The 20 Microgram Ethinyt Estradiol plus 150 Microgram
`Desogestrel Pill
`Multicenter Study on 235 Women for Months
`
`CONTRACEPTION
`
`Artide reahed publisher
`
`on March 21 1990 acccpted
`
`May 22 1900
`
`Merckrd Or
`
`ion Company
`
`Sei1atv
`
`estradiol
`
`The efficacy
`
`new oral contraceptive Mercilun 2O mcg ethinyl
`tolerance of
`and clinical
`150 meg desogestrel were studied in 23i women tar
`105 cycles This was
`an open non Comparative multicenter study lasting
`cycles earned out by 37 French
`
`physicians
`No pregnancies
`Cycie control was satisfactory
`
`were observed
`
`only 55% of the women in the study discontinued
`bleeding
`to irregular
`
`Is hi east
`
`tcridet ness which is
`
`low dose
`
`oral
`
`this contraceptive due
`The incidence
`of subjective side effects paruculai
`known
`was very low
`to be esimpen-dependent
`The Mereilon total continuation rate at months was high fat
`86%
`
`contraceptiVe
`
`Because
`
`of the clinical characteristics
`
`and eycellent metaboln
`
`tolerance already
`
`shown this 20 ct FE pill
`
`can
`
`he prescribed as the
`
`no contraindications
`
`Iirst-line choice to all women
`ore
`
`for combination
`
`seen
`
`for contraception and having
`
`contraceptives
`
`Key words pill 20 meg ethinyl estradiol desogestrel
`235 woirien efficacy
`arid continuation rate are good
`cycle control
`
`French rnultieenter
`
`clinical
`
`stLidy
`
`INTRODUCTION
`
`The cotnpositiun at oral contraceptives OCs
`has evolved
`since the 1960s
`considerably
`when the coritiaceptive
`
`pill
`
`decreasing
`
`acceptability
`
`the side effects
`
`first appeared by
`and increasing the
`of this contraceptive method
`
`the frequency
`
`complications
`
`of thromboembolic
`of OCs is estrogen
`
`dose-
`
`dependent
`
`associated with
`
`in hemostasis
`the changes
`COCs are esirogen-dependent
`sometimes reported
`many of
`by pill users
`
`the side effects
`
`such
`
`as breast
`
`tenderness
`
`and
`
`should
`
`be ioted
`
`compouncli
`
`nausea
`
`are attn hutable to the estrogen
`
`Three main changes
`Reduction
`
`from ISO meg
`in estrogen
`to 40 or 30
`fEE per pill
`ethinyl estradiol
`meg the latter are known
`combined oral contraceptives COCs
`
`dose
`
`as
`
`low-dose
`
`doses from 100
`Since this reduction in estrogen
`to 30 meg EE the fiequency
`of venous
`thrombuembolic incidents
`
`has decreased
`
`There are several
`
`reasons for this reduction
`
`Reduction
`
`in estrogen
`
`frequency
`
`in ptogestin dose because
`of eardtos ascular and ccrebrovascu
`
`the
`
`ar
`
`Contraception-fertilitØ-sexualitØ 1990 Vol 18 No
`
`pp 407-412
`
`PaInflffs ExhibIt
`Cae No 1tO4LJAPTJ
`2O292LJAP-TJ
`
`Nca
`
`PTX 078
`
`WCLP0405495
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2016, Pg. 1
`
`

`
`episodes
`
`from OCs depends
`on the progestin
`dose and the metabolic changes particularly
`observed
`lipid changes sometimes
`in pill
`the progestin dose This
`
`users
`
`also depend oil
`
`reduction in progestin dose
`
`is illustrated in the
`
`three-phase pills
`
`Development of
`
`new generation of
`
`progestins with powerful progestin properties
`low androgenic
`
`activity
`
`that are
`
`and
`
`inetaholical
`
`ly very well
`
`tolerated Three
`
`progestins Lised in oral contraception appear
`among these new progestins desogestrel
`DSG gestodene
`and norgestimate
`It was logical
`
`to try to reduce the estrogen
`
`dose still
`
`further
`
`to the low-
`
`by comparison
`and
`dose combined pills already in existence
`for example to use pills with 20 meg of EE in
`the hope of further
`increasing the
`of oral contraceptives
`
`acceptability
`
`and
`
`furiher
`
`reducing
`
`the vascular risk of this
`
`contraception
`
`This was first
`
`generation progestin
`
`first-
`
`This study showed excellent contraceptive
`and
`efficacy
`cycle control
`
`satisfactory
`
`minimal
`
`incidence
`
`of side effects
`
`goal
`
`the results of
`
`is 10 rcpor
`multicenter study of this Liltra-low
`pill already on the market
`
`in six countries
`
`French
`dosed 7CC
`
`MATERIALS AINI METHODS
`
`The goal of this study was to confirtn
`of Mcrcilon
`efficacy and acceptability
`single-
`combined oral contraceptive
`containing 20 meg ethinyl
`150 meg
`estradiol
`and
`It was an open-label con-
`
`phase
`
`low-dose
`
`desogestrel
`
`the
`
`comparative multicenter study in which
`
`37
`
`French physicians collaborated
`
`Audberi
`
`Bouschhachr
`
`run
`
`3iirsieaux
`Hscissc Moritpeilieri
`Mctz
`Breries Breat
`Iran ohm Paris
`Romaria
`hi
`Pe.sic
`Coste Lunoges
`Rouen
`hi Couture
`Dat
`loulouse
`Dciienharh Schiiiighewt
`0ohrncl Groin
`tOny Marsciiie
`Faveaa Sua.cbourg
`Giltet Nice
`Grail
`Paris
`i.sy-FrØhaul Lounges
`Lops
`FlousOnu Cagnes-sur-Meri
`tNice
`4ahtiisn(cid:244)vici
`NØny Tours
`Toulouse
`Nsrites
`
`.ilfc
`
`Katin-Nailiaii
`
`1i1ris
`nrsrdeauxi
`Nari
`
`Lerrier
`
`Foniotittier
`
`meg
`1972 Bounds
`
`tried by combining
`norethisterone EE 20
`mg Preston
`norethisterone acetate
`et al 1979 then with
`fG
`NG 300 meg or EE 15 meg -F
`EE 20 meg
`NG 400 meg or EE 20 meg
`NG 500 meg
`l.C et al 1977
`Arnt
`
`second-generation
`
`progestin norgestrel
`
`However
`
`the first
`
`15 meg EE pills
`20 meg or
`due to inadequate
`rapidly abandoned
`
`were
`
`contraceptive efficacy
`
`andlor poor cycle
`
`control
`
`resulting
`
`above
`
`all
`
`in unacceptably
`
`irregular
`
`bleeding
`
`The appearance
`of the third-generation
`progestins 1982 dcsogcstrel
`lcd to the
`COC
`possibility of once more developing
`pills containing less than 30 meg EE
`
`contraceptive preparation containing 150
`
`20 meg ethinyl
`meg desogestrel and
`Mercilon was the subject
`of
`
`estradiol
`
`European
`1684 women and
`
`multicenter study involving
`
`25970
`
`cycles
`
`Paris
`Qaecies Roubx
`de Rcilitac
`Ropert Monticrrneii
`Miirsriiie
`Ii RosstnotMdot
`ii Rormnhautu Paris
`Sailly
`Lute
`Scrfary Paris
`
`Sas.ary
`
`Lon
`
`Rossni-Arnar
`Naiicy
`fOurcoittg
`Thoulon
`
`The study lasted
`
`months i.e
`
`Meicilon
`
`cycles
`
`after
`
`visit
`
`cycles
`
`The patients
`were
`seen at the screening
`Mereilon cycles and after
`filled out
`
`During
`
`the cycles the patients
`
`bleeding diary indicating
`the withdrawal bleeding days and
`pill was taken
`
`the days on which
`
`the
`
`any irregular
`
`bleeding
`
`At each
`
`office
`
`visit
`
`the investigator
`
`reported in
`
`the case
`
`report
`
`form
`
`data using the diary that the
`cycle control
`patient was to hring back
`at each visit
`
`weight
`blood
`
`pressure
`
`Contraception-fertilitØ-sexrialite
`
`1990 Vol 18 No
`
`pp 407-412
`
`WC_LP0405496
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2016, Pg. 2
`
`

`
`any side
`
`effects
`
`reported by the patient
`months and
`
`occurring in the first
`effects
`in months
`
`to
`
`reasons
`
`for dropout
`
`if any
`
`Patients
`
`to be fet-tile
`
`but
`
`to have
`
`supposed
`
`aged over 30
`
`eligible for the study were
`in good health and
`17 women under
`the age of 30 were
`included in this study They were
`nonetheless
`none of the classical COC
`of significant
`
`contraindications
`
`no history
`
`cycle disturbances on oral contraceptives
`
`not
`
`have
`
`progestogen
`
`used contraception by injected
`within the past six months or oral
`or macrodosed
`
`progestogens micropill
`
`progestogens
`
`for the last
`
`three months due to
`
`possible atrophic
`
`effect
`
`on the
`
`endometriurn nor have
`
`given birth or had
`
`termination within the
`months prior to
`entering the study Also women who smoked
`day were excluded
`more than 10 cigarettes
`
`estradiol
`
`was taken
`
`but bleeding starting
`
`on or after
`
`the
`
`-a
`
`Ion and continuing for
`18th day of taking Merci
`was counted
`
`as withdrawal
`
`the drug-free interval
`the women themselves
`
`bleeding as
`
`considered
`
`this type of bleeding as
`
`their normal periods
`
`In the case of bleeding beginning
`day and continuing during the rest days the
`
`before the
`
`18th
`
`bleeding days were
`until day 21 and
`as withdrawal bleeding starting
`on day 22
`
`irregular
`
`bleeding
`
`counted
`
`as
`
`Spotting irregular
`
`bleeding requiring only one
`item per day
`
`protection
`
`Metrorrhagia irregular
`
`bleeding requiring the
`
`use of at
`
`least
`
`protection items per day
`
`All the patients
`analysis including those who skipped
`
`were
`
`counted
`
`in the cycle control
`
`pills or
`
`had
`
`history of metrorrhagia
`
`CHARACTERISTICS OF PATIENTS AT
`SCREENING
`
`The analysis
`
`was conducted
`
`on 235 patients
`
`One tablet of this pill 20 mcg ethinyl
`150 meg dcsogcstrel was to he
`the same time of
`taken each day preferably at
`tablet was taken on
`day for 21 days The first
`the first day of the period When the first strip
`was completed
`drug-free interval
`of
`days
`the women started
`had
`to elapse after which
`new strip Women who were switching the
`to observe
`oral contraceptive were
`drug-free
`days or
`as the case may be
`this new combined pill
`
`interval
`
`of
`
`before starting
`
`Evaluation
`
`of cycle control was based on
`
`highly precise definitions
`
`Withdrawal
`
`bleeding bleeding occurring in
`
`the drug-free intervaL
`
`Irregular bleeding bleeding occumng
`
`during the 21 days in which
`
`the contraceptive
`
`In the European multicenter
`
`study on
`
`1684 women
`
`b\ D.Scrfatv
`23.970
`use cycles
`totaling
`women 23.04- were
`less than 20 years of age The
`inde.x was 0.05 when this pill was
`taken correctly
`
`citcd
`
`387
`
`Pearl
`
`The efficacy
`
`for all
`
`ages
`
`of Mercilon
`
`has hence
`
`been demonstrated
`
`The number of cycles studied was 1305
`
`The patient characteristics
`235 pattents arc
`
`the screening
`listed in Table
`
`at
`
`visit
`
`Table
`
`screening
`
`Characteristics
`235 patients
`
`of patients at
`
`Age
`
`sd
`
`30
`
`30io35
`
`36to40
`40
`
`Parity
`
`Nulliparous
`
`Multiparous
`
`Smoking
`
`cigarettes/day
`
`cigarettes/day
`
`Contraception
`
`before
`
`screening
`
`None
`
`Oral
`
`local
`
`Cycle characteristics
`
`before
`
`Mercilon
`
`acIc duration di
`
`33.3 5.4
`7.3%
`
`46.1%
`
`30.8%
`
`15.8%
`
`24.3%
`
`75.7%
`764%
`
`10.3%
`
`13.3%
`
`209%
`59.t%
`
`14.9
`
`1%
`
`28.39
`
`Contraception-fertilite-sexualitd 1990 Vol 18 iVo
`
`pp 407-412
`
`WC_LP0405497
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2016, Pg. 3
`
`

`
`it sd
`
`Regular cc1e
`
`Inegular
`
`cucle
`
`93.2%
`
`6.8%
`
`l.eiigtli
`
`ot period
`
`4.4
`
`.4
`
`Menstruation
`
`volume
`
`Lon 1-2 proiect/d
`
`Moderate
`
`proluct/d
`
`High
`
`protect/d
`
`28.5%
`
`60.Oci
`
`Irregtilar bleeding
`
`during
`
`pre
`
`screening
`
`cycle
`
`Spotuiiig
`
`Meirorrhagia
`
`Total
`
`Systolic blood pressure
`mm Hg in
`
`sd
`
`Diastolic
`rum Hg
`
`blood pressure
`
`vi
`
`sd
`
`Weight kg
`
`2.1%
`
`10.2%
`
`120.3
`
`10.7
`
`71.1
`
`7.3
`
`37.2 it 8.3
`
`leI 223
`
`211
`
`203
`
`201
`
`1.3%
`
`0.5%
`
`1.3%
`
`1.0%
`
`Cycle
`
`Cycle
`
`Cycle
`
`Table
`
`Before
`
`Mccci
`
`Ion
`
`Cycle
`
`Cycle
`
`_Cyclc
`
`Duration of withdrawal bleeding
`msd
`
`235
`
`229
`
`220
`
`198
`
`4.4
`
`4.1
`
`3.9
`
`3.9
`
`t.4
`
`1.7
`
`1.3
`
`1.3
`
`Overall withdrawal
`
`bleeding was
`
`shorter
`
`0.0000
`
`test
`
`of the same or
`
`Students
`for matched
`series and
`less volume than the cycle
`Tables
`and
`preceding Mcrcilon
`these two effects
`
`ingestion
`
`are generally considered
`
`beneficial
`
`by the patients
`
`RESULTS
`
`Evaluation of an oral contraceptive is based
`
`on three
`
`criteria efficacy
`
`cycle control
`
`and
`
`tolerance
`
`Efficacy
`
`observed
`
`skipped
`
`In terms of efficacy
`
`no pregnancies
`pills had
`though
`in 5.9% of the cycles studied
`
`even
`
`to
`
`lable
`
`Menstruation volume relative
`
`to pre
`
`screening
`
`cycle
`
`Menstruation
`
`volume
`
`Unchanged
`
`were
`
`been
`
`Cycle
`
`Cycle
`
`Cycle
`
`32.7%
`
`34.9%
`
`51.9%
`
`49.5%
`
`36.9%
`
`50.5%
`
`15.3%
`
`15.6%
`
`12.6%
`
`Cycle
`
`control
`
`Table
`
`Incidence
`
`of irregular bleeding
`
`Cycle
`n235
`3.4%
`
`Cycle
`n225
`0.0%
`
`17.6%
`
`14.3%
`
`Cycle
`n201
`1.0%
`
`6.5%
`
`2.9%
`
`23.9%
`
`1.3%
`
`15.6%
`
`1.0%
`
`8.5%
`
`Metrorrhagi
`
`Spotting
`
`Metrorrhagia
`
`spotting
`
`Total
`
`The results obtained
`
`for cycle control
`to those of other low-dose
`
`are fully
`
`oral
`
`comparable
`
`contraceptives
`
`Withdrawal
`
`bleeding was present in 98.7% of
`the cycles studied and only
`
`patients
`
`the study before the 611 cycle for
`interrupted
`amenorrhea The rates of amenorrhea
`
`per
`
`cycle are listed in Table
`
`Table
`
`91 Amenorrhea
`
`per cycle
`
`________
`
`Cycle
`
`233
`
`228
`
`1.7%
`
`1.7%
`
`Contrctception-fertilitØ-sexualttØ
`
`1990 Vol 18 No
`
`pp 407-412
`
`WC_LP0405498
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2016, Pg. 4
`
`

`
`TabEe
`
`Overall
`
`percentage
`
`of cycles with
`
`tenderness
`
`irregular bleeding
`
`starting
`
`in patients
`this contraceptive Figure
`
`who had them before
`
`Metro rrhagi
`
`Spotting
`
`Metronhagia
`
`spotting
`
`Total
`
`1.4%
`
`10.7%
`
`.4%
`
`13.5%
`
`Over half
`these symptoms disappeared
`three months of switching to this new
`
`first
`
`in the
`
`contraceptive
`
`Weight
`
`is
`
`acceptability
`
`very important parameter
`of an oral contraceptive Weight
`
`in
`
`gain is
`
`very frequently invoked
`If we consider
`
`reason for
`
`who
`
`the patients
`stopping the pill
`the study and whose weight was
`months of
`
`completed
`known
`
`prior
`
`and after
`
`With respect
`be noted that all
`
`to irregular
`
`the patients
`
`it should
`
`hecding
`were counted
`
`in
`
`the evaluation of this criterion including
`those who had irregular
`bleeding before their
`inclusion 10.2% and those who reported
`skipped Mercilon pills The incidence
`having
`
`of
`
`these irregular
`
`bleedings is listed in Tables
`
`and
`
`As is normal with low-dose
`
`oral
`
`taking this pill
`
`test
`
`this
`
`contraceptives
`
`this incidence
`
`decreases
`
`as the
`
`test
`
`to screening
`there was no significant
`change
`for matched series
`in weight Students
`patient 0.4% stopped
`pill before
`Only one
`the end of the study clue to weight gain
`
`As in the case of weight the blood pressure
`numbers did not change
`statistically
`significantly
`for matched series during the
`Students
`study Only one woman 0.4% stopped
`this
`before the months were
`up due to increased
`
`pill
`
`blood pressure
`
`Dropouts
`
`the initial 235 patients 33 withdrew
`
`from the
`
`study before the end of the 6th cycle namely
`14.0% Of
`these 33 25 patients
`stopped
`to intolerance namely 10.6%
`
`treatment due
`
`The reasons
`
`for these dropouts
`
`are listed in Table
`
`The side
`
`effects
`
`causing
`
`this new pill
`
`to be
`
`dropped before months in 25 patients are
`One patient may have more
`shown
`in Table
`side effect
`
`than one
`
`that
`
`it should
`
`he noted
`
`cycles progress moreover
`the great majority of these
`irregular
`by spotting The
`
`bleedings is represented
`main factor
`
`in evaluating irregular
`bleeding is
`its acceptability with this new combination
`
`is high as only 13 patients
`pill acceptability
`out of 235 or 5.5% stopped
`
`taking the
`
`pill
`
`during the study or after completing
`months due
`
`to rnetrorrhagia
`
`and/or spotting
`
`the
`
`Tolerance
`
`this multicenter study looked
`
`at clinical
`
`tolerance of this contraceptive preparation
`
`containing only 20 nicg of ethinyl estradiol
`The side effects occurring in the first
`and between months
`months of the pill
`
`and
`
`were
`
`gathered
`
`Table
`
`lists the main side effects
`
`reported To
`
`be noted is the high frequency
`
`before the
`
`contraceptive studied was taken of breast
`
`tenderness
`to be estrogen-
`acknowledged
`dependent 17.4% headache
`20.8% and
`nervousness 14%
`
`dose
`
`by 33% the estrogen
`The benefits
`of reducing
`DSG 50 meg are
`in EE 20 meg
`clearly evident when we look at
`the change
`
`in
`
`these symptoms
`
`particularly
`
`breast
`
`Conzraception-ferriilitØ-.sexualitc/
`
`1990 Vol 18 No
`
`pp 407-4/2
`
`WC_LP0405499
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2016, Pg. 5
`
`

`
`No pregnancies
`were
`
`skipped
`
`were
`
`observed
`
`even
`
`though pills
`
`in 5.9% of the cycles
`
`The excellent efficacy of this new contraceptive
`is based
`on desogestrel
`powerful
`the leader of the new-
`
`antigonadotropic
`
`generation progestogens
`
`Cycle
`
`control
`
`pmved satisfactory withdrawal
`
`bleeding tended to be shorter
`it was absent
`
`on this pill
`cycles studied
`
`and
`
`less abundant
`
`in only 1.3% of the
`
`As with all oral contraceptives
`
`irregular
`
`as
`
`it
`
`was found
`
`spotting
`
`the cycles progressed
`bleeding decreased
`in only 8.5% 6.5% of which were
`by the 611 cycle The
`of the patients
`rate is high as only 13 patients
`acceptability
`namely 5.5% of the study population
`
`Mastoclynii n4l
`
`Hesdaclie
`
`ii
`
`49
`
`clout
`
`before
`
`3dnic
`
`rd
`
`enw
`
`95
`
`Figure
`
`Change
`
`in the incidence
`
`of pre
`and headache
`
`existing breast
`Mercilon
`
`tenderness
`
`taking this contraceptive due
`to irregular
`bleeding 10 stopped before months and
`the end of
`not wish to continue with the pill until
`
`did
`
`on
`
`the study
`
`stopped
`
`Table
`
`Main side effects
`
`reported
`
`The clinical
`
`benefits
`
`of the 33% reduction in
`
`Before
`
`EB
`
`20 LflcC
`DSG ISO
`
`nicg
`
`is
`
`235
`
`4.7%
`
`During tirsi
`
`TreaiweliL
`
`cycles
`
`to
`
`21
`
`treatment
`
`cycles
`
`235
`
`3.4%
`
`dose
`
`to the estrogen contained
`estrogen
`of
`in low-dose pills are the low incidence
`
`relative
`
`subjective estrogen-dependent
`
`side effects
`
`breast
`
`tenderness
`
`who
`
`in patients
`particularly
`this symptom before taking this pill breast
`
`had
`
`tenderness
`disappeared
`over 50% of cases
`
`in the first
`
`months
`
`in
`
`for one patient who stopped this
`Except
`contraceptive before the end of the study due to
`gain arid another who stopped due
`
`weight
`
`to an
`
`increase in blood pressure neither weight nor
`blood
`nLimbers
`
`changed
`
`to
`
`statistically
`
`pressure
`degree
`
`significant
`
`Vaginal dryness
`
`which
`
`reducing
`
`esiradiol
`
`level could theoretically
`
`the ethinyl
`bring about
`
`was not reported by any of the 235 patients
`
`Nausea
`
`Breast
`
`tndriss
`
`tclldache
`
`Nervousness
`
`Depression
`
`lucr
`
`libido
`
`Deer
`
`libido
`
`Lower
`
`limb
`
`pain
`
`C000S
`
`irisufliciency
`
`18.7%
`
`15.3%
`
`5.5%
`1%
`
`1.7%
`
`4.2%
`
`7.4%
`
`211.8%
`
`14.0%
`
`5.1%
`
`2.5%
`
`3.0%
`
`2.1%
`
`19%
`
`13.7%
`
`2.3%
`
`2.8%
`
`2-1%
`
`0.9%
`
`2.4%
`
`8%
`
`COMMENTS AND CONCLUSION
`
`The efficacy and clinical
`tolerance of
`oral contraceptive Mercilon 20 mcg
`150 meg desogestrel were
`ethinyl
`studied in 235 women over
`1305 cycles
`
`estradiol
`
`new
`
`This was multicenter open-label non-
`
`comparative
`
`study lasting
`
`cycles in which
`
`37 French physicians collaborated
`
`continuation rate for Mercilon at
`The overall
`months is high for
`low-dose
`It was 86% Indeed the actual
`for this new pill
`at months is 88.9% 202 out of
`227 women if only stoppages
`due
`are counted
`
`oral contraceptive
`
`continuation rate
`
`to taking the
`
`pill
`
`Contraception
`
`jrtilitd-sexua1itØ
`
`1990 Vol 18 No
`
`pp 407-412
`
`WC_LP0405500
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2016, Pg. 6
`
`

`
`Table
`
`Reasons
`
`for Irolout
`
`Certain contraindications
`
`for combined oral
`
`Intolerance
`
`Patients wish
`
`Intercurrent
`
`medical
`
`reason
`
`Non-medical
`
`reason
`
`No.of
`
`patients
`
`25
`
`10.6%
`
`2.6%
`
`0.4%
`
`0.4%
`
`Table
`
`Reasons
`
`for stopping Mereilon
`
`lrernattl rely
`
`Cycle disorder
`
`amenorrhea
`
`spotting
`
`oligornenorrhea
`
`spotting
`
`metrorrhagia
`
`spotting
`
`monoiThagia
`
`decreased
`
`libido
`
`Breast tenderness
`
`Headache
`
`Weight gain
`
`legs
`
`venous
`
`insufficiency
`
`Heavy
`Nausea
`
`Nervousness
`High BP
`Exacerbation
`
`of depression
`
`Metabolic
`
`disorders
`
`contraceptives linked
`
`to age smoking
`discrete metabolic disorder
`for example and
`
`or
`
`certain
`
`forms of
`
`intolerance of other low-dose
`combined oral contraceptives such as weigh
`gain headache
`breast
`tenderness
`and
`lower limb pain may be second-choice
`of this new low-dose pill
`indications
`
`nervousness
`
`This pill ushers in lie fourth generation of
`combined oral contraceptive pills namely pills
`and
`containing less than 30 meg etbioyl
`estradiol
`
`so-called
`
`new-generation
`
`progestogen
`
`desogestrel
`
`gestodene
`
`norgestimate
`
`The reasonable
`
`hope
`
`is that
`
`thanks to this
`
`significant
`
`of these
`
`reduction in estrogen dose
`new progestogens
`
`that are metabolically
`
`and
`
`the use
`
`very well
`will continue
`
`to decline
`
`tolerated the vascular risk of the
`
`pill
`
`REFERENCES
`
`Sonata
`
`eihinyf
`
`estradiol
`
`of
`
`17-27
`
`published
`
`by
`
`A155iA
`
`dc
`
`cc
`
`unnail
`
`lid
`
`Cl
`
`II
`
`212
`
`tIc9
`
`rrliicylccrndnc.l
`
`bynncclcigc
`
`Rpkcrn
`
`cai Cnflhnncnnnrcniai_
`
`nndinp
`Obcicnoic
`
`of
`
`and
`
`c0npn-
`Ccc
`do
`
`The pill sith 30 micrograms
`to Fourth Scieniifir Meeting
`National Fedei anon of Medical Gynecology
`January 13 1989 pages
`Associations
`Paris
`Brun
`Cc bib donod
`iloilcc
`ni9 99iir.colnpl
`dcc Xii 9p0 cana
`loon beIC
`.ac
`of
`Iannbn
`Cc nIh and
`
`ndl
`
`rIp /9122
`
`$592
`
`an
`
`iaainncn
`
`Pabihinbc9
`
`uncap
`
`fccf ccnccp
`bc/c
`
`Finarri
`
`ccci
`
`canons
`
`and
`
`ncuaincic
`
`Jima
`
`Cci
`
`50
`
`dmogcccnl
`
`nlndy of
`con
`Cncccpp
`
`ncdacn
`9/1
`
`99
`
`.9
`
`ci
`
`cdi..Eifrnucf
`0.029
`picc
`ni.anyinnfcadicl
`rolijnlro .%ud I7iaul
`
`rig
`
`cnn
`
`cc
`
`.naadptcaacllauijlan
`ccbclcdnr
`incolab
`
`con
`
`rbronaf Sd 9/2
`
`app
`
`20
`
`IlOf clnnlcladcl
`229.243
`
`YArd IfLO 9509
`dccclpl
`0150
`mob
`bobby
`2natalo
`ill 2972
`
`iSLALA
`211
`019 dnsnrcc
`non
`nni
`
`proi
`179cm
`
`and
`
`rIcanna
`
`Oucrcl.ScanJ
`
`ccli
`
`fOnts
`
`of
`
`17121/
`
`org
`
`ndcicylnroodjoi
`
`anniihuonbin
`
`dcc ttl colrlcnpnin
`cci dcci
`lijdd SI/SQ
`fiVrcfyic
`conoo Anna
`
`iii
`
`orniciry
`
`cn00aocinn
`
`0.120
`
`in Ircolcry
`
`Off 5m 124.57-nd
`
`OAi.7i1
`n/mont
`nalcc
`49592
`
`79
`
`ccii
`
`coo
`
`In nodomnoac
`
`ioa-daco
`and
`
`nalaogon
`
`oaal
`
`cOOinlCnprac
`
`lipid
`
`onaIcs
`
`Crcaracrpri..a
`
`nnmtb
`
`19/7
`
`ponaodlnrc
`
`Lipothymia
`
`The advantages
`
`the estrogen dose
`of reducing
`new
`to 20 meg associated with those of
`desogestrel make
`
`generation progcstogen
`
`Mereilon
`
`remarkably
`
`effective
`
`pill with
`
`satisfactory
`
`clinical
`
`cycle control and excellent
`tolerance numerous other stLidics
`
`also show the
`confirm these results
`and
`excellent metabolic tolerance 3-6
`lipid tolerance and hemostasis
`
`particularly
`
`reducing
`
`effect
`
`9Directur
`
`Birth Conan Center Saint-Louis
`
`Uospiial
`
`Paris
`
`These characteristics
`
`mean that
`this pill
`FE and
`150
`containing 20 micrograms
`micrograms DSG can be the first choice
`all women seen
`for contraception and having
`for this method
`no contraindications
`
`for
`
`Coirraceptiori-fertilird-sexuolird
`
`1990
`
`Vo/
`
`18 No
`
`pp 407-412
`
`WC_LP0405501
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2016, Pg. 7
`
`

`
`tLPI
`
`UAi uEyi/ s/_
`
`contraception
`5exuallte
`
`FtFfLJ1
`
`FE838KE
`04 26 8/01
`
`Contraception-fertilitØ-sexualitØ 1990 Vol 18 No
`
`pp 407-412
`
`WC_LP0405502
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2016, Pg. 8
`
`

`
`TRANS PERFECT
`
`CERTIFICATION
`
`Katharine Perekslis
`
`am fluent
`
`in the French
`
`and English Languages
`
`hereby
`
`certi that
`
`the document
`
`identified
`
`below was translated
`
`from French to English by
`
`competent
`
`translator
`
`of the English and French languages
`
`was edited
`
`by
`
`roN
`
`Transperfect Quality Manager
`
`qualified
`
`to review and edit
`
`the French and English
`
`languages
`
`and
`
`that
`
`the translation
`
`is true accurate
`
`and complete to
`
`the best of my
`
`knowledge and belief
`
`The 20 Microgrim Ethinyl EstNd ol plus
`Microgr ml Desogestrel
`on 235 Women
`for Months
`
`MLiltrcenter
`
`Study
`
`Pill
`
`declare under penalty of perjury
`
`under
`
`the laws of the United
`
`States
`
`of America tliar
`
`the foregoing is true and correct
`
`Signature
`
`Sworn to before nic
`
`tins
`
`29th day of Jan nary 2007
`
`Signature Notar
`
`ic
`
`BRENDA tONZALEZ
`NOTARYTATt0EWfO
`
`OUAUFIED
`MY COMMISSION
`
`IN BRONX
`
`EXPIRES
`
`COUNTY
`MAY 10 20_
`
`Stamp Notary
`
`PLiblic
`
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`
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`
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`
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`
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`
`212.6895555
`
`212.689.1059
`
`WWW.TfiAN5FERFECT.COM
`
`WC_LP0405503
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2016, Pg. 9