Jdiioi1a1
`
`U1ua-LovDose
`
`OiaI Contraceptives
`
`Medscap
`
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`corn
`
`To Print Click your browsers PRINT button
`NOTE To view the article with Web enhancements go to
`rticle/408944
`http//wwwmedscape.com/viewa
`
`Ultra-Low-Dose Oral Contraceptives Are They Right for Your
`Patient
`
`Ian
`
`Thorneycroft PhD MD Medical Writer Sophia
`
`Cariati
`
`Medscape General Medicine 34 2001
`
`2001 Medscape
`
`Plaintiffs Exhibit
`11.OO9JAP-rJ
`1-2U$.JAPTJB
`
`PTX 099
`
`Posted 07/03/2001
`
`Introduction
`
`Oral contraceptives OCs are currently
`reversible method of contraception in the
`the most popular
`150 micrograms
`United States The pills first marketed in the United States 40 years ago contained
`to ethinyl estradiol EE By contrast most
`mcg of
`that metabolizes
`synthetic estrogen mestranol
`This striking reduction in the EE dose
`OCs prescribed today contain 35 mcg or less of EE Figure
`side effects
`of adverse cardiovascular
`was prompted primarily by efforts to reduce the incidence
`
`Medscape
`
`www medcape om
`
`140
`
`120
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`100
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`10
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`

`
`Editorial
`
`Ulua-LowDosc Oral Contraceptives
`
`Figure
`
`Declining hormone levels in OCs
`
`35 mcg EE provide the same level of
`Studies have established that so-called low-dose pills
`contraceptive efficacy as their higher-dose forerunners but are associated with
`lower risk of venous
`thromboembolism VTE stroke and myocardial
`producing OCs with progressively lower doses of estrogen the first OC containing 20 mcg EE was
`introduced in 1973 and promoted for women with
`because
`disease
`high risk of cardiovascular
`smoking or age Recently other formulations
`containing 20-mcg EE have become available
`are advocated for general use
`
`of
`
`and
`
`infarction Ml In keeping with the trend toward
`
`This review is designed to assist clinicians involved in prescribing contraceptive regimens by
`these ultra-low-dose 20-mcg EE 00 preparations
`providing an overview of the risks and benefits
`As clinical
`patient populations to using them as
`practice shifts from reserving these pills for specific
`first-line therapy clinicians should be familiar with the efficacy menstrual cycle control side-effect
`profile and continuation rates associated with low-dose OCs Table
`lists the issues to be
`in determining whether 20-mcg FE 00 preparations should be the new standard
`considered
`
`of
`
`Contraceptive Efficacy
`
`OCs prevent pregnancy through
`several mechanisms They suppress ovulation by decreasing
`of estradiol and
`secretion which results in diminished cycling concentrations
`gonadotropin
`causes the cervical mucus to become viscous and virtually
`progesterone The progestin component
`by spermatozoa OCs also inhibit endometrial proliferation
`
`impenetrable
`
`the number of pregnancies
`is measured by assessing
`Contraceptive efficacy
`using OCs Transvaginal ultrasonography
`can be used to examine follicle-like
`ovulation occurs when the follicle is 18-20 mm in diameter
`
`that occur
`
`in women
`
`structures Generally
`
`is of utmost concern when
`For healthcare providers and consumers alike contraceptive efficacy
`choosing an 00 The dramatic decline in steroid hormone doses has caused some concern
`00 preparations to prevent pregnancy Numerous studies
`regarding the ability of these combination
`however have demonstrated that OCs containing 20 mcg of EE combined with gestodene
`inhibit ovulation and decrease cervical mucus scores
`desogestrel or levonorgestrel effectively
`
`But
`
`is the contraceptive efficacy of
`to that provided by the numerous
`these newer products equivalent
`tried and true 30135-mcg preparations available Rosenberg and colleagues shed light on this
`20-mcg EE products Alesse Mircette to
`35-mcg EE
`issue by comparing the efficacy of
`randomized trial of 463 women Contraceptive efficacy
`formulation Ortho Tri-Cyclen
`in an
`differ between
`pregnancies occurred
`the treatment groups In all
`in Tri-Cyclen users
`Index rates were 4.4 1.5 and
`Alesse user and none among Mircette users Corresponding Pearl
`Index is defined as the number of unintended
`0.0 per 100 woman-years of use The Pearl
`is the number of pregnancies
`pregnancies per hundred women per year -- that
`months of use
`
`in
`
`did not
`
`in 1200 observed
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`
`Editorial
`
`UliraLow-Dose
`
`Oral Contraceptives
`
`20-meg EL pills Alesse Levlite
`Reisman and colleagues similarly compared
`the effects of
`or TriNovum preparations in 167 women for
`Loette to that of 35-meg EE Ortho-Novum 7/7/7
`cycles Their results also demonstrate that 20-meg EL preparations provide equivalent contraceptive
`reliability to that obtained with an OC containing 35 mcg EL
`
`or
`
`to
`
`combination OC containing 100 mcg
`Archer and colleagues recently
`evaluated
`the efficacy
`and 20 meg EE Alesse in 1708 women Over the course of 26554 menstrual cycles
`levonorgestrel
`Index of 0.88 Similarly an 18-month multicenter trial of
`Pearl
`occurred giving
`18 pregnancies
`to be 1.02
`1143 women using Mircette found the Pear Index for total pregnancies during treatment
`the efficacy of 20-meg preparations is
`These and other comparative studies have found that
`the Pearl rates for women
`by 30/35-mcg formulations of OCs.11521 Overall
`similar to that provided
`taking 20-meg EE formulations
`range from 0.2 to 1.0
`
`of
`
`Cycle Control
`
`lower doses of EE has raised the issue
`of OCs with progressively
`The ongoing trend of development
`of whether pills containing 20 mcg of EL can produce normal menstruation-like bleeding patterns and
`products Cycle control
`bleeding rates as low as the higher estrogen-containing
`breakthrough
`of other side effects is the strongest predictor of
`extremely important as it along with the incidence
`woman will use OCs correctly
`and continue with their use.E22-24 In
`whether
`intermenstrual bleeding was associated
`women Rosenberg and colleagues demonstrated that
`.3 and discontinuation RR .9 Other side
`with an increased
`risk of missing pills relative risk
`effects and reasons women discontinue OC use are listed in Tables
`and
`
`study of 6676
`
`is
`
`Although estrogen dose is major determinant cycle control
`by patient
`is most frequently evaluated
`characteristics estrogen and progestin dose and type Cycle control
`are the
`bleeding spotting or both Other indicators
`the percentage of cycles with breakthrough
`of amenorrhea duration of menses mean intensity of menstrual bleeding and cycle
`
`incidence
`
`is also affected
`
`by
`
`length
`
`in women taking 20- and 35-meg EE preparations are limited and
`Data comparing cycle control
`factors affecting
`comparisons of
`true head-to-head
`is due to the lack of
`The variation
`inconsistent
`tolerability and continuation rates in addition to the disparate definitions of abnormal bleeding
`in some studies differ with regard to both estrogen dose and progestin
`Products
`compared
`and phasing However when OC formulations with the same progestin component are
`compared the lower the dose of estrogen the more diminished is the cycle control
`
`component
`
`Rosenberg and colleagues demonstrated the effect of progestins on cycle control by analyzing
`75
`included 15421 cycles among 2767 women One study compared
`data from clinical
`trials that
`30 meg EL while the other compared
`30 meg EE with 150 meg desogestrel
`mcg gestodene
`20 meg EE They found that
`the risk of
`same gestodene preparation with 150 meg desogestrel
`is significantly lower in women taking preparations containing
`intermenstrual bleeding or spotting
`20 meg or
`regardless of whether
`the pills contained
`gestodene than in those containing desogestrel
`
`the
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`Editorial
`
`UltraLowDose Oral ontraceptivec
`
`30 mcg of EE Better cycle control with gestodene preparations has similarly been demonstrated in
`other studies examining combined OCs containing 20 mcg of EE.L2728
`
`half-life than norethindrone1291
`
`formulations.1418301
`
`in differences in cycle control
`Pharmacokinetic differences between progestin types may also result
`For example levonorgestrel has
`various 20- and 30/35-mcg of EE preparations
`between
`difference that may cause the longer
`is greater for levonorgestrel
`In addition oral bioavailability
`levonorgestrel
`in serum
`whereas norethindrone undergoes first-pass metabolism which results in wider variations
`levels and biologic effects
`
`latent period associated with
`
`longer
`
`Taken as whole the data on ultra-low dose pills and cycle control are ambiguous Bounds and
`colleagues studied 555 women in one of the earliest
`randomized trials that compared
`formulation consisting of 30 mcg EE
`containing 20 mcg EE and mg norethisterone
`acetate with
`result of abnormal
`as
`the rate of discontinuation
`They found that
`and 150 mcg levonorgestrel
`the 20 mcg LE preparation 27% than for those
`for women taking
`bleeding was significantly higher
`taking the 30 mcg EE pill 3.7% World Health Organization WHO Task Force on Oral
`rates 23.2% attributed
`found similarly high discontinuation
`Contraceptives133
`20-mcg EE preparation plus 400-mcg
`for women taking
`norethisterone acetate
`other combination OCs Other studies have demonstrated
`intermenstrual
`of
`lower frequency
`compared with 20-mcg EE
`bleeding associated with the use of 30- and 35-mcg EE products
`formulations
`
`to poor cycle control
`
`compared with
`
`pill
`
`recent
`
`and colleagues114 however contradicts these findings They
`randomized trial by Reismann
`levonorgestrel with 20 mcg EE to 167
`in 155 women who took 100-mcg
`cycle control
`compared
`triphasic preparation of 500 750 and 1000 mcg norethindrone with 35 mcg EE
`women who took
`of normal
`the
`Overall cycle control was comparable between
`similar percentage
`groups with
`cycles and cycles with intermenstrual and withdrawal bleeding In the 20-mcg EE group there was
`significantly shorter withdrawal-
`latent period and
`statistically significantly longer
`
`statistically
`
`bleeding episode
`
`20-mcg EE preparation provided
`Similarly Chavez and colleagues demonstrated that
`better
`product containing 35 mcg of EE They compared
`in women taking
`cycle control
`than
`cycle control
`triphasic 500 750 and l000pg
`20 pg EE formulation to those using
`100 mcg evonorgestrel
`in women taking
`69.9% of cycles were normal
`35-mcg EE preparation
`norethindrone
`By cycle
`in those taking the 35-mcg EE
`the 20-mcg EE formulation and only 54.4% of cycles were normal
`.05
`
`preparation
`
`result from the disparate manner in which abnormal bleeding is
`Variations in data on cycle control
`of women bleeding during
`incidence
`is reported in terms of
`defined and measured Typically
`bleeding and
`interval As such there is no differentiation between women with prolonged
`the same weighti34
`
`specific
`
`it
`
`those with minor spotting and any degree of spotting or bleeding carries
`
`Overall however studies that have used the WHO criteria for intermenstrual bleed ing have
`for 100 mcg levonorgestrel plus 20-meg EE
`demonstrated consistent
`rates of cycle control
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`Edliorial
`
`LJliraLowDose
`
`Dial Contiaccpuves
`
`preparations
`
`The total proportion of women who had normal cycles when taking
`
`this formulation
`
`ranged from 64% to 82%
`
`Estrogenic Side Effects
`
`role the frequency of bloating breast tenderness and
`Although cycle control plays an important
`and compliance in OC users Estrogenic side effects are
`nausea also predict satisfaction
`particularly common in new users Their incidence
`population which approach 50% during the first year of use
`
`contributes to the discontinuation rates in this
`
`Many studies have suggested that 20-mcg EE formulations are associated with
`lower frequency
`side effects
`For example results of
`than their higher estrogen-dose
`counterparts
`estrogen-related
`tenderness and nausea were
`randomized trial demonstrate that bloating breast
`recent
`approximately 50% more common in women using the 35-mcg EE as compared with the 20-mcg EE
`the 35-mcg EE
`rates for women taking
`preparations Notably however discontinuation
`formulation were not significantly higher Other studies have demonstrated that
`tolerability profiles of
`ultra-low-dose preparations are better or comparable to those of the 30135-mcg EE pills.M 6171
`
`of
`
`Ultra-Low-Dose Pills and Cardiovascular Disease
`
`Cardiovascular
`The incidence
`
`side effects are the most
`of thromboembolic events
`
`in
`
`important potential adverse events associated with OC use
`is directly related to the dose of estrogen Meade and
`60%
`the EE dose from 50 to 30 mcg resulted
`demonstrated that
`colleagues138
`reducing
`the dose of EE to
`decrease in deaths from cardiovascular events Many assumed that
`reducing
`2Omcg would further diminish the rate of OC-related cardiovascular events Currently however there
`of 20-mcg EE OCs on
`trials to define the influence
`data from large long-term clinical
`is not enough
`number of studies however have
`these formulations on coagulation and lipid profiles Changes in these
`risk of cardiovascular disease
`for increased
`the potential
`
`cardiovascular
`
`disease
`
`and thromboembolic events.39
`
`investigated the effect of
`
`parameters may predict
`
`Lipids and Lipoproteins
`
`number of trials have demonstrated that 20-mcg EE OCs have
`and lipoproteins
`
`than do higher-EE-dose OCs
`
`more favorable effect on lipids
`
`levonorgestrel
`
`the effects of an OC containing 100 mcg of
`For example Young and colleagues evaluated
`and 20 mcg EE on serum lipid concentrations
`years Concentrations
`period of
`over
`total cholesterol high-density lipoprotein HDL cholesterol
`of triglycerides
`low-density lipoprotein
`LDL cholesterol and apolipoproteins A-I and
`were analyzed for 24 cycles in 28 women and
`compared with their baseline levels
`
`in lipid measures were noted they were smaller than those
`Although many significant changes
`reported for OCs containing higher doses of EE.14041 Furthermore all
`
`lipid values
`
`returned to
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`
`Editorial
`
`UltraLowDose Oral Cootraccpt
`
`yes
`
`to many studies of OC preparations
`baseline levels by cycles 12 to 24 of OC use This is in contrast
`remained significantly elevated after 12 cycles
`containing higher doses of EE in which lipid values
`
`the effects of 20-mcg EE and 35-
`between
`Very few studies have made head-to-head
`comparisons
`mcg FE preparations on lipid profiles The limited data however suggest that
`the newer ultra-low-
`dose pills exert comparable effects on these pararneters Reisman
`and colleaguesfl4l compared
`the effect of 20-mcg FE pills with that of 35-mcg FE preparations on serum concentrations
`of
`glucose and urea nitrogen They also compared mean systolic and diastolic
`cholesterol
`triglyceride
`laboratory values the mean changes
`from baseline
`the groups For most
`blood pressure between
`the mean increase in cholesterol concentration
`groups However
`the
`were comparable between
`the 20-mcg EE pill Furthermore many OCs in use today
`less in women taking
`was significantly
`such as desogestrel and gestodene which have been shown to
`contain third-generation progestins
`favorable increase in HDL cholesterol in users Thus 20-mcg EE pills containing these
`exert
`progestins may exert more favorable effect on lipid profiles compared
`containing other progestins
`
`with higher-FE-dose pills
`
`Coagulation and Hemostatic Factors
`
`When taken as whole data on the effects of ultra-low-dose EE OCs on the hemostatic
`system
`suggest that 20-mcg EE OCs exert an influence comparable to the 30135-mcg EE formulations.14751
`the 20-mcg EE preparations have less effect on
`Some studies have demonstrated however that
`
`factors than do OCs containing higher doses of EE
`
`hematologic
`
`double-blind study on the effects of OCs
`Winkler and colleagues conducted
`randomized
`containing 150-mcg desogestrel and either 20 or 30 mcg EE on hemostatic
`parameters in 1633
`months of OC use prothrombin fragment
`D-dimer and protein
`women After
`activity
`activity decreased in both
`in both groups whereas antithrombin-lll
`activity and protein
`increased
`the 20-mcg EE preparations experienced
`significantly lower
`groups However women taking
`from baseline levels This less pronounced effect on hemostasis with the 20-
`magnitude of change
`mcg EE pill may be significant with regard to thromboembolic risk Basdevant and colleagues
`the dose of FE in OCs from 30 mcg to 20 mcg EE minimizes
`similarly demonstrated that
`reducing
`and
`antithrombin Ill protein
`parameters such as plasminogen
`their effect on hemostatic
`
`fibrinogen
`
`Cardiovascular Risks Associated With OC Use
`
`Although
`
`current
`
`low-estrogen-dose
`
`35 mcg OCs are associated with
`preparations
`compared with the older higher-estrogen-dose
`events
`cardiovascular
`stroke However among low-dose OC users cardiovascular
`exist including VTE and ischemic
`occur primarily in smokers and in women with predisposing factors such as hypertension
`diseases
`the 1995 WHO study found that
`relative risk estimates of VTE
`Of note however
`is that
`associated with OC use were unaffected
`history of hypertension excluding hypertension in
`by
`pregnancy or in any consistent way by smoking
`
`lower incidence
`
`of
`
`real risks
`
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`
`Editorial
`
`LIltra_Low_Dose
`
`Oral Contraceptives
`
`Venous Thromboembolism
`
`in OC users independent of the presence of risk
`VTE is the one cardiovascular
`event
`that occurs
`to 35 mcg EE the risk of
`factors Even in women using low-dose OCs containing less than or equal
`VIE is 3-4 times that of non-OC users However
`to note that
`risk estimates are
`generally higher for deep vein thrombosis DVI minor health problem than for pulmonary
`embolism PE The estimated annual
`risk of death due to VIE associated with 00 use is
`risk of VIE associated
`million women.156 Furthermore the annual
`twice as great as that associated with OC use
`
`with pregnancy is approximately
`
`per
`
`it
`
`is important
`
`The 1995 WHO Study examined the risk of
`idiopathic VIE events DVIand/or PE associated
`with OC use in 1143 women aged 20-44 years and 2998 age-matched controls
`in centers across
`Africa Asia Europe and Latin America 00 use was associated with an increased
`risk of VTE in
`Cl 3.09-5.57 and in non-European countries OR 3.25
`Europe odds ratio 4.15
`
`2.59-4.08
`
`Progestin type seems to influence the risk of VIE The 1995 WHO report531
`VIE risk associated with OCs containing
`or gestodene
`third-generation progestin desogestrel
`compared with levonorgestret- or norethindrone-containing OCs The increased
`risk of VIE
`with preparations containing desogestrel and gestodene has been confirmed
`in other
`associated
`body mass index BMI has also been shown to be modifiable risk factor
`
`studies.L56-581
`
`for VIE
`
`Increased
`
`demonstrated
`
`higher
`
`Myocardial
`
`Infarction
`
`Current use of OCs increases the risk of Ml but essentially
`all of the excess risk appears to be
`to cigarette smokers In addition data consistently demonstrate that past use of
`confined
`00 is not associated with any significant
`increase in the risk of cardiovascular disease
`recent
`of 13 studies on past OC use found an estimated relative risk of 1.0195% Cl 0.91-
`meta-analysis
`heart disease
`
`1.13 for coronary
`
`Data from the Royal College of General Practitioners Study show that
`of Ml among nonsmoking current or past 00 users compared
`with non users By contrast
`smoking
`OC users or nonusers had an increased
`risk of Ml
`In addition the risk of Ml was significantly greater
`smokers who used OCs compared with those who did not suggesting
`in cigarette
`interacts with 00 use to further
`increase the risk of Ml
`
`there is no increased
`
`risk
`
`that smoking
`
`study of US women conducted from 1985 to 1988 found similar resultsAmong
`case-control
`women aged 45 or younger OC users who smoked had 30 times the risk of Ml compared with their
`risk of Ml
`nonsmoking counterparts Smokers who did not use OCs had an 8.7 times greater
`risk of Ml compared with nonsmoking OC
`Nonsmoking 00 users however were not at
`increased
`non users
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`Ediioria
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`liRra-Low-Dose
`
`Oral Contraceptives
`
`younger
`
`1998 review of data from case-control and cohort studies also concluded that current 00 users
`risk of Ml Similarly
`than 40 years of age who do not smoke have little or no increased
`between OC use and Ml
`study found no relationship
`case-control
`recent community-based
`nonsmoking users
`
`in
`
`is the risk of Ml
`
`from OC use directly related to other cardiovascular
`
`risk factors aside from smoking
`
`Some data suggest that hypertension may interact with OCs to increase the risk of Ml recent
`
`case-control
`
`study found significantly higher increased
`
`risks for Ml
`
`in low-dose OC users than those
`
`risk factors and inadequate
`to the authors coexistent
`seen in most previous studies.1631 According
`In nonsmoking women who reported having their
`screening were responsible for this inconsistency
`before using OCs the relative risks of Ml were not statistically
`blood pressure checked
`higher than for non-OC users Croft and Hannaford also demonstrated that hypertensive
`rate of Ml compared with normotensive 00 users However
`taking OCs had an increased
`patients
`non-OC users to hypertensive patients who take OCs
`when one compares hypertensive
`is not significantly different
`of MI
`
`significantly
`
`their rate
`
`of Ml or stroke has not been fully
`The effect of third-generation progestins on the incidence
`elucidated Case-control studies of OCs containing these progestins suggest
`these formulations
`but the data are inconciusive.E636768
`than earlier preparations
`carry lower relative risks for Ml
`by smoking status
`to interpret because
`they were not stratified
`addition these data are difficult
`that OCs containing these progestins also interact with cigarette
`smoking
`Nevertheless they indicate
`increase the risk of Mi beyond that associated with smoking alone
`
`that
`
`In
`
`to further
`
`Stroke
`
`DC use has also been shown to increase the risk of stroke Data indicate that women using OC
`risk of thrombotic
`significantly increased
`have
`least 50 mcg of estrogen
`formulations
`containing at
`and hemorrhagic stroke compared with non-OC users Low-estrogen dose 00 users however
`risk of thrombotic or hemorrhagic stroke
`do not seem to be at any increased
`
`in the Royal College of General Practitioners Oral Contraception Study
`An analysis of data collected
`in women using OCs containing at
`least 50 mcg of
`showed that
`the risk of stroke was increased
`number of
`estrogen but not in users of OCs containing 35 mcg of estrogen
`or less Furthermore
`studies have consistently found nonsignificant relative risks for hemorrhagic
`other recent case-control
`stroke in OC users However
`the WHO study does suggest that women older than 35 years of
`age are at an increased risk OC users 35 years and older had an odds ratio greater than
`hemorrhagic stroke compared with the age-matched controls
`
`for
`
`Several
`
`between OCs smoking and stroke risk Han naford
`studies suggest
`synergistic
`in 00 users with
`the risk for fatal stroke was higher
`and colleagues found that
`history of
`1.5-33.0 than in nonsmokers RR 0.3
`0.0-3.0 In former DC
`smoking relative risk 7.1
`users risk for fatal stroke appeared to be higher only among smokers Another study70 found
`stroke The WHO case
`significant effect of smoking in 00 users on hemorrhagic but not ischemic
`
`interaction
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`Editorial
`
`IJItra-Low-Dose
`
`Oral Contl1ccptivcs
`
`control study also suggested cigarette
`the risk of
`ischemic
`stroke
`
`smoking and 00 use had
`
`synergetic effect on increasing
`
`this
`
`relationship
`
`correlation
`
`stroke associated with 00 use however are less clear although
`The data on the risk of
`ischemic
`has been studied for more than 40 years The numerous studies evaluating the
`stroke provide conflicting results Some have shown
`between 00 use and ischemic
`risk in 00 users while others have suggested that past 00 use confers protection
`an increased
`against stroke Some of the difficulty
`conclusions
`from this vast source of data lies in the
`in drawing
`risk factors particularly smoking and
`the published studies were all observational
`fact
`that
`hypertension may not have been equally distributed
`across the groups compared these studies are
`potentially biased
`
`Because
`
`Large studies that adjusted for smoking and hypertension found statistically
`stroke associated with 00 use However Cis were wide making it
`to differentiate between
`no increase and small increases in risk
`
`increased
`
`risks of
`
`ischemic
`
`difficult
`
`insignificant
`
`Johnston and colleaguesl90
`recently conducted
`of 16 studies examining the risk of
`meta-analysis
`stroke with DC use Although
`ischemic
`smaller estrogen dosages were associated with
`lower risk
`stroke for all DOs regardless of estrogen dose The summary
`there was an increased
`risk of
`ischemic
`RR was 1.93 95% Cl 1.35-2.74 for low-estrogen preparations in studies that controlled
`for smoking
`and hypertension
`
`Overall
`
`studies of
`
`Because
`
`conclusive
`
`stroke
`
`low-dose DOs suggest that
`they produce little increase in risk for ischemic
`studies are lacking however one must assume that
`2- to 3-fold increase in
`risk is possible Any increase in risk however should be interpreted
`in the context of absolute risk
`stroke is extremely rare in women of reproductive age An RR of 1.93 due to low-
`because
`ischemic
`estrogen DOs for example would translate
`ischemic
`stroke per year
`into approximately
`per 24000 nonsmoking normotensive women.190
`
`additional
`
`When one interprets the literature it
`is important
`stroke and DOs combine all
`between
`
`relationship
`
`attacks in order
`
`events
`
`for statistical
`
`to keep in mind that most studies examining the
`types of strokes and include transient
`This can lead to confusing
`to achieve enough
`significance
`results In addition in the few studies that separate out specific
`causes the numbers
`often conflicting
`are usually too small to come to any meaningful
`conclusion
`Furthermore biologic plausibility for
`mechanism through which DOs may increase the risk is also lacking except
`in the cases of
`strokes
`thrombotic venous
`
`ischemic
`
`and
`
`Noncontraceptive Benefits of OCs
`
`Although DOs are associated with an increased
`risk of VTE the absolute effect
`is very small with the
`current doses of estrogen and progestin in popular DOs Therefore any additional
`health benefits of DOs
`outweighed by the contraceptive and noncontraceptive
`
`risk is likely
`
`Noncontraceptive
`
`benefits of DOs were originally described
`
`over 10 years ago Recent studies have
`
`httpl/www.mcdscapc.corn/viewarticlc/40O44prin
`
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`
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`WC Ex. 2012, Pg. 9
`
`

`
`Editorial
`
`UlnaLowDose
`
`Oral Contraceptives
`
`tow-dose
`confirmed
`that
`OC users These benefits
`endometrial cancer ovarian cancer
`
`functional
`
`35 mcg of estrogen formulations also bestow these same benefits
`of menorrhagia irregular menses
`include decreased incidence
`ovarian cysts benign breast disease dysmenorrhea
`
`to
`
`and salpingitis Table
`tension iron deficiency anemia osteoporosis
`premenstrual
`Because OCs containing 20 mcg EE have been shown to be effective
`in preventing ovulation j20
`benefits of suppressed ovarian activity
`they should hypothetically maintain the noncontraceptive
`
`Recent studies demonstrate that
`
`low-dose
`
`benefits on users
`
`combination OC use bestows additional
`and colleaguesMO2l
`such as reduced acne and hirsutism.M2lhi2I For example Thorneycroft
`androgen profiles and clinical outcomes associated with OCs containing 20 mcg EE plus
`compared
`Fifty-eight women were randomized to
`or 1000 mcg norethindrone acetate
`100 mcg levonorgestrel
`levels of and rogens and
`cycles of either treatment Both OCs reduced the circulating
`receive
`in their acne
`Furthermore women experienced
`an improvement
`testosterone
`
`bioavailable
`
`randomized trial comparing two 20-mcg FE preparations Alesse Mircette and one 35-
`Similarly in
`acne decreased in users of both 20-mcg EE
`mcg EE preparation Ortho Tri-Cyclen self-reported
`an increase in acne The change
`in intensity of acne
`products whereas Tri-Cyclen users experienced
`even when starters and switchers were
`was more pronounced in starters than in switchers However
`differences in acne intensity were statistically
`combined no product-specific
`
`significant
`
`Conclusion
`
`number of clinicians prescribe 20-mcg FE OCs for the general population of
`As an ever-increasing
`should become the
`women of reproductive age the question arises as to whether
`these products
`the efficacy safety and side-
`this question one must consider
`of care In order to answer
`standard
`compared with those of 30135-mcg FE formulations
`
`effect profiles of
`
`these products
`
`the ultra-low-dose preparations cause fewer estrogenic side effects
`Studies demonstrate that
`rate of continuance
`In addition contraceptive
`users and may thereby provide for an increased
`dose to 20
`is comparable in the 20- and 30/35-mcg FE products Lowering the estrogen
`efficacy
`large tong-term studies are not yet available
`mcg however may impair cycle control Although
`is comparable if not superior to that of the
`the safety profile of these formulations
`seems likely that
`higher-dose forerunners And finally because ovulation inhibition is retained in these products one
`health benefits are retained with OCs containing 20-
`can theorize that
`the numerous nonreproductive
`mcg EE
`
`in their
`
`it
`
`Tables
`
`Table
`
`Should 2Oamcg EE OC Preparations Be the New Standard
`
`Do they preserve
`
`high contraceptive efficacy
`
`hnp//www.rncdscapccom/vicwaiticle/408944_print
`
`JO of 1912/21/2007
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`120231
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`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2012, Pg. 10
`
`

`
`Editorial
`
`ultra-LowDose
`
`Oral Contraceplves
`
`Do they retain nonreproductive
`
`health benefits
`
`Are they as safe as 30/35-mcg EE preparations
`
`Do they have an acceptabie
`
`side-effect profile
`
`Table Why Women Discontinue OCs
`
`Number of Side Effects
`
`j1
`
`Specific
`
`Side Effects
`
`Nausea
`
`Bleeding/spotting
`
`Breast tenderness
`
`Mood changes
`
`Hairgrowth
`
`rRelative
`
`Risk
`
`2.1
`
`.8
`
`1.8
`
`1.7
`
`From Rosenberg and Waugh.M031
`
`Table
`
`Reasons for OC Discontinuance
`
`--
`
`_______
`
`__
`
`rSide Effects
`
`flŁleeding irregularities
`
`Mood changes
`
`enderness
`
`Headaches
`
`12%
`
`5%
`
`4%
`
`httpIlwww.inedscape.conhIVieWartiClCI4QS944_PJitJt
`
`II of 191212112007
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`WC Ex. 2012, Pg. 11
`
`

`
`Editorial
`
`UltraLow-Dose Ora ontraecplives
`
`recommended disconUnuance
`
`No further need for contraception
`
`Method-related
`
`Toohardtouse
`
`Concern about hormones
`
`Too expensive
`
`Other unspecified
`
`From Rosenberg and Waugh.1103
`
`Table
`
`Nonreprocluctive OC Health Benefits
`
`23%
`
`6%
`
`6%
`
`8%
`
`17%
`
`Ovarian/endometrial
`
`cancer protection
`
`Menstrual
`
`regulation
`
`Relief
`
`from dysmenorrhea
`
`Protection against ectopic pregnancy
`
`Improvement
`
`in acne/hirsutism
`
`Decreased risk of benign breast disease
`
`Prevention
`
`of functional
`
`ovarian cysts
`
`Maintenance of bone mineral density
`
`References
`
`Stadel BV Oral contraceptives
`and cardiovascular disease
`Stampfer MJ Epidemiology of oral contraceptives
`Chasan-Taber
`
`EngI Med 1981
`
`and cardiovascular
`
`disease Ann Intern Med 1998
`disease Am Obstet Gynecol 1997
`
`Rosenberg
`
`Palmer JR Sands Ml et al Modern oral contraceptives
`
`and cardiovascular
`
`Lewis MA Myocardial
`
`infarction and stroke in young women what
`
`is the impact of oral
`
`hup//www.rnedscape.corn/vicwarticle/408944_lJrillt
`
`12 of 1912/21/2007
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`120231
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`PM
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2012, Pg. 12
`
`

`
`Edilorial UltraLowDose Oral ofloaceplises
`
`contraceptives Am Obstet Gynecol 1998 pt 2S68-S77
`Sartoretto JN Ortega-Recio JC Clinical evaluation of
`low dosage estrogen-progesterone
`association 100 pg of d-norgestrel and 20 pg of ethinyl estradiol Rev Bras din Terap
`
`Feichtinger
`Fitzgerald
`low dose oral contraceptives
`Crosignani PG Testa
`
`Vegetti
`
`Spona
`
`et al
`
`comparison of the effects of two monophasic
`
`Parazzini
`
`Ovarian activity during regular oral
`
`974
`on the inhibition of ovulation Adv Contracept 1994
`contraceptive use Contraception 996
`Reprod Health Care 1996
`ethinylestradiol Contraception 996
`
`Teichmann
`
`Martens
`
`Bordasch
`
`Petersen
`
`combined oral contraceptive containing levonorgestrel
`
`The effects of new low-dose
`Lorkowski
`on ovarian activity Eur Contracept
`
`Spona
`Feichtinger
`contraceptive containing 100 micrograms levonorgestrel
`
`Wunsch
`
`Brill
`
`Kindermann
`
`Inhibition of ovulation by an oral
`with 20 micrograms
`in combination
`
`OBrien FB Efficacy
`10 Archer DF Maheux
`low-dos