A Clinical Guide for Contraception
`
`II
`
`l pill missed
`
`~r
`
`Take missed pill
`as soon as
`possible
`
`Resume
`schedule
`
`Back-up not
`necessary
`
`2 pills missed
`
`During week 1 or 2
`1lr
`
`During week 3
`
`Take 2 pills
`daily (or 2 days
`then finish pack
`
`Unlikel y
`b ack-up needed,
`but advised for
`7 days
`
`Day 1 start
`
`•
`
`Start new pack
`
`Sunday start
`
`•
`
`Take da ily pill
`until Sunday,
`then start new
`pack
`
`Use back-up
`immediately
`and for 7 days
`
`Use back-up
`immediately
`and for 7 days
`
`3 or more
`pills missed
`
`Day 1 stan
`
`Start new pack
`
`Use back-up
`immediately
`and for 7 days
`
`Studies have quesrioned whether [
`cepcion. One srud.y demonstrated
`varying rimes in che cycle did not
`women dcliberacely lengthened rhe
`ro show signs of ovulation.,., ... ~ So .
`lower doses has had an impact or
`follicular activity with the lowesr-dc
`e.ffcccivdy preveored..~l The srud
`women and given the wge individu
`·women rn.ighc be at risk with a s
`However, the progesr:arional e.ffcca
`serve to ensure good contracepci"
`current recommend.acions ace roo a
`of geccing pregnane with missing
`conservative advice is the safest me:
`
`The most prevalent problems rhat c
`em oral conrraceprive &il.ures ace vc
`have bun missed, pamnts should b.
`at least 7 days after an episode of.
`tu.red vaginAl for oral ruiministrati.,
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 76
`
`

`
`missed
`
`missed pill
`::>n as
`b\e
`
`me
`ju\e
`
`:-up not
`ssary
`
`Oral Contraception
`
`3 or more
`pi \Is m issed
`
`I
`
`Day 1 start
`~\r
`
`Start new pack
`
`Use back-up
`immediately
`and (or 7 days
`
`Sunday start
`
`~·
`
`Take daily pi\\
`until Sunday,
`then start new
`pack
`
`Use back-up
`immediately
`and for 7 days
`
`II
`
`Srudies have questioned whether missing pills has an impact on conrra(cid:173)
`ceprion. One study demonstrated char skipping 4 consecutive pills ar
`varying times in the cycle did nor result in ovulation . .}j' Studies in which
`women deliberately lengthened rhei£ pill-fee interval up ro 11 days failed
`ro show signs of ovulation."'~ So far there is no ev:idence th.ar moving co
`lower doses has had an i,mpacc on the margin of error. Despite greater
`follicular activity with the lowest-dose oral conrraceprives, ovulation is still
`effecrivdy prevented " 1 The srudies have involved small numbers of
`women and given the large individual variation, ir still is possible char some
`women might be at risk wit:h a small increase in the pill-free intervaL
`However, the progestational effects on endometrium and cervical mucus
`serve co ensure good conrraceptive efficacy." We may well prove that
`current recomme.ncb.rions are wo conservative, and that a woman's chance
`of gercing pregnant with missing pills is nearly zero. Neverthdess, chis
`conservative advice is the safes£ message ro convey.
`
`.-.-·
`
`The most prevalent problems chat can be identified associated with appar~
`ent oral conrracepcive failures are vomiting and diarrhea. "'20 Even if no pilb
`have bun missed, patients should be instructed to use a backup mahod for
`at least 7 days after an episode of gastroent"itis, un/.e$s they have substi(cid:173)
`tuted vaginal for oral ndminirtratum without missing a day.
`
`During week 3
`
`Day 1 start
`
`Sunday start
`
`new pack
`
`:>ack-up
`_ :diately
`'or 7 days
`
`Take daily pill
`until Sunday,
`then start new
`pack
`
`Use back-up
`immediately
`and for 7 days
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 77
`
`

`
`A Clinical Guide for Contraception
`
`Clinical Problems
`Breakthrough Bleeding
`A major continuation problem js breakthrough bleeding. Breakthrough
`bleeding gives rise to fears and concerns; ic is aggravating, and even embar(cid:173)
`rassing. Therefore, on scarring oral comracepcion, patients need to be fully
`informed abour breakthrough bleeding.
`
`There are two characceriscic breakthrough bleeding problems: irregular
`bleeding in che fuse few months aft-er starring oral conrracepcioo, and
`unexpected bleeding after many morirhs of use. Efforr should be made to
`manage che bleeding problem in a way mar allows me patient tO remain on
`low-dose oral cootncepcion. There is no evidence that the onset of bleed(cid:173)
`ing is associated with decreased efficacy, no matter what oral contraceptive
`formulA-tion is used, even the lowest d<>se products. Indeed, in a cardi.J
`srudy, breakthrough bleeding did not correlate wirh changes in rhe blood
`levels of che contraceptive sreroids.146
`
`The most frequently encountered breakthrough bleeding occurs in the fust
`few moochs of use. The iJlcidence is greatest in the ficsr 3 monrhs, ranging
`from 10-30% ia che first month to less dun 10% in the third.
`Breakthrough bleeding rates are higher with the lowest dose oral comra(cid:173)
`ceprives, buc nor d.ramacically.H7 Breakthrough bleeding is fun:her
`increased in women who smoke and in smokers who use formulations with
`20 ~ ethinyi estrad.iol..W However, che differences among the various
`fonnuiacioas currencly available ace of minimal clinical significance. The
`basic pattern is the same, highest in the fuse month and a grearer preva,
`lence in smokers, especially in laxer cycles.
`
`.; .
`
`Early breakilirough bleeding is best managed by encouragemeac and reas(cid:173)
`sw-ance. This bleeding usually disappears by rhe third cycle in the majority
`of women. If necessary, even this early pattern of breakthrough bleeding
`can be ueared as oudined below. Ic is helpful co explain to the patient chat
`mis bleeding represents tissue breakdown as che endometrium adjustS from
`irs usual thick stare to rhe relatively thin state allowed by me hormones in
`oral contracepcives.
`
`Breakthrough bleeding chat occurs after many monili.s of oral contracep(cid:173)
`tive use is a consequence of rhe progestin-induced decidualization. This
`endomecri~ aud blood vessels within the endomeuium rend to be frag(cid:173)
`ile and prone to breakdown aud asynchronous bleeding.
`
`There are twO recognized factors (bor.h prevencab}e) mat are associated
`with a greater incidence of bre3kthrough bleeding. Consistency of use and
`smoking incre:~se spotting and bleeding, but inconsistency of pill caking is
`
`more imporram and has a grea
`exerts a general effect from beg
`coosisrem pill caking can help 1
`inkccion can be another cause c
`cervical chlamydia! infections
`who report breakthrough bleed;
`
`If bleeding occurs just before u
`by having me pacienc stop rhe
`breakthrough bleeding is pro!ot
`regardless of the point in the
`achieved wim a shon course of
`1.25 mg, or e.<itradiol, 2 mg, i
`bleeding i:s present, oo matter
`pacienr comioues to adhere co
`course of estrogen solves the
`unusual (bur if ir does recur, an
`
`Responding to irregular bleedir
`not effective. The progestin co
`hence, doubling the number c
`impact and its decidualizing, a
`destabilizing effecr on endomc
`estrogen while keeping the pro
`rive. Tbis allows th~ patient to
`its advantage of greater safery. _
`sufficient reason to expose pat'
`higher dose oral contraceptives
`rourine requires Investigation fi
`
`There is no evidence char an)
`approximately equivalenr in est:
`different in rhe rates of breakt
`impressed that swicching to at
`through bleediog. Ir is .mort
`responsible fact:or, and bleedin;
`ing and regardless of product.
`
`Amenorrhea
`With low-dose piJJs, the estrog.
`to stimu1are endometrial grow
`such a degree rhac a shallow a
`sufficient tissue to yield wichdr.
`permanent atrophy of the end
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 78
`
`

`
`1 is breakthrough bleeding. Breakthrough
`:oncems; ic is aggravacing, and even embar(cid:173)
`>ral contraception, paciems need tO be fully
`Jleed.ing.
`
`>reakwough bleeding problems: iuegular
`1ths aft:er starting oral contraception, and
`.y months of use. Effon: should be niade to
`rr a way that allows the patient co remain on
`1ure ir no evidence that the onsa of bleed(cid:173)
`, efficacy, no matter what ordl contrtUeptive
`lowest dose products. lodeed, in a careful
`:lid not correlate wich changes in the blood
`>ids.~
`
`·ed bre:aktluougb bleeding occurs in the ftm
`n.ce is greatest in the first 3 monchs, ranging
`month (0 less than 10% in me third.
`re higher with the lowest dose oca.l conrra(cid:173)
`J.ly.'" Brea.kcluough bleed.ing is further
`e and in smokt:rs who use formulations wi_th
`>wever, the differences among t:he various
`le are of minimal clicica.l significance. The
`lest in me first month and a greater preva.(cid:173)
`l.ater cycles.
`
`s best: managed by encouragemenr and reas(cid:173)
`disappe.a.rs by the third cycle in the majoriry
`this early panern of breakthrough bleeding
`oW. lt is helpful tO explain to me pacimt that
`breakdown as the endomeuium adjusts from
`civcly thin state allowed by me hormones in
`
`cc.urs a.&er many months of oral concracep(cid:173)
`the progestin-induced decidualization. This
`1s within the endometrium cend co be frag(cid:173)
`nd asynchronous bleeding.
`
`:rors (both preventable) char are associated
`:.akrhrough bleeding. Coruistency of use and
`1 bleeding, bur inconsistency of pill raking is
`
`Oral Contraception
`
`more impona.ot and has a greater effect io later cycles, whereas smoking
`~rrs a general effect from beginning to larer cycles.~9 Rein.fotcemeut of
`consistent pill raking can help minimi:ze breakthrough bleeding. Cc.rv:ical
`
`infection can be another cause ofbreakduough bleeding; the prevalence of II
`
`cervical chlarnydial infectioru is higher among oral conrraceptive users
`who reporc breakthrough bleeding.l50
`
`•
`
`If bleeding occurs just before the end of the pill cycle, it can be managed
`by having !he pacieor srop me pills, wait 7 days and start a new cycle. If
`broJcth..rough bleeding is prolonged or if ir is aggravating for the patimc,
`regardless of the point in the pill cycle, control of rhe bleeding can be
`achieved with a short course of exogmous esuogen. Conjugated estrogen,
`1.25 mg, or esuad.iol, 2 mg, is administered daily for 7 days when the
`bleeding is present, no matter whe.re the patient is in her pill cycle. The
`pacient continues to adhere to the schedule of pi.U taking. Usually; one
`course of estrogen solves the proble~ and recurrmce of bleeding is
`unusual (bur if ic does recur, another 7-day course of estrogen is effective).
`
`Responding to irregular bleeding by having rhe patient take 2 or 3 pills is
`nor effective. The progestin component of the pi.U wiU always domi11:1te;
`hence, doubling the nwnber of pills will also double the progesrarional
`impact and its decidu.alizing, auophic effect on the eodomerriwn and its
`des!4.bilizing e:ffecr on endomerrial blood vessels. The addirion of extra
`estrogen while keeping the progestin dose Wlcilanged is logical and effec(cid:173)
`tive. This allows the paciem to remain on the low-dose formulation with
`its advantage of greater safety. Breakthrough bleeding, in our view, is not
`sufficient reason to expose patients to che increased risks associated with
`h.igher dose oral contraceptives. Any bleeding rill.c is not bandied by chis
`routine requires i.mresrigarion for the preseoce of pathology.
`Tbere is no evidence mat any oral contraceptive formulations r.har are
`approximately equivalent in estrogen and progestin dosage are signi6ca.ncly
`different in me races of breakthrough bleeding. Clinicians often become
`inlpressed that switching to another producr effectively stops che break(cid:173)
`through bleeding. Ir is more likely mac me passage of rime is the
`responsible faeroe, and bleeding would bave stopped regardless of swirch(cid:173)
`ing and regardless of produce.
`
`Amenorrhea
`With low-dose pills, the estrogen conre.nr is not sufficie.nc in some women
`w stimulate endomeuial growth. The progestarional effect dominates to
`sucb a degree mat a shallow auophic endoroeuiwn is produced, lacking
`sufficient cis sue co yield wiilidrawa1 bleediog. It should be emphasized that
`pe.rm.anem auophy of the endomeuium does noc occur, and ceswnpcion
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 79
`
`

`
`A Clinical Guide for Contraception
`
`of normal ovarian function will r~mre endometrial growth aud develop(cid:173)
`me.m. L1deed, there is no harmful, pennmenr consequence of amenorrhea
`while on oral concracepcion.
`
`Tbe major problem wich. amenorrhea while on oral concracepcion is the
`anxiety produced in born pacienc and clinicim because the lack of bleed(cid:173)
`ing may be a sign of pregnancy. The pacieut is anxious because of the
`uncen:aincy regarding pregnmcy, and me clinician is anxious because of
`me medicolegal concerns stemmi.ng from the old srud.ies which indicated.
`increased risk of congen.iral abnormalities among the offspring of
`m
`women who inadverrendy used oral concraception in early pregnancy. We
`reviewed chis problem earlier, and emphatically srated chat mere is no asso(cid:173)
`ciation berwee.n oral contraception md an increased risk of congenital
`malformation, and cheye is no increased risk of having abnormal children.
`
`The incidence of amenorrhea in me firsr year of use wim low-dose oral
`concracepcion is less chan 2%. This incidence increases with duration,
`reaching perhaps 5% afr:er several yean; of use. It is important co alen
`patients upon srarcing oral conuacepcion mat diminished bleeding and
`possibly no bleeding may ensue.
`
`Amenorrhea is a difficult managemt.nr problem. A pregnmcy rest will
`allow rdiable assessment for the presence of pregnmcy even at this early
`srage. However, routine, repeared use of such resting is expensive md
`annoying, and may lead to discominuacion of oral connacepcion. A simp!£
`test j01· pregnancy is to assess the basal body temperature during the END
`of the pill-free week; a basal body tempmzture less than 98 degrees
`(36. 6°C) is not ctm.Sistent with pregnancy, and oral contraception tan he
`continued.
`
`Many women are reassured wim m understanding of why there is oo
`bleeding and are able to continue on the pill despite che amenorrhea. Some
`women cannot reconcile themselves to a lack of bleeding, and iliis is an
`indicacion for uying other formul.acioru (a practice unsupponed by aoy
`clinical uials, and, therefore, the expectations are uncertain) . Bur again,
`iliis problem does not warfaflt exposing patients ro the greare.r risks of
`major side effecrs associated with higher dose produa:s.
`
`Some clinicians have observed that the addition of exrra c.mogen for l
`month (1.25 mg conjugated estrogens or 2 mg esuadiol da.ily throughout
`me 21 days while raking the oral conuaccpdve) will rejuvenate rhe
`endomeuium, and wirhd.mval bleeding will resume, persisting for many
`months.
`
`Weight Gain
`The complaint of weighr gain is fi
`compliance. Yer, srudies of rbe loVI
`signifiCaflt wei.ghc gain with oral c
`among the various produces.~~~"'
`cion, a condusion supported by a
`low-dose oral conrracepcives and
`gain and headaches was idencica
`groups. 171 The clinician has m ca
`berween low-dose ocal conrrace1
`patient on the real· culprit: diet ar
`moderate amount of weight as the
`rives or oot.
`
`Acne
`Low-dose oral contraceptives imp
`3 st-m The low progestin d
`used. 1
`'"
`rions} curremly used are insufficie
`
`Ovarian Cysts
`Anecdor.a.l repons suggested. chat .
`more frequemly and suppress b
`This observarion failed co wirhsra·
`cysts occurred less frcquemly in
`tion.m TIUs protection is reduced
`the poinr where little effect Cafl I
`cysts is not d.iminaced; md, there
`in patienrs raking any of me oral
`
`Drugs That Affect Efficacy
`There are many anecdotal repo
`contraceptives wh.ile raking ancib
`that antibiotics such as ampicillin
`cline, which reduce the bacterial
`oral conuaceptive efficacy. Srudie
`the excretion of contraceptive src
`mere is uo evidence of ovulacio
`patients derived from dermarolog:
`of pregnancy in women on oral
`antibiotics (terracyclines, penicilli
`
`There is reason ro believe char drr
`capacicy, can affect oral contracep
`of a large database failed to disc
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 80
`
`

`
`l resrore endomcrrial growth and dcvdop(cid:173)
`UI, permanent consequence of amenorrhea
`
`tarrhea while on oral contraception is the
`m and clinician because rhe lack of bleed(cid:173)
`cy. The pacienr is anxious because of the
`:y; and rhe clinician is anxious because of
`ning from the old studies wh.ich ind.ic..a.ted
`a1 abnormaliries among rhe offspring of
`. oral conaacepcion in early pregnanty. We
`r1d empharically stared that there is no asso(cid:173)
`nion and an increased risk of congenital
`increased risk of having abnormal children.
`
`in the fim y= of use with low-dose oral
`'· This incidence increases with duration,
`tcral years of usc. It is irnportanr to alert
`m:.racepcion rhar diminished. bleeding and
`e.
`
`nagemenc problem. A pregnancy test will
`1e presence of pregnancy even at this early
`aced use of such rescing is expensive and
`:onrinuacion of oral contraa:pcion. A simple
`~e basal body temperature during the END
`.J. body temperature less than 98 degrees
`1 pregnancy, and oral contraccptum am be
`
`vith an undemanding of why there is no
`ue on che pill despite the amenorrhea. Some
`1selves co a lack of bleeding, and rhis is an
`rmulacions (a pracrice unsupported by any
`the expectations are uncerra.in). But again,
`n exposing patients to the greater risks of
`irh h.igher dose products.
`
`:l. rhac rhe addition of excra estrogen for
`strogens or 2 mg emad.iol da.ily cluoughout
`1e oral contraceptive) will rejuvenate the
`1 bleeding will resume, persisting for rnany
`
`Oral Contraception
`
`Weight Gain
`The complainr of weight gain is frequenrly cited as a major problem with
`compliance. Yer, srudics of rhe low-dose preparations fail ro demonstrate a
`
`significant weighr gain wich oral comraceprion, with no major differences I
`
`among the various producrs. '.s.'70 This is obviously a problem of percep-
`cion, a conclusion supported by a. placebo-controlled randomized trial of
`low-dose oral contraceptives and acne, in which me incidence of weight
`gain and headaches was identical in borb the treated and the placebo
`groups.171 The cl.in.ician has to carefully reinforce the lack of associacion
`between low-<lose oral contraceptives and weight gain and -focus the
`patient on the real· culprit: diet and level of exercise. Most women gain a
`moderate amount of weight as rhey age, wberhe.r they take oral contracep-
`tives or nor.
`
`-
`
`Acne
`Low-dose oral conrracepcives improve acne l:'egard.less of wh.ich product is
`used.'~&.nt.)~s The low progestin doses (jnduding levonorgesucl formula(cid:173)
`tions) currenrly used are insufficient ro stimulate an androgenic resp;nse.
`
`Ovarian Cysts
`Anecdotal reports suggesred t:bar functional ovarian cysts a.re encoumered
`more frequencly and suppress less easily wirh multiphasic formulations.
`nus observation failed co withstand careful scrutiny.'55 Functional ovarian.
`cysrs occurred less frequencly in women on higher dose oral conuacep(cid:173)
`rion.m Th.is proc.ection is reduced with the current lower dose products to
`me point whcre liule effect can be measured.'1 .. "'' Thus, rhe risk of such
`cysts is not eliminated; and, therefore, clinicians c..a.n encounter such cym
`in patients t:ak.ing any of the oral concracepcive formulations.
`
`Drugs That Affect Efficacy
`Thcre are many anecdoca.l reports of patienrs who conceived on oral
`conuacepcives while caking antibiocics. There is lircle evidence, however,
`thar antibiotics such as ampicillin, metronidazole, quinolone, and tetracy(cid:173)
`cline, which reduce me bacterial flora of the gasuointestinal rracr, alfecc
`oral comracepcive efficacy. Srudies indicac.e !hat while ancibiorics can alrer
`the excretion of conuacepcive sreroids, plasma levels are unchanged, and
`there is no evidence of ovu.larion.3''M
`6s A review of a large number of
`patients derived ITOm dermatology praccices failed CD find an increased rate
`of pregnancy in women on oral contraceptives and being ueatcd with
`antibiotics (tetracyclines; penicillins, cephalosporins).'66
`
`There is reason to bdieve char drugs, which stimulate the livcr's metabolic
`capacicy, can affecc oral comracepcive efficacy. On rhe other hand, a search
`of a large database failed to discover any evidence mat lower dose oral
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 81
`
`

`
`A Clinical Guide for Contraception
`
`concraceptives are more likely co fail or to have more drug interaction
`problems when ocher drugs are used..367 Indeed. a careful pharmacokinetic
`study in 12 women indicated rhar ri&mpin and rifaburin increased oral
`contraceptive estrogen and progestin cleac:mce, bm ovulation was not
`decected.%.1 Troglicazone decreases me circulating levels of erhinyl esuad.iol
`' This drug effect may not be
`and norethindrone by apprmcimatdy 30o/o.l6
`sufficient to allow escape ovulations. Because srud.ies have been limited by
`relatively small numbers and only a small number of women mighc be
`susceptible ro escape ovuiarion, ic is berrer to be cautious; pariems on
`medications iliac affect liver mecaholism should choose an alcerna.cive
`contraceptive. These drugs are as follows:
`
`Carbamazepine (Tegrerol)
`Fdbamare
`Ox:carbazepine
`Phenobarbital
`Pbenytoin (Dilancin)
`Prim.idooe (Mysoline)
`Rifabucin,
`Rifampicin (Rifampin)
`Topiramare
`Vigab:min
`Possibly erboswcimide, griseofulvin, and rroglitazone..
`
`Other Drug Interactions
`Although not extensively documented, r.h.ere is reason ro believe that ora!
`contraceptives porenciace cbe accioo of diazepam (Valium), chlordiazepox(cid:173)
`ide (Libriwn), tricyclic antidepressants, and theophyllineY0 Th.us, lower
`doses of these agents may be effective in oral conrraceprive users. Because
`of an influence on clearance races, oral contraceptive users may require
`larger doses of acet.aro.ioophen and aspirin." '
`
`Migraine Headaches
`True migraine headaches ace more common in women, while tension
`headaches occur equally in men and women. There have been no wcll done
`studies co determine the impact of oral contraception on migraine
`headaches. Patients may report rhac their headacl1es :ue worse or bertcr.
`
`Srud.ics with high-dose pilli indicated that migraine headaches were linked
`w a risk of stroke. More recent srnd.ies rdlecring che use of low-dose
`formulations yield mixed resul[S. One failed m find a nmher increase in
`stroke in pariems with migraine who use oral concracepcion, another
`concluded that the use of oral concraception by migtaineurs was associated
`with a 4-fold increase of the already increased risk of ischemic suoke.572·" '
`
`;,.·
`
`~.-'
`
`:··
`
`A third case-conrrol study conduc
`increased the risk of ischemic srrokc
`with migraine headaches, and :me
`ischemic and hemorrhagic suok~
`history of migraine headaches.' 10-"74
`migraine headaches, one would ex1
`recent srud.ies of cluombosis co !
`migraineurs. Ao adverse effect of I
`risk in m.igraineurs should have m;
`an increased risk of stroke in these
`
`· Because of the seriousness of this
`visual symproms or severe headach
`at a higher dose, a move co a I
`headaches. Swirching co a differen t
`placebo respo nse. Oral comracepti
`have migraine with aura, or if add
`age, smoking, hypertension).'''
`
`Clues To Severe Vascular Headach
`
`• Headaches char last a long t
`Diu.iness, nausea, or vomit
`• Scotomata or blurred visior
`Episodes of blindness.
`• Unilateral, unremiuing hea
`Headaches thac con1inue d<
`
`In some women, a relationship ex
`levels during a mensuual cycle an'
`headaches characteristically coinci(
`. success (anecdor.al co be sure) all
`menstrual cycle, eirher with. che usc
`ad.mi.ni.macion of a proges[ational
`te.rone acetate) or the use of dep
`women with migraine headach~
`Women who experience an exac
`contracepcion should consider one
`
`Summary: Oral Contraceptive Us4
`
`Gestational Diabetes. There is
`contraceptive use following gescat
`wich breascfeeding women using t
`Chapter 3).
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 82
`
`

`
`·o fail or to have more drug imeraccion
`used.m [ndeed, a careful pbarroacokineric
`hat rifampio and ri&hucin increased oral
`•gescin clearance, but ovulation was nor
`~ che circulating levels of ethinyl estradiol
`tacely 30o/o.l&9 This drug tffccr may not be
`ions. Because Studies have been l.iruited by
`n1y a small number of women migbx be
`, it is bener co be cautious; patients on
`necabolism should choose an alcemacive
`LS follows:
`
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`
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`-... ~ -
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`
`Oral Contraception
`
`A third case-concrol study concLuded that the use of oral conrracepcives
`increased the risk of ischemic stroke hue nor hemorrhagic stroke in women
`wirh migraine headaches, and another indicated thar the risk for bom
`ischemic and hemorrhagic strokes is increased among women with a
`
`history of migraine headaches. 110·m Because 20-30% of women experience g.
`
`migraine headaches, one would expect rhe srudy popularions in the mosc
`recem: srud.ies of thrombosis to have included substantial nwnbers of
`migraiaeurs. An adverse effect of low-dose oral conrracepcives on stroke
`risk in m.igraineuxs should have manifested itsdf in the data. The lack of
`ao increased risk of srroke in these srudies is reassuring.
`
`· Because of che seriousness of cltis potencial complication, the onset of
`visual symptoiDLS or severe headaches requires a response. If rhe patient is
`at a higher dose, a move ro a low-dose. formulation may relieve me
`headaches. Switching ro a different brmd is worthwhile, if only to evoke a
`placebo respoDLSe. Oral concracepcives should be avoided in women who
`have migraine with aura, or if additional srroke factors are present (older
`age, smoking, hypertension).'-''
`
`Clues To Severe Vascular Headaches;
`
`• Headaches that la.sr a long time.
`• Dizziness, nausea, or vomiriag wich headaches.
`• Scorornatl or blurred vision.
`• Episodes of blindness.
`• Unilateral, unremitting headaches.
`• Headaches rhac continue despite medication.
`
`iseofulvio., and uoglirazone.
`
`mc:nced, mere is reason (0 believe that oral
`xiou of diazepam (Valium), chlordW..cpox:(cid:173)
`prc.ssants, and t:beophylline.370 Thus; lower
`ffeccive in oral conrra.ceptive ULSers. Because
`cares, oral com:raceprive users may require
`and aspirin.m
`
`more common in women, while rension
`1 and women. There have qeen no well done
`•pact of oral conuaception on migraine
`: chat their headaches are worse or better.
`
`iicated chat migraine headaches were linked
`:em srudies reflecting the we of low-dose
`Irs. One failed m ·find a IUn:her increise in
`aine who we oral concraception, another
`CDntra.ception by migraineurs was associated
`· k f · ch
`'
`k ~n_;n
`lready increased ns o 1s e.rruc stro e.
`
`In some women, a relationship exists between their fluccuaring hormqne
`levels during a mensuual cycle and migraine headaches, with rhe onset of
`headaches chara.creriscically coinciding with menses. We have had personal
`success (mecdoral to be sure) alleviating headaches by diminaring the
`meost:rt1al cycle, eirher with the use of daify oral coorraceprives or the dally
`adrninisuarion of a progesrational agenc (such as 10 mg medroxyproges(cid:173)
`te.rone acetate) or che use of depoc-medroxyprogescerone acetate. Some
`women with migraine headaches have exrremcly gratifying responses.
`Women who experience an exace(bacion of c.heir headacl1es with oral
`conuacepcion should consider one of the progestin-only methods.
`
`.(
`
`Summary: Oral Contraceptive Use and Medical Problems
`Gestational Diabetes. There is no comraind.icacion co combined oral
`concraceprive use following gestational diabetes. l l-!.ll-4 There is a concern
`wim breastfeeding women using che progestin-only minipill (discussed in
`Chapter 3).
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 83
`
`

`
`A Clinical Guide for Contraception
`
`Diabetes Mellitus. Oral contraception am be used by d1abecic women
`less than 35 years old who do nor smoke and are otherwise healthy (espe(cid:173)
`cially an absence of diabetic vascular complications). A case-control srudy
`could find no evidence thac oral contraceptive use by young women with
`insulin-depeodenc diabetes mellitus increased the developmenr of
`retinopathy or nephropathy.156 In ;~ one-year study of women with insulin(cid:173)
`dependenc diabetes meBitus who we.re using a low-dose oral contraceptive,
`no deterioration could be documenced .in upoprccein or hemostatic
`biochern.ica.l markers for cardiovascular risk. 117 And fina.lly, no effect of oral
`contraceptives on cardiovascular monal.icy could be detected in a group of
`women with diabetes mellirus.m
`
`Hypertension. Low-dose oral contraception can be used in women less
`man age 35 years old wich h.ypenension well conaolled by medicacion,
`and who are otherwise hca.lthy and do uoc smoke. We recommend che
`lowest estrogen dose formulations.
`
`Pregnancy-Induced Hypertension. Women with pregnancy-induced
`hyperrension am use oral contraception as soon as the blood pressure is
`normal in che posrpartwn period.
`
`Hemorrhagic Disorders. Women with hemorrhagic disorders and
`women taking a.ncicoaguiants can use oral contraception. Inhibition of
`ovulation can avoid che real problem of a hemorrhagic corpus lureum in
`rhesc pacicnts. A reduction io mensrrual blood loss is another benefic of
`importance.
`
`Gallbladder Disease. Oral conu-aception use may precipitate a sympco(cid:173)
`macic arrack in women known to have stones or a positive history for
`gallbladder disease and, che.refore, should either be used very cautiously or
`not ar all.
`
`Obesity. An obese woman who is otherwise healrhy can use low-dose oral
`concraceprion.
`
`Hepatic Disease. Oral conaacept.ion can be ut.il.ized when liver funccion
`tests rctUiu to normal. Follow-up liver funccion resrs should be obra.ined
`a.frer 2-3 months of use.
`
`Seizure Disorders. There is no impacr of oral conaaceptives on panern
`or frequency of seizures. The concern is that anticonvulsant-induced
`hepatic enzyme acrivicy can increase rhe risk of contraceptive failure. Some
`clinicians advocate che use of higher dose (SO !Jg csrrogen) products;
`however, no studies have been performed to demonstrate rh.ac chis higher
`dose is necessary.
`
`Mitral Valve Prolapse. Oral cone
`patients who a.re asymptomatic (1
`There is a small subsec of patients
`increased risk of du-omboembol
`migraine headaches, or cloning
`progeStin-only methods or me rur
`IUD insertion if rnirra.l regurgiracic
`
`Systemic lupus Erythematosus
`systemic lupus erythematous, an•
`lupus, when present, represents a •
`oral concra.cepcives.m The proges1
`However, in patients wich stable OJ
`mcm and b..igh anriphospholipid :
`can be cons.idered.377 SElENA (Sal
`National Assessment) is an on-goi
`of oral conuaceprive therapy in
`lupus erythe.macosus (as well as pc
`
`Migraine Headaches. Low-dost
`dose formulation) can be uied -w
`common migraine headaches. Dai
`migraine headaches. Oral cancra<
`classic migraine headaches assoc
`factors tbac increase cbe risk of :
`hypertension).
`
`Sickle Cell Disease. Patients wi
`cion. The risk of thrombosis in w
`diseases is theoretical (and medic
`against pregnancy in !hese pari<
`conrracepuon. In che only long-te
`with sickle cell disease and using
`effects were observed (at a. time
`lem).378 A study of erythrocyte <
`anemia could detect uo adverse e.l
`mind mac depO[-medroxyproges
`associated with inh.ibicion of si
`patients with sickle cell di.sease.'8<
`
`Benign Breast Disease. Benig~
`for oral contraception; with 2 ye:
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 84
`
`

`
`·,
`t ~-..
`-~--
`
`·:-. .,
`
`:raception can be used by diabetic women
`1or smoke and are otherwise healthy (espe(cid:173)
`scular complications). A case-conuol srudy
`!.I conuaceptive use by young women with
`rneliirus increased the development of
`{n a one-year srudy of women with [n.sulin(cid:173)
`to wcre using a low-dose oral contraceptive,
`ocumemed in lipoprore.in or hemosraric
`vascular risk..'SJ And finally, no effect of oral
`LT roonality could be detected in a group of
`!la
`
`l contraception can be used in women less
`rpertension well controlled by T!le.dication,
`y and do nor smoke. We recommend rhe
`ens.
`
`1ension. Women with pregnancy-induced
`uaceprion as soon as the blood pressure is
`od.
`
`Women with hemorrhagic disorders and
`can use oral contraception. Inhibition of
`roblem of a hemorrhagic corpus luceum in
`roeusnual blood loss is another benefic .of
`
`:onuaception use may precipirare a sympto(cid:173)
`m ro have scones or a posicive history for
`ore, should either be used very cauriously or
`
`w is otherwise healthy can use low-dose oral
`
`-accption can be urilized when liver fimcrion
`r-up