Oral Contraception
`
`of hypertension ro be using oral contraceptives; however, rhis was not the
`case in developing counrries. Duration of use and rype of p(ogesrin had no
`impacr, and past users did not have an increased risk, bur smoking 10 or
`rnore cigarettes da.i.ly aerred a synergisric effect with oral contraceptives,
`
`increasing the risk of iscben1ic suoke, approximating rhe effecr of.hyper- II
`
`rension and oral comraceprives. The risk was greater in women 35 years
`and older; however, this, coo, was believed robe due ro an cffecr of hyper-
`tension. Thus, the conclusion of this study was that the risk of isc/mnic stroke
`is extrmuly low, concentrated in those who use higher dose products, mwlu, or
`have hypertension.
`
`In t:b.e WHO srudy on h=orrhagicstroke, there were 1068 cases.11( Current
`use of oral conaacepcivcs was associated wit:b. a slightly increased risk of
`hemorrhagic scroke only in developing cownries, not in E1.Uope. Th.is again
`rellects the lack of sa:een.ing for hypen:=ion, because the greatest increased
`risk (abour 10- to 15-rold) was identified in curre.nr users of oraJ concracep(cid:173)
`tives who had a h.ist:ory of hypene.nsion. Curre.nr cigarecre smoking also
`inc.ceased rhe risk in oral contraceptive users, bur nor as dramarically as
`hypertension. For hemorrhagic stroke, rhe dose of esuogen had oo dfecc on
`risk, and neither did duration of use or rype of progestin. This study
`concludd that tht risk of htn~orrhagic stroke diU: to oral conr:raceptives is
`in~o.red only ;lightly in older women, probably occurring only in wonun with
`risk factors such as hypertension.
`
`A second Danish case-conrrol srudy included th rombocic srrokes and tran(cid:173)
`sitory cerebral
`ischemic attacks analyzed
`rogerher as cerebral
`cluomboembolic attacks.97 In this srudy, rhe 219 cases di.Uing 1994 and
`1995 included 146 cases of cerebral infarction and 73 cases of cransiem
`ischemic attacks. Only users of 2nd gcncracion oral contraceptives
`(levonorgescrel, norge.md, and norgestimare) had a stacisrically significant
`increased risk (abom 2.5-fold). There was a dose-response relationship
`wirh estrogen in the dose ranges of20, 30-40, and 50 flg echinyl estradiol,
`although the number of 20 )lg users (5 cases, 22 conaols) was nor suffi(cid:173)
`cient to establish a lower risk at this lower dose. This analysis claimed a
`reduced. risk associare.d with desogestre1 and gesrodene; however, che odds
`ratio did not adueve sra.ciscica.l significance. Risk was increased with smok(cid:173)
`iog, created hypertension, diabetes, he:m diseases, frequent mi.gra.ine, a
`f.unily bisrory of myocardiaJ infarction, bur nor duration of use, or family
`hisrory of venous thromboembolism.
`
`asized the safery of low-dose oral contra(cid:173)
`ase-conuol srud.y of 408 srrokes from rhe
`(cdical Care Program found no increase in
`or hemorrhagic stroke. 109 The identifiable
`e were smoking, hypertension, diabetes,
`socioeconomic starus. The risk facrors for
`.1e plus greater body m.a.ss and heavy use of
`· oral contraceptives did not have 1Ul increo.red
`tro!u compared with former users and with
`ce for an adverse effecr of increasing age or
`aoke, there was a suggestion of a positive
`J com:.raceprive use and smoking.. but the
`resuh was not stacisticaJly significant). A
`ml scudies from U.S. concluded that there
`or hemorrhagic suoke in current users of
`
`,aly.red mcir clara for ischem)c srroke .in a
`hemic suokes in the United Kingdom,
`and Ausrria. ' 11 Overall, there was a 3-fold
`ic stroke associared with the use of oral
`; observed in smokers (more than I 0 ciga(cid:173)
`hypercension, and in users of higher dose
`ces were observed comparing second and
`similar analysis of t:b.e General Pracri~
`:reC[ no difference in suoke risk comparing
`
`on data on srroke come from the same
`. the publications on venous thromboem(cid:173)
`Nere published as two separate reports, one
`:r on hemorrhagic saoke. 113
`' In addition,
`11
`•
`ic progesci.ns could detect no differences
`containing desogestrel or gesrodene with
`rgestrel."S
`
`<on.trol srudy from 2 1 ce.orers in 17 coun(cid:173)
`sc.hemic suoke, 141 from Etuope and 556
`"he overall odds ratio for ischemic suoke
`sed risk In Europe, however, rhe risk was
`tigher-dose productS, and NOT statistically
`s chan 50 )lg ethinyl esrradiol. In develop(cid:173)
`t ere.nce in risk with low-dose and h.ighe.r
`believed w be due to the strong influence
`ms uncommon for women with a h.istory
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 41
`
`

`
`A Clinical Guide for Contraception
`
`Incidence of Stroke in Reproductive Age Women 105
`,
`
`109
`,
`
`113
`'
`
`114
`
`I
`
`Incidence of
`ischemic stroke
`
`5 per 100,000 per year
`
`1·3 per 100,000 per year in women under age 35
`
`10 per 100,000 per year in women over age 35
`
`... ...
`
`Incidence of
`hemoiThagic stroke
`
`6 per 100,000 per year
`
`Excess cases
`per year due to
`OCs, including
`ST1Wkers and
`hypertensives
`
`2 per 100,000 per year in low-dose OC users
`
`1 per 100,000 per Ye3I in low·dose OC users under age 35
`
`8 per 100,000 per year in high-dose users
`
`Arteriallhrombosis- Current Assessment
`There has bee.n no evidence wich respeccable staristical power thac the new
`progescins have an appreciable difference in ris.k for ancrial disease, an
`event that is NOT increased wich low·dose older type progestin oral
`conrracepcives. It is possible char as these studies continue and acquire
`gre::H<:r statistical power, a difference will emerge, but even if this is the
`case, chc difference in actual incidence will be minor and likely tuunea·
`sureable. Conclusions based on a limited number of cases are prem;;~cure,
`and a. critical accicude toward arterial chrombosis is appropriate jusr as such
`an approach fioa.lly revealed explanations for me initial findings with
`venous thrombosis.
`
`Most imporran.cly, che new srudies fail ro find any substancial risk of
`ischemic or hemorrhagic scroke with low-dose oral contracepcives in
`healthy, young women. The WHO study did find evidence for au adverse
`impacr of smoking in women under age 35; the Killer S"tudy did not. This
`difference is explained by the confounding dfccr of hypcnension, chc
`major risk factor identified. In ilie WHO srudy, a history of hypenension
`was based on whether a paciem reported ever having bad !Ugh blood pres(cid:173)
`sure (ocher chan in pregnancy) and nor validated by medical records. In the
`Kaiser srudy, women were classified as having hypertension if they reported
`using antihypertensive medication (less than 5% of oral contraceptive users
`had neared hypertension, and there were no users of higher dose producrs).
`In the WHO srudy:, the effect of using ora.! comracepcives irt rhe presence
`of a high-risk factor is appa.rem in che different odds ca.cios when Emopean
`women who received good screening from clinicians were compared with
`
`women in developing countries
`more women wich cardiovascular
`using oral comraccpcives.
`
`Over the years, chere has been rea
`oral contraceptives over the coun!
`in the WffO reporc make ao im
`The increased risk of myocardial
`ing councries where 70% of the
`from a non..din.ica.l SOllfce. Depri•
`cula.r risk factors in developing co
`an:e.rial thrombosis.
`
`Oral contraCeptives containing f,
`increase the risk of myocardial inj
`women, regardkss of age. The effec
`as we have long recognized, nor d.
`Afi:er age 35, rhe subtle presence .
`bur the Kaiser scudy indicates tb:;
`selves have urtle inlpacc on ilie risl
`llSers. The screening of patients in
`ing in few women with hypenen
`studies indicate that hypertension
`rega.rds to the risk of stroke. Ccrcai
`sion should nor liSe oral contra.cef
`have believed that wcli·ueated hYJ
`cion for oral contraceptive use. 1
`problem because ir is impossibl.
`paciencs in the stUdies into groups
`treatme.nr. Nevertheless, the ourst
`com.raccpcives io these srudies sup
`comraceptives in rrcared and well·
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 42
`
`

`
`Oral Contraception
`
`women in developing countries who received little screening; therefore,
`more women with cardiovascuLar risk f.Iaors in devdopiog countries were
`using oral coniiaceprives.
`
`Over the years, there has been recurring discussion over whether to provide II
`
`oral conrracept!ves over the counter on a non-prescriprion basis. The data
`in rhe WfiO report make an impressive argument against such a move.
`The increased risk of myocardial infarction was most evident in develop-
`ing countries where 70% of me cases received their oral concraceptives
`from a non-clinical source. Deprived of screening, women wicb. cardiovas-
`OJ.lar risk &cw~ in developing countries were exposed to a grearer risk of
`arterial thrombosis.
`
`•
`
`0Tol contraceptives containing less than 50 }Jg ethinyl estradiol do not
`increase the risk of myocardid infarction or stroke in healt.hy, nonsmoking
`women, regardkss of age. The e.ffecr of smoking in women uoder age 35 is,
`as we have long recogrUud, nor det=hle in the absence of hyperrension.
`After age 35, the subrle presence of hyperteos.ion makes analysis difficult,
`but the Kaiser srudy indicates char increasing age and smoking by ¢em(cid:173)
`selves have Licrle impact o.n che risk of suoke in low-dose oral conrraccprive
`users. The screening of patients in the Kaiser program was excdlenr, result(cid:173)
`ing in few women with hypertension using oral conc.racepcives. The new
`studies indicate that hypertmsum should be a major concern, especially in
`regards to the risk ofstrolu. Ccrcainly, women with unconuolled hyperten(cid:173)
`sion should not use oral contraceptives. Generally, fam.i.ly planning c::x:perts
`h.ave believed r.hac well-rreaced hypertension should not be a contraindica(cid:173)
`tion for oral concracepcive use. The new data do nor hc::lp us with this
`problem because ic is impossible to accuratdy categorize hypertensive
`pa.cients in the srudies into groups representing successful and unsuccessful
`aeacrnent. Neven:hdess, the oumandiog safety of low estrogen dose oral
`contraceptives in these srudies supports the continued use of low-dose oral
`contraceptives in created and well-coucrollc::d hyperrensive women.
`
`.ductive Age Women 105
`
`09
`113
`•
`'
`
`·'
`
`114
`
`:r year
`
`per year in women under age 35
`
`per year io women over age 35
`
`e.r year
`
`er year io low-dose OC users
`
`er year in low-dose OC users under age 3 5
`
`cr year in high-dose users
`
`·rent Assessment
`h respectable stacistical power rhat the new
`c:liffereoce in risk for arterial disease, an
`wirh low-dose older type progestin oral
`tat as rhese studies conrinue a.od acquire
`:renee wiU emerge, bur even if chis is the
`1cidence will be minor and likely unmea-
`a limired number of cases are premarure,
`:erial thrombosis is appropriate just as such
`:x.plaoacions for the inicial findings with
`
`udies fail w ft.nd any substantial risk of
`ke with low-dose oral conuacepcives in
`HO srudy did find evidence for an advcrse
`nder age 35; che Kaiser study did not. This
`confounding effect of hypertension, the
`:he WHO scudy, a history of hyperrensioo
`reponed ever having had high blood pres(cid:173)
`nd not validated by medical records. In the
`Sed as having hypenension if they reponed
`on (less than So/o of oral coouaceprive users
`1ere were no users ofhighu dose produces) .
`,f using oral conuacepcives in rhe presence
`in t:he different odds ratios when European
`ening from clinicians were compared with
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 43
`
`

`
`A Clinical Guide for Contraception
`
`Estimated Annual Cardiovascular Mortality Rates Associated with
`Oral Contraceptive Use and Smoking Compared with Pregnancy
`
`Cardiovascular
`mortality rate
`per 100,000
`
`Cardiovascular
`mortality rate
`per 100,000
`
`70
`60
`so
`40
`30
`20
`
`Age
`
`After Schwing! P; et al 116
`
`Smoking. Smoking continues to be a difficult problem, not only for
`pacienr management, but for analysis of data as well. In large U.S. surveys
`in 1982 and 1988, the decline in me prevalence of smoking was similar in
`users and nonusers of oral. conrraccpcioa; however, 24.3% of 35- w 45-
`yea..r-old women who used oral contraceptives were smokers!m In chis
`group of smoking, oral contraceptive-using women, 85.3% smoked 15 or
`more cigarettes per day (heavy smoking). Despite che widespread reaching
`and publicity rhac smoking is a contraindication to oral contraceptive use
`over che age of 35. more older women who use oral comracepcives smoke
`and smoke heavily, compared wich young women. Thi.s srroogly implies
`chat olde.r smokers are less than honest with clinicians when requesting oral
`contracepcion, and further raises serious concern over how well chis
`confounding variable can be conuolled io case--concrol and cohort studies.
`A former smoker must have stopped smoking Jo,. at least 12 consecutive
`months to be regarded as a nonsmoker. \'%men who have nicotine obtained
`from patches or gum in their bloodstreams should be regarded as smokers.
`
`Lipoproteins and Oral Contraception. The balance of escrogen and
`progestin potency io a given oral concracepcive formulation can potencially
`influence cardiovascular risk by its overall dfecr on lipoprotein leveJs. Oral
`
`conrraceprives wiili rclacively high
`wday's low-dose formulacions)
`changes. m T he levonorgestrel rri!
`HDL-cholestero1, LDL-cholestero
`increase io apoprorcin A, while clu
`combination has a tendency to io
`B, and m decrease HD~olesreJ
`desogesud p ills have a favorable d
`uiphasic norgescimarc and gescod
`acions in rhe LDL:HDL and apo1
`rhe triphasic levonorgesu-el pills, [
`significant impacc on the lipopr·
`sum77!Llry, stwlw of low-dose fonnu
`prog~tins are Limited to the fo
`levonorgm-rel that exceeds that in th
`tion mat contains 100 pg levor
`produces short-term changes in rl
`seen with other low-dose oral con'
`levels revert to rhose obseiYed ar b
`
`An important srudy in monkeys i
`againsr atherosclerosis, bur by a 1
`cerol-lipoprocein profile. Oral. adm
`aod progescin to monkeys fed
`decreased the extent of coronary
`HDL-cholesterol levels. 1'->-127 In st
`ueatmem markedly prevented art·
`In considering chc impact of pcogc
`neCCSSdrily atherogenic if accomf
`These animal srudies he! p explair
`which had an adverse impacr on
`subsequent cardiovascular disease
`protection through a direct elfecr <
`e:ncing vasomotor and plarde[ fact
`
`Tnis conclusion is reinforced by a
`women wirh myocardial iofarcri<
`have less diffuse arherosderosis tb
`srudy indicated chat the risk of r
`older, high-dose levonorgesrrel-cot
`experienced with pills containing
`
`In the past decade, we have been s
`abom the imponance of the imp:
`te.rol-lipoprotein profile. lf ind<
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 44
`
`

`
`·;,.._
`. •: ',.
`
`'
`
`--;,·
`
`.
`
`'
`
`·r·
`
`•
`
`• l ~-•
`
`~~
`I
`I -,
`
`I
`l
`I
`l I
`I
`i
`I
`I
`I
`!
`I
`
`ortality Rates Associated with
`ng Compared with Pregnancy
`
`CardiovasCJ.Jiar
`mortality rate
`per 100,000
`
`70
`60
`50
`40-
`
`30
`20
`10
`0
`3<- 4~4
`.>,39
`30'34
`<~9
`<o. .. 2
`Age
`ls_
`4
`19
`
`After Schwing! P, ct al" 6
`
`be a difficulr problem, nm only for
`sis of dara as weU. In large U.S. surveys
`lC prevalence of smoking was similar in
`:eprion; however, 24 .3% of 35- to 45-
`:onrraceprives were smokers!"' In rills
`.ve-usiog women, 85.3% smoked 15 or
`·king). Despire me widespre-ad teaching
`n.rraindicacioo to oral contraceptive use
`nen who use oral contraceprives smoke
`1 young women. This strongly implies
`1tst with dinicians when requesting oral
`serious concem over how well this
`)Ued in case-control and cohort studies.
`·ed smoking for tit least 12 consecutive
`ker. Women who have nicotine obtained
`lstreams should be regarded as smokers.
`
`ception. The baknce of esrrogeo and
`maaceprivc formulation can potentially
`overall effecr on lipoprorein levels. Oral
`
`Oral Contraception
`
`conrracepcives with rdacivdy high doses of progestins (doses not used in
`today's low-dose formulations) do produce unfavorable lipoprotein
`changes."' The levonorgesrrd triphasic exen:s no significant changes on
`HDL-cholesrerol, LDL-dwlesterol, apoprotein B, and no change or an
`increase in apoprocein A. while the higher dose levonorgesrrd monophasic
`combination has a tendency co increase LDL-cholesrecol and apoprotein
`B, and co decrease HDL-cholescerol and apoprorein A The monophasic
`desogesrrd pills h.ave a favorable effect on the lipoprotein profile, while the
`triphasic norgescimate and gesrodene pills also produce beneficial alrer(cid:173)
`arions in the LDL:HDL and apoprorein B:apoprotcin A rar.ios.'J?.m Like
`the triphasic levonorgesrrel pills, norethindrone multiphasic pills have no
`significant impact on the lipoprotcin profile over 6-12 months.1
`>J In
`summary, studies of fow-dou formulmions indicate that the adverse effects of
`progenins arc limited to the fixed-dose combination with a dou of
`levonorgmrel that txeeeds that in r.he multiphasic formulation. The formula(cid:173)
`cion that comains 100 p.g levonotgestrel and 20 p.g erhinyl esrradiol
`produces shorr-cerm changes in the lipid profile that are similar to those
`seen 'tlll'ith other low-dose oral conrracepcives, and with long-term use, the
`levels revert to those observed. at baseline before trearmem."~
`
`An important study in monkeys indicated a protecrive action of estrogen
`against atherosclerosis, but by a mechanism independent of the choles(cid:173)
`terol-lipoprotein profile. Oral administration of a combination of estrogen
`and proges-tin co monkeys fed a high-choleste.rol, atherogenic diet
`decreased the extent of coronary atherosclerosis despite a reducr.ion in
`HDL-cholesterol level.s.'<>-' 27 In somewhaL similar experiments, esuogen
`rreatmenr markedly prevented aneriallesion development in rabbirsY'·130
`In considering the impaa of progestational agents, lowering ofHDL is not
`necessarily atherogenic if accompanied by a significant estrogen effect.
`These animal srud.ies help explain why older, higher dose combinacions,
`which had an adverse impact oo rhe lipoprotein profile did nor increase
`subsequenr cardiovascular disease!~-" The esuogen component provided
`protection through a d.irecr effect on vessel walls, especially .favorably i.n.flu(cid:173)
`encin.g vasomotor and plarelec factors such as nitric oxide and prostacydin.
`
`Ths conclusion is reinforced by angiographic and autopsy srudies. Young
`women with myocardial infaretioos who have used oral contraceptives
`have less diffuse atherosderosis than ooousers.' 1U Jl Indeed, a case-conaol
`srudy indicaced chat the risk of myocardial infarction in patients taking
`older, high-dose levonorgesad-containing formulations is the same as that
`experienced wim pills containing other progesriru.0
`
`In the pasr decade, we have been subjeaed w considerable marketing hype
`abouc the importance of the impaet of oral concraceprives on the choles(cid:173)
`terol-lipoprotein profile. If indeed certain oral coorracepcives had a
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 45
`
`

`
`A Clinical Guide for Contraception
`
`II
`
`n~tive impacr on the lipoprotein profile, one would expect m find
`evidence of atherosclerosis as a cause of ao increase in subsequent cardio(cid:173)
`vascular disease. There is no such evidence. Thus, rhe mechanism of the
`cardiovasculAr complic:arions is undoubredJy a short-term acme mecha(cid:173)
`nism-thrombosis (an esuogen-relared effect).
`
`Hypertension
`Oral conrracepLive-ioduced hypertension was observed in approri.mately
`5% of users of higher dose pills. More recent evidence indicates that small
`increases in blood pressure can be observed even wirh 30 )lg estrogen,
`monophasic pills, including those coma.iniog the new progesrins.
`However, ao increased incidence of clinically significant hypenension Ius
`not been reponed. >lH-'6 The lack of clinical hypertension in mosr studies
`may be due ro the raril}" of its ocCtUrence. The Nurses' Health Smdy
`observed an increased risk of clinical hypertension in current users of low(cid:173)
`dose oral concraceptives, provid.ing an incidence of 41.5 cases per 10,000
`women per year. '17 Therefore, an annual assessment of blood pressure is
`still an important element of clinical swveiUancc, even when low-dose oral
`contraceptives are used. Posaneoopausal women in rhe Rancho Bernardo
`Scudy who had previously used oral contraceptives (probably high-dose
`products) bad slightly higher (2-4 mm Hg) diasrolic blood pte.ssurcs. 138
`Because pasc users do nor demonsrrate differences in incidence or risk
`factors for cardiovascular disease, ic is unlikely this blood pressure differ(cid:173)
`ence has an important clinical effect.
`
`Variables such as previous preeclampsia of pregmncy or previous renal
`disease do noc predict whether a woman will develop hrpc.n:ension on oral
`concraceprion. " 9 Likewise, women who have developed hypertension on
`oral coocraceprion are ooc more predisposed ro develop p reeclampsia of
`pregnancy. Overall, cl1crc is no evjdence thac previous oral conaaceprive
`users have an increased risk of hypertension during a subsequeor preg(cid:173)
`nancy.''~142 The Nurses Health Srudy has indicated chac rece!)[ uscrs for a
`long duration (8 or more years) have a 2-fold increased risk of preeclamp(cid:173)
`sia, a finding based on a small number of cases.'0 These epidemiologic
`associations are hard to esrablish because of the role of underlying hyper(cid:173)
`tension in pregnancy-induced hypertension and the difficulty in assessing
`the efficacy of hypertension screening in oral contracepcive users.
`
`The rn~banism for an effecc on blood pressure during oral contraceptive
`use is thought to involve che renin angiotensin sysccm. The most consisc(cid:173)
`enc find.ing is a marked increase in plasma aogiocensinogen, the renin
`submace, up ro 8 rimes normal values (on higher dose pills). In nearly all
`women, excessive vasoconstriction is prevented by a compensatory
`d ecrease in plasma reo in concencration. If hypertension does develop, the
`
`renin-angiotensinogeu changes
`ping combined oral conrraceptic
`
`One muse also consider the e.ffe
`preexisting hypcn:ension or cu
`control of che blood pressure an<
`che pacienr and her clinician c
`Close follow-up is also indicate.
`renal disease or a strong family
`disease. It seems prudenr co su
`reserve should utilize other meaJ:
`cardiac output and plasma vo!u
`ceptive use (higher dose piUs), p
`
`Cardiovascular Disease- :
`The outpouring of epidemiolo;
`construction of a clinical fonnu
`ing conclusions are consistent w
`
`SUMMARY: Oral Contracepti,
`
`• Pharmacologic esrrogen i
`faccors.
`• Progestins have no signil
`• Past users of ora! contra
`incidence of card.iovascul·
`• All low-dose ora.! wncr:
`type, have an increased :
`wacencrated in the first ·
`venous thrombosis wilb
`lower in the oew srud.i~
`Some have argued that th
`and the healthy user effe
`the lower risk reflects bet
`escrogen doses (although
`.in. .risk associated with CS1
`• Smoking has no effect o~
`• Smoking and esrrogen ha
`arrcrial tlu-ombosis. Wb
`venous and arterial clot!
`flow with a scate of higl
`contrast to the high-fl.ov..
`low fibrinogen and high
`able why these two di
`different ways.
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 46
`
`

`
`otein pro£le, one would ex.peci: to find
`:ause of an increase in subsequent card.lo(cid:173)
`ch evidence. Thus, tbe mechanism of the
`undoubred.ly a shore-term acute mecha(cid:173)
`-relaced effecr).
`
`Jenension was observed in approximately
`. More recent evidence indicates chat small
`1 be observed even with 30 pg esuogen,
`chose containing the new progestins.
`:e of clinically significant hypercension bas
`k of dinica! hypertension in most sruclies
`rs occurrence. 1ne Nurses' Health Srudy
`nical hypertension in currem users of low(cid:173)
`ling an incidence of 41.5 cases per l 0,000
`m annual assessment of blood pressure is
`nica1 surveil1ance, even when low-dose oral
`:nopausal women in the Rancho Bernardo
`d oral contraceptives (probably high-dose
`.2-4 mm Hg) d.iascol.ic blood pressures. oJa
`nonsrr-ate differences in incidence or risk
`:e, ic is unlikdy this blood pressure differ(cid:173)
`:ffect.
`
`eclampsia of pregnancy or previous renal
`1 woman will develop hypertension on oral
`nen w ho have developed hypenension on
`re predisposed ro devdop preeclampsia of
`· cvjdence that previous or-al contrace_pcive
`f hypertension during a subsequenr preg(cid:173)
`Srudy has indicated that recent users for a
`1 have a 2-fold increased risk of preedamp-
`1 number of cases. 141 These epidemioiogic
`h because of the role of underlying hyper(cid:173)
`lypertcnsion and the difficulty in assessing
`ecning in or-al conuacepcive users .
`
`n blood pressure during or-al contraceptive
`:nin angiotensin system. The most consisr(cid:173)
`ase in plasma angiotensinogen, the renin
`\values (on higher dose pills). In nearly all
`iction is prevented by a compensatory
`ncrarion. If hypertension does develop, rhe
`
`Oral Contraception
`
`r~nin-a.ogi~rensinogm changes take 3-6 months to disappear after swp(cid:173)
`pmg combmed oral concraceprion.
`
`One must also consider the effects of oca.l conuacepcives in pacie.nts with
`preexisting hypenension or cardiac disease. In our view, with medical ~~ •
`
`conuol of the blood pressure and close follow-up (at least every 3 monch.s),
`me patient and her clinician may choose low-dose oca.l contraception.
`Close follow-up is also indicated in women with a history of p(eexisring
`renal disease or a strong family history of hyperrension or cardiovascular
`disease. It seems prudent to s~est mar patients with marginal cardiac
`reserve should utilize other means of concraccprion. Significant increases in
`cardiac output and plasma volume have been recorded with oral conrra(cid:173)
`cepcive use (higher dose pills), probably a result of fluid rerencion.
`
`Cardiovascular Disease -Summary
`The outpouring of epidemiologic data in the lase rew years allows the
`consuuction of a clinical formulation that is evidence-based. The follow(cid:173)
`ing conclusions are consistent with me recent reporcs.
`
`SUM.iv1A.RY: Oral Contraceptives a.o.d Thrombosis
`
`• Pharm.a.cologic esuogen increases the production of clotting
`factors.
`• Progestins have no significant impact on clotting factors.
`• Past users of oral contraceptives do not have an increased
`incidence of cardlovascular disease.
`• All low-dose oral conrraceptives, regardless of progestin
`type, have an increased risk of Vt:IlOUS chromboernbo.lism,
`concentrated in the first 1-2 years of use. The actual risk of
`venous thrombosis with low-dose oral contr-aceptives is
`lower iu the new smd.ics compared with previous reports.
`Some have argued that this is due to prefercntial .prescribing
`and the healthy user effecc. However, it is also logical that
`the lower risk reflects b etter scree.ning of pacients and lower
`esuoge.n doses (alrhough there are o.o apparent di1Ierencc.s
`in risk associated v.-ith estrogen doses below 50 fig).
`• Smoking has o.o effect o.n the risk of venous thrombosis.
`• Smoking and estrogen have a.o. additive e.ffect on the risk of
`arterial thrombosis. Why is there a difference between
`venous a.od arterial clotting? The venous system has low
`.flow with a state of high fibrinogen and low platelets, in
`cono:ast to ilic high-flow state of the arterial system with
`low fibrinogen and high platelets. Thus, it is understand(cid:173)
`able why these two different systems can respond in
`d.if:ferenr. ways.
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 47
`
`

`
`A Clinical Guide for Contraception
`
`•
`
`• Hypertension .is a very important additive risk factor for
`stroke iu oral contraceptive users.
`• Low-dose oral cantracepcives (le~ than 50 pg eclllo.yl estra(cid:173)
`diol) do not inqease the risk of myocardial i..ofarcrion or
`stroke in healthy, nonsmoki.ag women, regardless of age.
`• Almost all myocardial infarctions and strokes in oral contra(cid:173)
`ceptive users occur i.e. users of high-dose products, or users
`with cardiovascular risk factors over the age of 35.
`• Arterial thrombosis (myocardial infarction and stroke) has a
`dose-response relationship with estrogen, but there are
`insufficient data to determine whether there .is a difference
`in risk with products that contain 20, 30 or 35 pg ethinyl
`estradioL
`
`The recent studies reinforce the belief thn:t the risks of arterial and venous
`thrombosis are a consequence of the I!Strogen component of combination
`oral contraceptives. Cwren.t evidence does not support an advantage or
`disadvantage for any particular formulation, except for ilie greater safety
`associated with any product containing less than 50 p.g ethinyl estradiol.
`Alrhough it is logical ro expect the greatest safety with the lowest dose of
`estrogen, t:b.e ra.re occurrence of anerial and venous rhrombosis in healthy
`women makes it unlikely that there will be any measurable differences in
`the amibucable incidence of clinical events among low-dose produces.
`
`The new studiti emphasize. the importMtce of good pa.tierrt screening. The
`occurrence of anerial thrombosis is essentially limited co older women who
`smoke or have cardiovascular risk factors, especially hypertension. The
`impact of good screening is evident in the repeated fa.i.lure to detect an
`increase in mortality due co myocardial infarction or scroke in several scud(cid:173)
`ies.""·11'1 Although the risk of venous thromboembolism is slighcly increased,
`the actual incidence is stili relatively rare, and the mon:ality rate is abom
`l% (probably less with oral contraceptives, because enos( dearhs from
`thromboembolism are associated with t!auma, surgery, or a major illness).
`The minimal risk of venous c.hrombosis associated with oral contraceptive
`use does not juscify the cost of routine screening for coagulation deficien(cid:173)
`cies. Nevert:b.eless, rhe importance of this issue is iUuscrared by the
`increased risk of a very rare event, cerebral sinus thrombosis, in women
`who have an inherited prcdisposilion for cloning and use oral comracep(cid:173)
`cives.l5,t.O
`
`q a patient has a close family history (parent or sibliing} or a previous
`episot:k of idiopathic thromboembolism, an evalUEJ.tion to search for an
`underlying abnormality in the coagulation system is wan-anted.?• The
`following measurements are recommended, and abnormal results require
`consulcacioo wich a hemacologist regarding prognosis and prophylaxis. The
`
`.·;
`
`~-
`•,
`
`lise of laboratory rests is long, :
`field, th.e besc advice is to coo:
`congenital defici.mcy is made,
`members .
`
`Hypeccoaguahie Co11.di1
`Antithrombin III defici<
`Protein C deficiency
`Protein S deficiency
`Factor V Lcide.n mutaci<
`Prothrombin gene mut<l
`Auliphospholipid syndr
`
`Combination oral contraceptit
`history of idiopathic venous t1
`have a close family history (pa
`hoembolism. These women ~
`de.ficiencies in imponan.t do
`protein C, protein S, and re
`patient who screens negatively
`still consider ilie use of oral c.(cid:173)
`decision with unknown risks f
`more prudent to conside.r oth•
`for rh.romboembolism that sh<
`acquired predisposition such
`malignancy, and immobility 01
`unless they are very extensive.s
`
`The concbtsion once again is tl
`for healthy, young women. B
`smoking and cacdiovasculu ri.
`women, we can limit, if oor eli.J
`associated with low-dose oral
`emphasize that there is no iow
`with long-cerro use.
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2005, Pg. 48
`
`

`
`> v · r·- .. ~ ·
`
`! I
`
`Oral Contraception
`
`list of laboratory rests is long, and because this is a dyuamic and changing
`field, the best advice is to consult with a hematologist. If a diagnosis of a
`congenital deficiency is made, JCreming should be offired to otlm family
`members.
`
`I
`
`I I I
`l
`l I
`I
`\
`I
`I
`\
`
`I
`
`Hypercoaguable Conditions
`Anticb..rombin lJI deficiency
`Protein C deficiency
`Protein S deficiency
`Facror V Lciden mucacion
`Prothrombin gene murarion
`Ancipbospholipid syndrome
`
`Thromboprulia Screening
`Antithrombin m
`Protein C
`Protein S
`Activated protein C
`resistance ratio
`Activated partial
`thromboplascio time
`Hexagonal activated partial
`tb.roroboplasrin time
`Ancic.ardiolipin antibodies
`Lupus anticoagulant
`Fibrinogen
`Prothrombin G mutation
`(DNA test)
`Thrombin Time
`Homocysteine level
`Complete blood count
`
`Combination oral cont:raceptum is cont:raindicated in women who have a
`history of idiopathic venous thromboembolism, tmd also in women who
`have a close family history (p11.rent or sibli11g} of idiopathic venous throm(cid:173)
`boembolism. These women will have a higher incidence of congeru