Optimizing
`
`the
`
`estrogen
`
`dose in
`
`oral
`
`contraceptives
`
`Edited by
`
`Newton ond
`
`op ten Rerg
`
`The Parthenon Publishing Group
`
`nternatjonaJ
`
`Publishers
`
`in Medicine
`
`Science
`
`Technology
`
`Casterton Hall Carnforth
`Lana LAb 2LA UK
`
`120 Mill
`
`Park Ridges
`New Jersey USA
`
`Paintiffs Exhibit
`14cvOO4LJAP.TJ
`Case
`Case Ne 12O2$2LJAPTJ
`
`PTX 052
`
`W0LP0405346
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2017, Pg. 1
`
`

`
`Published in the UK and Europe by
`The Parthenon
`Publishing Group
`
`Ltd
`
`Casterton Hall
`
`Carnforth
`
`Lancs
`
`LA6 2LA
`
`Published
`
`in North America
`The Parthenon
`
`by
`
`Publishing Group
`
`Inc
`
`120 Mill Road
`
`Park Ridge
`New Jersey NJ USA
`
`ISBN 185070-445-7
`
`Copyright
`
`1992 The Parthenon
`
`Publishing Group Ltd
`
`No part of this
`
`publication
`
`retrieval
`
`system or
`
`transmitted
`
`reproduced
`
`stored
`
`in
`
`may be
`in any form or by any
`
`means electronic
`
`mechanical
`
`photocopying
`
`recording
`
`or
`
`otherwise without
`
`prior permission fiom the publishers
`
`Typeset
`
`Printed
`
`Butler
`
`by AMA Graphics Ltd Preston
`and bound in Great Britain
`by
`Tanner Ltd Frome and London
`
`Lancashire
`
`WC_LP0405347
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`

`
`Contents
`
`List of principal
`
`contributors
`
`Introduction
`
`Newton
`
`Experiences
`
`of Dutch women with the Pill
`
`Parent
`
`and
`
`Venuix
`
`Choosing the right combined oral contraceptive for the
`individual woman
`
`Guillebaud
`
`International multicenter
`
`clinical
`
`trial of an oral
`
`contraceptive containing 20 .tg ethinylestradiol
`desogestrel Mercilon
`
`and 150 jig
`
`op ten Berg
`
`11
`
`17
`
`33
`
`Oral contraceptive estrogen content
`
`metabolic risk markers
`
`for coronary
`
`and carbohydrate
`heart disease
`
`and lipid
`
`39
`
`Godsiand
`
`Crook and
`
`Wynn
`
`Cigarette smoking
`
`contraceptive users
`
`risk factor
`
`for cardiovascular disease
`
`in oral
`
`51
`
`Fruzzetti
`
`Ricci
`
`Nicoletti
`
`Arcidiacono
`
`and
`
`Fioretti
`
`of ovarian hormone production by
`Quality of inhibition
`combined oral contraceptive containing 20 jig ethinylestradiol
`and
`150
`per tablet
`
`jig desogestrel
`
`Rozenbaum and
`
`Degrelle
`
`Double-blind
`
`acceptability
`
`study with two
`comparative
`combined oral contraceptives containing 20 jig ethinylestradiol
`or norethisterone acetate
`Lammers WJ Atsma
`
`plus
`
`desogestrel
`
`Index
`
`van den Heuvel andJ Picard
`
`59
`
`67
`
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`

`
`Double-blind comparative
`acceptability study with two combined
`oral contraceptives
`containing 20 p.g
`ethinylestradiol plus desogestrel or
`norethisterone acetate
`
`Lammers W.J Atsma
`
`van
`
`den Heuvel andJ Picard
`
`INTRODUCTION
`
`Since the introduction
`
`of
`
`the first combined
`
`in 1960 the dosage
`contraceptive market
`estrogen and progestogen
`has demonstrated
`the years
`
`lated
`
`over
`
`have changed
`
`on the
`oral contraceptive
`and type of its two components
`accumu
`
`considerably Experience
`
`that
`
`dose-dependent
`
`metabolic
`
`alterations
`
`as side-effects
`
`are associated
`
`with the use of oral contra
`
`estrogen
`
`diated side-effects
`
`like increase
`
`have
`
`are the serious
`
`side-effects
`
`associated with the
`
`to
`
`result
`
`the estrogen
`unsuccessful
`because
`
`preparations
`even
`
`dose
`
`as well
`ceptives and these changes may be induced
`the synthetic
`by either
`in these preparations or even by both Estrogen-me
`used
`or progestogen
`and breast
`in body weight nausea headache
`been extensively studied and well-documented
`tenderness
`More important
`however
`use of synthetic estrogens
`in the pill was found
`The dosage
`of estrogen
`ofthromboembolic events5 As
`related to the occurrence
`be directly
`down to 35 or 30 jig ethinyl
`dose has been brought
`of this the estrogen
`estradiol per tablet which is most commonly used
`in low-dose
`been made
`Several
`to reduce
`attempts have
`further These attempts
`and the emergence of undesirable metabolic
`of efficacy poor cycle control
`alterations312 The latter were the result of the intrinsic androgenic
`effects
`in combined
`on lipid and
`of
`used
`the progestogens
`oral contraceptives
`carbohydrate metabolism that were not counteracted
`low estrogen
`
`have
`
`been rendered
`
`of
`
`loss
`
`dosages
`
`any more by such
`
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`
`Optimizing the estrogen dose
`
`The
`
`availability
`
`of new highly
`intrinsic androgenicity
`like desogestrel
`
`selective
`
`with minimal
`
`progestogens
`has created the possibility of corn
`of 20 ig of ethinylestradiol
`
`bimng these with
`dosage
`The study presented
`acceptability
`monophasic preparation of 20 tg ethinylestradiol
`terone acetate with
`combination
`
`is
`
`double-blind
`
`estradiol
`
`plus
`
`recently developed
`150 .Lg of desogestrel
`
`study comparing
`plus 1000
`.tg norethis-
`of 20 JIg ethinyl
`
`MATERIAL AND METHODS
`
`in the study
`
`total of 270
`
`list based
`
`subjects
`
`mental condition
`
`of reproductive
`
`normally exposed
`
`6-month
`
`of2O J.Lg
`
`combination
`
`of
`
`acetate
`
`cyclic
`
`Five university
`centers in Belgium participated
`women entered
`the study after having
`given verbal consent Selection was
`made with the help of an eligibility check
`on the following
`inclusion and exclusion criteria
`had to be in good physical and
`age to have
`regular menstrual cycles and
`to be
`to the risk of pregnancy Excluded were women
`for whom the generally accepted
`contraindications
`for hormonal contra
`ception were applicable The women were randomly assigned to
`treatment with one oftwo monophasic preparations
`combination
`.tg desogestrel Merdion or
`150
`ethinylestradiol
`plus
`20 1g ethinylestradiol
`plus 1000 Lg norethisterone
`Loestrin-20
`Minestnil-20 The preparations were administered orally in 28-day
`weeks on medication
`regimen
`followed by
`week off
`Each woman was provided with
`to record tablet-taking
`were subdivided
`
`calendar
`
`on which she was instructed
`
`days as well
`
`as bleeding episodes Bleeding
`
`episodes
`
`into
`
`Bleeding
`
`any bleeding requiring more than one sanitary
`
`towel per day
`
`and
`
`Spotting
`
`scanty bleeding requiring no or only one sanitary
`
`towel per
`
`day
`
`Bleeding
`
`cards were reviewed
`
`at each
`
`return visit
`
`after
`
`the first third and
`
`sixth cycle
`
`was recorded
`
`of treatment
`respectively Also the occurrence
`of side-effects
`and blood pressure and body weight were measured
`In the statistical
`the
`parameters were used
`
`analysis
`
`following
`
`for cycle
`
`control assessment
`
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`
`Acceptability
`
`study
`
`yo
`
`number of consecutive
`
`bleeding days at the start of the first cycle of
`
`tablet
`
`intake
`
`number of days with spotting
`
`number of days with withdrawal bleeding definition
`
`number of days with withdrawal bleeding definition
`
`and
`
`number of days with breakthrough
`
`bleeding
`
`Because
`
`of differences
`
`withdrawal
`
`withdrawal
`
`in the way withdrawal
`are defined in the literature
`bleeding
`bleeding were used
`
`bleeding
`
`and absence
`
`of
`
`two definitions
`
`for
`
`vaginal bleeding starting
`
`in the tablet-free
`
`interval and
`
`vaginal bleeding starting
`
`in days 1821 of
`withdrawal bleeding or in the tablet-free
`
`interval
`
`tablet-intake
`
`early
`
`Seventy-four
`
`women were disqualified
`
`from the statistical
`
`evaluation
`
`mostly because
`
`they did not meet
`
`to
`
`the inclusion criteria or were lost
`on 196 women were analyzed
`before the first
`return visit Data
`follow-up
`98 women on Merdion 498 cycles the other
`98 were treated with
`Loestrin-20
`analyses were performed using the
`470 cycles Statistical
`Wilcoxon
`test with correction for ties or Fishers exact
`test for
`tables
`tests were performed at the 5% level of significance
`
`All
`
`RESULTS
`
`In both groups the
`varied between 17 and 45 years Of
`age at enrolment
`the women in the norethisterone acetate group 27.6% were starters which
`means that
`they had not used any form of hormonal
`in the
`contraception
`months preceding
`the start of the study The remaining 72.4% were
`from another
`combined
`or from
`
`last
`
`switchers
`
`either
`
`oral contraceptive
`
`progestogen-only-pill
`The corresponding
`percentages
`65.3% respectively For all other
`duration of period body
`age at menarche average cycle
`length
`average
`and blood
`pressure the two groups were fully comparable with
`weight
`
`in the desogestrel
`
`relevant variables
`
`group were 34.7% and
`checked
`at enrolment
`
`each other Table
`
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`
`Optimizing the estrogen dose
`
`Table
`
`and range
`
`Demographic
`
`characteristics of participating women at entry median
`
`Age years
`Age at menarche
`
`Average
`
`cycle
`
`years
`length days
`of bleeding
`duration
`Average
`Parity number of women
`
`nulliparous
`
`Body weight kg
`Blood pressure mmHg
`
`systolic
`
`diastolic
`
`days
`
`Loestrin-20
`
`Mercilon
`
`28 1745
`13 1018
`28 2632
`27
`
`43
`
`55
`57 4295
`
`29 1745
`13 917
`28 2631
`27
`
`39
`
`59
`60 3992
`
`120 95170
`70 50110
`
`120 100145
`70 50105
`
`Table
`
`nons
`
`Mean number of days of regular withdrawal bleeding
`for withdrawal bleeding
`y2
`text
`
`see
`
`using
`
`two defmi
`
`Cycle
`
`Loestrin-20
`
`Mercilon
`
`Loestnn-20
`
`Mercilon
`
`Y2
`
`Y3
`
`2.5
`2.8
`2.7
`
`37
`
`3.8
`
`3.6
`
`2.9
`3.2
`
`3.3
`
`4.2
`
`4.2
`
`3.6
`
`0.05
`
`No pregnancies
`months No
`occurred
`during the study period of
`found in the mean number of bleeding days at start yo
`difŁrence
`was
`between the two preparations 2.0 and 1.9 days in the norethisterone acetate
`and desogestrel
`groups respectively
`With both definitions
`
`absence
`
`significantly
`
`combination
`
`of withdrawal bleeding the norethisterone acetate
`preparation was found to induce
`0.05 shorter with
`On the other
`drawal bleeding than the desogestrel
`Table
`hand
`of withdrawal bleeding or amenorrhea was more frequently
`users and
`and
`
`recorded
`
`in the norethisterone
`
`acetate
`
`statistically significant
`
`0.05 in cycles
`
`this difference
`
`was
`
`with both
`
`definitions
`
`Table
`
`Data
`
`on irregular
`
`bleeding are listed in Tables
`
`and
`
`Women treated
`
`with the desogestrel
`
`combination
`
`experienced
`
`significantly
`
`lower mean
`
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`
`Acceptability
`
`study
`
`Table
`
`Absence of withdrawal bleeding
`
`of women using two definitions
`
`for
`
`withdrawal bleeding
`
`y2
`
`see text
`
`Cycle
`
`Loestrin-20
`
`Mercilon
`
`Loestnn-20
`
`Mercilon
`
`32
`
`28
`
`20
`
`18
`11
`10
`
`11
`
`27
`
`22
`
`12
`
`0.05
`
`Table
`
`Mean number of spotting yi and breakthrough
`
`bleeding
`
`y4 days
`
`during treatment
`
`Spotting
`
`Breakthrough
`
`bleeding
`
`Cycle
`
`Loestrin-20
`
`Mercilon
`
`Loestrin-20
`
`Mercilon
`
`1.5
`
`1.3
`
`1.0
`
`1.1
`0.9
`0.3
`
`0.7
`
`0.6
`
`0.4
`
`0.3
`0.1
`
`0.1
`
`0.05
`
`number of spotting days in cycles
`0.05 The number ofbreakthrough
`
`users
`
`and
`
`than norethisterone
`
`acetate
`
`bleeding days was also smaller
`
`in the first group reaching
`When expressed as percentages
`bleeding occurred with
`
`statistical
`
`significance
`
`0.05 in cycle
`of the total number of women irregular
`0.05 in the
`higher
`significantly
`frequency
`than in women treated with the desogestrel
`group
`This is also reflected by the higher number ofwomen
`on norethisterone acetate
`of bleeding irregularities
`that dropped out because
`
`norethisterone acetate
`
`preparation Table
`
`Table
`
`Statistical
`
`analysis
`
`This was the only major difference
`of subjective
`of the frequency
`showed
`
`headache
`
`and
`
`breast
`
`tenderness
`
`no differences
`
`in the drop-out
`
`reasons
`
`side-effects
`
`like nausea
`between the two
`
`preparations
`
`DISCUSSION
`
`of combined oral
`have been made to reduce the estrogen
`content
`Attempts
`per tablet The combination
`contraceptives below 30 .tg ethinylestradiol
`
`of
`
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`

`
`Optimizing the
`
`estrogen dose
`
`Table
`
`Spotting
`
`cycles of treatment
`
`and breakthrough
`of women
`
`bleeding
`
`dunng six
`
`Cycle
`
`Loestrin-20
`
`Mercilon
`
`0.05
`
`98
`
`84
`
`68
`
`98
`
`89
`
`74
`
`Spotting
`
`Breakthrough
`
`bleeding
`
`47.0
`
`33.3
`
`33.3
`
`16.9
`
`17.3
`
`14.8
`
`25.3
`
`15.8
`13.8
`
`12.0
`
`5.3
`
`5.2
`
`Table
`
`Drop-out
`
`reasons and number of drop-outs
`
`Drop-out
`
`reason
`
`Irregular
`bleeding
`withdrawal bleeding
`
`and/or
`
`Loestrin-20
`
`Mercilon
`
`absence
`
`of
`
`12
`
`Irregular
`
`bleeding
`
`side-effects
`
`Sideeffects
`
`Other
`
`reasons
`Unknown
`
`20 JIg
`shown in several
`
`ethinylestradiol
`
`studies
`
`was
`
`1000 Jg noretbisterone
`however
`acetate
`to suppress the pituitaryovarian axis insufficiently
`high incidence
`of unintended
`and
`relatively
`of irregular bleedirsgut2
`
`with
`
`pregnancies
`
`high rate
`
`Also cycle
`
`control with
`
`combination
`
`100 .tg gestodene
`
`was
`
`found
`
`with
`
`of
`
`of 20 j.tg ethinylestradiol
`to be less good than with the combination
`30 JIg ethinylestradiol
`75 .tg gestoden
`In contrast with this cycle
`
`control with
`
`combination
`
`of 20 Jig ethinyl_
`in two large multicenter
`proved
`to
`be comparable
`recorded with combined oral contraceptives contain
`ing 30 J.tg ethinylestradiol3 This study shows
`the desogestrel
`combination
`better cycle control
`than the combination
`provides
`of 20 gig
`1000 gig norethisterone acetate Apparently not only the
`
`estradiol
`
`plus
`
`150 Jig desogestrel
`
`to that
`
`ethinylestradiol
`
`studies
`
`clearly
`
`that
`
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`

`
`Acceptability
`
`study
`
`combined oral contraceptive but also the type
`estrogenic component of
`used
`of progestogen
`an important
`role in cycle
`control
`plays
`The use in this study of two defInitions
`for withdrawal
`bleeding shows
`between preparations regarding cycle
`that alleged differences
`control may
`used When use is made of the
`only be the result of different
`of early withdrawal
`
`concept
`
`bleeding
`
`this is reflected
`
`by
`
`decrease in
`
`definitions
`
`irregular
`
`as well
`
`as
`
`decrease
`
`in the absence
`
`of withdrawal
`
`bleeding
`bleeding as is shown
`in this study for the latter
`The present study provides further
`
`proof
`
`that
`
`the availability of deso
`
`gestrel
`
`reducing
`
`izing reliability cycle
`
`highly selective
`up the possibility of
`opened
`progestogen
`the estrogen dose below 30 .tg ethinylestradiol without
`control and acceptability
`
`has
`
`jeopard
`
`ACKNOWLEDGEMENTS
`
`The authors would like to thank the following doctors for their cooperation
`and expertise
`the study
`in conducting
`van Bilsen
`Bayot Brussels
`Mons
`Caufriez Brussels
`Cession Liege
`Debuyl Brussels
`Lepiece Mons
`Herinckx Brussels
`Ide Louvain
`Schwers
`Thiery Gent
`Vekemans
`Brussels and Wilkin Brus
`
`Brussels
`
`sels
`
`REFERENCES
`
`Bottiger
`
`contraceptives
`
`Boman
`thomboembohc
`
`Eklund
`
`and
`
`and Westerhoim
`
`1980 Oral
`
`disease
`
`effects
`
`of lowering oestrogen
`
`content
`
`Lancet
`
`1097101
`
`General Practitioners
`
`Larnmers
`
`oral contraceptive
`
`containing
`
`and health
`
`trial with
`
`new
`
`and 20 jig ethinylestradiol
`
`Royal College ofGeneral Practitioners 1974 Oral contraceptives
`an interim report
`from the oral contraception
`study of the Royal College of
`London Pitman Medical
`1991 Phase III clinical
`and Op ten Berg
`150 jig desogestrel
`Acta Gynecol Obstet Scand 70 497500
`Layde
`
`Beral
`
`among oral contraceptive
`Gen Pract 33 7582
`
`1983 Incidence
`and Kay
`users RCGP Oral contraception
`
`73
`
`of arterial
`
`disease
`
`study
`
`Coil
`
`WC_LP0405355
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`

`
`1735
`
`Preston
`
`1974
`
`formulations
`
`report of the correlation between
`the pregnancy
`and pill-taking habits of females studied.
`
`rates
`
`Rep rod
`
`Optimizing the estrogen dose
`
`Inman
`
`Thrombo-emboljc
`
`Vessey
`
`report
`
`Appel
`
`to the Committee
`
`Arman
`
`graduated
`
`estrogen
`
`formujation
`
`Westerhoim
`disease and the steroidal content
`of oral
`on Safety of drugs Br Med.
`and Birdsall
`1987
`comparison of
`with three constant-dosed
`
`and Engelund
`
`1970
`
`contraceptives
`2039
`
`new
`
`oral contraceptives
`
`Contraception
`
`35 52332
`
`Bounds
`
`Vessey
`
`and Wiggins
`
`1979
`
`randomized
`
`double-blind
`
`trial of two low dose
`86 3259
`
`combined
`
`oral contraceptives
`
`Br
`
`Obstet Gynaecol
`
`Preston
`
`1972
`
`report of
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`Contraception
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`WC_LP0405356
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`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2017, Pg. 11