to
`
`the
`
`of
`
`of
`
`the
`
`least
`
`the differ
`
`in
`
`less
`
`positive
`
`higher
`
`incidence
`
`of
`
`bleeding spotting
`irregular
`than women
`the
`
`using
`
`bleeding
`
`breakthrough
`combination
`
`This difference
`
`was
`
`seen
`
`in all cycles
`
`statistical
`
`significance
`
`in two-thirds
`
`of
`
`and
`them
`about
`
`consistently
`compared with
`never reached statistical
`
`reached
`
`Absence
`
`majority
`
`that
`
`cycles
`
`and was
`
`of withdrawal bleeding was
`combination
`higher in the 150/20
`150/30 pill but this difference
`The finding
`the percentages
`nificance
`that
`irregular
`is con
`bleeding in starters were higher than in switchers
`sistent with earlier observations Edgren et at 1989 The
`the lower EE dose
`and the higher EL
`between
`difference
`dose OC in treatment cycle
`was almost entirely
`caused
`by the group of switchers Taking into account
`that
`used OCs containing at
`of
`the switchers
`30 pg EE or more prior to the study it might be assumed
`part of this bleeding was due to the adaptation of the
`lower EE dose
`of
`target organs to daily administration
`an EE withdrawal phenomenon However
`ence between
`the preparations cannot be explained by an
`EL withdrawal phenomenon
`it was observed
`only since
`the whole year of
`the study
`in various
`throughout
`on OC The increase
`also
`in starters
`seen
`bleeding with the lower EE dose pill
`is not sur
`irregular
`prising since the steroid dose is one of the factors that have
`
`to influence
`
`cycle
`
`been
`control
`Increased
`recognised
`irregular bleeding was also reported when the EE content
`of OC pills was reduced to below 50 ig Gray 1980
`The incidence
`the 151720
`of irregular bleeding both with
`combination
`was higher than has been
`and with
`the 150/30
`these OCs using
`reported in other European studies
`with
`same definitions
`almost the
`for breakthrough
`bleeding
`and spotting Rekers 1988 Lainmers
`op ten Berg 1991
`Scan
`The present study was performed
`in
`homogenous
`dinavian population whereas
`women from 12 European
`in these earlier studies Therefore
`countries
`
`participated
`
`the data
`
`obtained
`
`on
`
`the
`
`150/30
`
`in
`
`current
`
`combination
`the
`with data on this same
`study have been compared
`combination
`from studies
`in Scandinavian
`also performed
`women Borglin eta 1982 Cullberg eta 1982 The inci
`dence
`was
`these
`studies
`of bleeding irregularities
`indeed comparable
`in our study
`The incidence
`
`in
`
`to that of
`
`irregular bleeding reported
`
`and
`
`spotting
`
`period particularly
`
`in
`
`and duration of breakthrough
`bleeding
`decreased in both groups during the study
`the first cycle This finding is
`after
`
`observations related
`or
`preparations
`to be assessed
`testing remains
`multiple
`With both OCs the main reason given
`for dropping out
`the study was insufficient
`cycle control This is in agree
`con
`ment with other observations that bleeding problems
`of OCs
`reason for discontinuation
`stitute an important
`et al 1988
`The number of drop-outs among
`Belsey
`and
`than among switchers
`starters was greater
`signifi
`cantly higher number of women taking
`combi
`the 150/20
`prematurely When
`terminated the
`the
`nation
`study
`they would like to continue
`asked whether
`women were
`the end of
`the trial period if
`using the study drug at
`that
`were possible the women who had used the 150/20
`combi
`The reasons for discontinuing
`were
`nation
`method are complex and may
`the use of any contraceptive
`as well as psychological The finding that hae
`he physical
`concentration did not vary between
`the groups
`moglobin
`it was not the amount of blood loss but the
`that
`suggests
`discon
`discomfort of unpredictable bleeding that caused
`On the other hand
`cycle
`bleeding and absence
`and
`increased
`affected
`anxiety
`in the method Hillard 1989
`demonstrated
`low pregnancy
`rates of
`combinations
`and very little difference
`which
`them in general side effects
`difference
`double blind com
`was demonstrated
`in this randomised
`was the less effective
`control
`cycle
`to more drop-outs
`leading
`in irregular bleeding with the
`rate remained
`low is
`
`tinuation
`
`breakthrough
`have
`ing may
`womens
`confidence
`Our study
`and 150/30
`150/20
`
`between
`
`parative
`
`investigation
`
`disturbances
`
`such
`
`as
`
`of withdrawal bleed
`some
`
`the
`
`with
`
`the 150/20
`
`the pregnancy
`the well-established
`
`combination
`for that reason The increase
`lower EE dose while
`with
`in agreement
`EE dose for cycle control
`However
`for inhibiting
`conception
`
`threshold
`
`is higher
`in view of
`
`fact
`
`that
`
`the
`
`than the dose
`
`the poten
`combination
`some additional
`
`tially
`
`large majority
`
`with
`
`tile 150/20
`
`better
`the
`150/20
`profile of
`safety
`many women can be expected to accept
`bleeding In addition for the
`discomfort due to irregular
`of women who have
`control
`perfect
`cycle
`combination
`is no reason to revert
`there
`higher EE dose preparation
`
`to
`
`of
`
`these
`
`pills
`
`results of previous trials
`with
`agreement
`Rekers 1988 Lammers
`op ten Berg 1991 and can he
`longstanding OC treatment on
`explained by an effect of
`endometrial
`1982
`vasculature
`Johannisson
`Ludwig
`response to endometrial bleed
`1982 and its haernostatic
`Astedt 1983 An ef