Warner Chilcott v. Lupin Ltd., et al.,
`C.A. 11-05048 (JAP) (TJB)
`Warner Chilcott v. Watson Labs.,
`C.A. 12-2928 (JAP) (TJB)
`
`DTX 520
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2026, Pg. 1
`
`

`
`Volume 64
`
`Number 2
`
`August 2001
`
`Contraception
`
`An International Iournal
`
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`
`ORIGINAL Flesenacn An'rrcLEs
`
`Case-controlled study on relevant factors of adolescent
`sexual coercion in China
`
`Cheng Yimin, Kang Baohua. Wang Tieyan. Han Xuejun, Snen Huan,
`Lu Yuren. Han Lihui. Cui Ying, Liu Hua, Yu Wenhuan, Wu Mei,
`Wang Jinying. Zhang Yongmei, and Yu Qiusheng
`
`Randomized trial of oral versus vaginal misoprostol at one
`day after mifepristone for early medical abortion
`Eric A. Schafl. Stephen L. Fielding, and Carolyn Westhoff
`
`Mifepristone followed on the same day by vaginal
`misoprostol for early abortion
`-lelen C. Pyrnar. Mitchell D. Creinin. and Jill L. Schwartz
`
`Immune response of male baboons to testis-specific
`LDH-C4
`Enivin Goldberg. John L. VancieBerg. Mary C. Mahony, and
`Gustavo F. Doncel
`
`Double-blind, rnulticenter comparison of efficacy, cycle
`control, and tolerability of a 23-day versus a 21-day low-dose
`oral contraceptive regimen containing 20 pig ethinyl estradiol
`and 75 [L3 gestodene
`J. Endrikat. M. Cronin, C. Gerlinger, A. Fiuebig. W. Schmidt, and
`B. Diislerberg
`
`Emergency contraception with Multiload Cu-375 SL IUD:
`a multicenter clinical trial
`
`Zhou Liying and Xiao Bilian
`
`REVIEW An'rIcLE
`
`Gel-rnicroemulsions as vaginal spermicides and intravaginal
`drug delivery vehicles
`Osmond J. D’Cruz and -:atih M. Uckun
`
`Omomm. Resenncn An1'ic|.E {CONTINUED}
`Risk of venous thromboembolism from oral contraceptives
`containing gestodene and desogestrel versus levonorgestrel:
`a meta-analysis and formal sensitivity analysis
`Sean Hennessy. Jesse A. Berlin, Judith L. Kinman, David J. Margolis.
`Sue M. Marcus, and Brian L. Strorn
`
`Subject Index Volume 63
`
`I ‘all acldrc
`" .-r oru-ny=Ii_-Jryarir:-‘or
`=
`lI..'p‘¥r'.fibhlJl':RL.illylhl?
`nanuge 10 |)3!5<:rI5 .-r properly as E.
`I
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`lirm any H55 or or v
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`
`n! :l by ii!» III.§i'..i.‘ar_'lure!r
`1932 iPv'tY|'Yl':|lH‘.|'|-CE oi Paperl
`®'"
`Ihin paper met.-Is m-.1 req1JirernP_11'.3 ril ANSI S1_-1n{1.3r{| 233 :8.
`
`.
`
`Contraception is indexed in Bibliography of Beproduction. Biological Abstracts.
`Chemical Abstracts, Elsevier BlOBASE/Current Awareness in Biological Sciences.
`Current Contents, EMBASE/Excerpts Meolca, index Medicus, lnternationalPi1arn1aI-
`ceuticaiAostracts, Berwent Drug File. and Population lndex. Articles are abstracted
`monthly in Core Journals in Obstetrics and Gynecology.
`
`Mylan v. Warner Chilcott
`
`lPR2015-0068
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2026, Pg. 2
`
`

`
` 7KLVPDWHULDOPD\EHSURWHFWHGE\&RS\ULJKWODZ7LWOH86&RGH
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2026, Pg. 3
`
`

`
`100
`
`J. Eiidrikrtt ct tn’. I Conrrrtt-t*p.rioii 64 [2tJtHl 99—.*(J5
`
`the present study, we investigated the effect of prolongation
`of treatment from 21 to 23 days. while shortening the
`hormone-free interval from 7 to 5 days. on the length of
`withdrawal bleeding periods and on intracyclic bleeding
`rates. Moreover. we examined whether the reduction in
`hormone concentration fiuctuations with this new regimen
`
`led to improvement in the general tolerability of the prep-
`aration. As shown in a previous study, the prolongation of
`the intake phase signiticantiy increased the degree of sup-
`pression of ovarian follicle development and resulted in
`lower 17,8-estradiol serum levels.
`
`2. Materials and methods
`
`In the present study, we compared contraceptive efti-
`cacy. cycle control, and tolerability of a 23-day versus a
`21-day OC regimen containing 20 pg ethinyl estradiolF"5
`,u.g gestodene. The study was conducted as a phase III,
`multicenter. double-btind, randomized, study in three Euro-
`pean countries over a period of seven treatment cycles. This
`prospective study was carried out from November 1994 to
`April 1998 at 32 centers in Denmark, the Netherlands. and
`Germany. The study protocol was reviewed and approved
`by all appropriate ethics committees.
`The investigators recruited a total of 832 healthy 18-35
`year old participants to the study, who requested contracep-
`tion for at least 7 months. A total of 806 participants (48T8
`treatment cycles) provided data for the efficacy analysis.
`New OC users and participants who wanted to change their
`OC regimen {switchers} were included in the study. The
`switchers had to observe at
`least one OC—free wash-out
`
`cycle prior to intake of study medication. Other exclusion
`criteria were the established OC intake contraindications,
`
`the use of parenteral depot-contraceptives during the 6
`months before the study began. specified concurrent dis-
`eases, vaginal bleeding of unknown origin, and a history of
`migraine accompanying menstruation. All participants gave
`informed consent prior to their participation in the trial.
`Starting on the first day of withdrawal bleeding period,
`the participants received either 23 or 2]
`tablets of 20 [.Lg
`ethinyl estradiolf75 itg gestodene followed either by 5 or by
`T placebos. The study medications were supplied in calen-
`dar packs. If a participant missed the scheduled intake time,
`she was instructed to take the tablet until up to 12 h after the
`scheduled time. All deviations from the specified intake
`
`regimen were recorded daily in a diary designed for this
`purpose.
`the participants underwent a
`Before treatment began,
`thorough medical and gynecological examination including
`cervical cytology by the Pap-anicolaou method and exclu-
`sion of pregnancy. Also in the Netherlands and Germany,
`routine laboratory examinations (liver enzymes, hemato-
`logic parameters, lipids, creatinine. bilirubin, alkaline phos-
`phatase. total protein and electrolytes) were carried out by
`two central laboratories (The Netherlands: Institute for Pre-
`
`vention and Diagnosis. Leiden; Germany: LKF, Laborato.
`rium ftir Klinische Forschung. Lise-Meitner—Str. Kiel, Ger.
`many).
`The participants were questioned about their cycle length‘
`and withdrawal bleeding patterns before being admitted to
`the study. Cycle control parameters, blood pressure, and
`body weight were recorded during the pretreatment cyc1e_
`treatment Cycles 3 and '1, and in the follow-up phase ofthg
`study.
`In the follow-up phase the participants were re.
`questioned about their general health during the treatment
`phase. Medical and gynecological examinations, including a
`Papanicolaou smear and routine laboratory examinations,
`were repeated at the end of the study.
`Bleeding patterns were documented by the participants
`throughout the stttdy on a daily basis in individual diaries. If
`withdrawal bleeding failed to occur. a human chorionic
`gonadotropin (HCG) test was performed to exclude preg-
`nancy before the treatment was continued. Pregnancies and
`all conditions during the preceding treatment cycles that
`might have impaired the reliability of contraceptive protec-
`tion were noted.
`
`Intracyclic bleeding during treatment Cycles 2-? was
`defined as all vaginal bleeding occurring between cycle day
`4 through cycle day 2! for 21-day regimen and between
`cycle day 6 through cycle day 23 for 23-day regimen.
`Therefore. the intracyclic bleeding assessment period was
`I? days for both regimens.
`lntr-acyclic bleeding was as-
`sessed as either “spotting," bleeding not requiring sanitary
`protection, or “normalr'excessive breakthrough bleeding,"
`bleeding requiring sanitary protection. The incidence of
`sporting and normaliexcessive breakthrough bleeding and
`the occurrence ofamenorrhea (missed withdrawal bleeding}
`
`and dysmenorrhea were included in the efficacy analyses.
`All unfavorable changes in the participant's condition
`were defined as adverse events and were recorded. The
`protocol included a list of adverse events that required study
`withdrawal. These included pregnancy and any evidence for
`an increased thrombotic risk. Treatment compliance. includ-
`ing a record of missed tablets. was monitored on a men-
`struation chart and was assessed by the investigator at each
`of the planned study visits.
`
`2. I. Sttm'.s'tt'cru' tnerh(Jd.\'
`
`Statistical analyses were performed on both the “intention-
`to-treat“ (ITT) and the “valid case" (VC) populations. All
`randomized participants who took at least one dose of t|16
`study medication were included in all ITT population anal-
`yses. All of the data from volunteers who had a major
`protocol deviation were excluded from the VC population
`analyses.
`The study primary target variable was the percent Of
`participants who had at least one intracyclic bleeding cpl‘
`sode from the 2nd to the 4th treatment cycle. The nil”
`hypothesis that the probability of the occurrence of at least
`one intracyclic bleeding episode under the 23-day regime i5
`
`Mylan v. Warner Chilcott
`
`|PR2015-006
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2026, Pg. 4
`
`

`
`J’. Eirdiilat at at’. I Cont:-ace_.on'o:r 64 (200!) 99—l't‘.l5
`
`not less than that under the 21-day regimen during the 2nd.
`3rd, and 4th pill-taking cycles was tested against its alter-
`native that this probability under the 23-day regimen is less
`than that under the 2l-day regimen. The null hypotheses
`was tested by using a Fisher's exact test at a significance
`level at of 5%.
`The Pearl Index was calculated as 1300 times the number
`
`of pregnancies divided by the number of cycles. All preg-
`nancies were included in the calculation, regardless of user
`failure. However, the study Pearl Indexes calculated should
`be interpreted with caution because the precision of the
`indexes is limited due to the sample size of the study.
`Also. an exploratory test comparing the length of with-
`drawal bleeding periods for Cycles 1-6 was performed for
`the two treatment groups. Cycle 7 was excluded because
`start of poslstudy medication prohibited correct deterrnina-
`Lion of length of the last withdrawal bleeding period. For
`each participant the number of short withdrawal bleeding
`periods.
`i.e. those lasting 1-4 days, was determined. Be-
`cause not all participants provided data for the same number
`of cycles,
`the percentage of cycles with short withdrawal
`bleeding periods was computed per participant. The null
`hypothesis that median of this variable is equal for the two
`regimens was tested against its alternative of inequality with
`a two-sided Wilcoxon rank sum test at a significance level
`a of 5%.
`
`3. Results
`
`Of the 832 participants randomized, 806 received med-
`ication as either a 23-day regimen (n = 395; 2533 cycles) or
`a 21-day regimen (n = 411; 2620 cycles). Major protocol
`violations. such as not meeting incl.usion criteria (age >40
`years. obesity. excessive smoking. incorrect wash-out cycle
`for women switching from another OC), prohibited co-
`medication intake or violation of the treatment schedule
`
`(irregular pill-intake) were recorded in 103 volunteers. The
`data from these participants were only included in the ITT
`analysis. The data from 703 participants were included in
`the VC analyses [23-day regimen. n = 342 (2362 cycles);
`21-day regime, It = 361 (2516 cycles)J. The demographic
`Characteristics of both treatment groups were well matched
`at baseline, as shown in Table 1.
`
`3.}. Co.'ttr'rrc'.eptr've efiit'ttc'_\’
`
`In each treatment group, one participant became preg-
`nant during the study medication phase. In the 23-day reg-
`imen group. one participant experienced vaginal bleeding
`and was hospitalized for evacuation. Fetal material was not
`found. but an “Arias-Stella-Phenomenon," a histomorpho-
`lfigical correlate typical either for an abortion or ectopic
`l-lfegnancy, was described by the consulting pathologist. The
`PflI1icipant's ensuing B-HCG blood tests declined rapidly
`from 40 to 0 IUIL. The investigator evaluated the incident as
`
`Table 1
`
`Demographic characteristics at baseline
`
`23-day regimen
`(n=395l
`
`21-day regimen
`tn=4|1l
`
`Mean age (years)
`[range]
`Mean weight (kg)
`{range}
`Mean height (cm)
`[range]
`Smoking prevalence (% ol' subjects)
`Prior OC use (% of subjects)
`Subjects with regular cycles (96)
`Median menstrual duration (days)
`[range]
`
`25.2
`[ 18-35]
`64.0
`[42—95|
`l68.fi
`[l49—l95I
`23.5
`42.3
`93.?
`3
`[I-11]
`
`25.2
`[l5—35]
`64,5
`[42—94]
`163,6
`[l52—|86]
`28.0
`49.9
`95.6
`5
`[2—10]
`
`:1 spontaneously reabsorbed ectopic pregnancy. Also. a par-
`ticipant in the 21-day regimen group became pregnant dur-
`ing the second treatment cycle. Both pregnancies were as-
`sessed as method failures. Based on this data. study Pearl
`lndices of 0.5 were calculated for each treatment.
`
`3.2. C_v(:t'e t'rJntr'm'
`
`Cycle control was good in both treatment groups. The
`cumulative percent of participants with any intracyclic
`bleeding episodes (spotting andfor breakthrough bleeding)
`from Cycle 2 to 4 (primary target) was 36.0% for the 23-day
`regimen and 37.1% for the 21-day regimen (Fig. I). This
`difference (1.1%) was not significant (p = 0.4055"). The
`cumulative intracyclic bleeding rates for Cycles 2-? and
`I-7‘ were similar (Fig. I).
`As the trial progressed. the percent of 23-day regimen
`participants with any intracyclic bleeding decreased from
`42.4% in Cycle 1
`to 14% in Cycle 7, and for the 21-day
`regimen participants from 44.6% to 12.3%, respectively
`(Fig. 2). Overall, in 2 1 .991’: of the 23-day regimen cycles and
`in 22.7% of the 21-day regimen cycles. intracyclic bleeding
`was reported.
`
`The results for spotting were very similar to those for any
`intracyclic bleeding: 21.3% (23-day regimen) and 22% (21-
`day regimen) of all cycles were affected. In about 6% of all
`treated cycles in both groups. normalilexcessive intracyclic
`bleeding was recorded.
`In each treatment cycle, a greater number of 23-day
`regimen participants had shorter withdrawal bleeding peri-
`ods, lasting [-4 days. than in the 21-day regimen group. At
`baseline (pretreatment cycle). 42% of the participants in
`both treatment groups reported withdrawal bleeding periods
`that lasted between 1 and 4 days. The percent of participants
`with withdrawal bleeding periods that lasted l-4 days in-
`creased to 60% in the 23-day regimen group during treat-
`ment (Fig. 3). Short withdrawal bleeding periods ( I-4 days)
`were reported in 55.1% cycles treated with the 23-day
`regimen and in 43.2% of the cycles in the 2l-day regimen.
`An exploratory analysis of the data showed that this differ-
`
`Mylan v. Warner Chilcott
`
`|PR2015-0068
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2026, Pg. 5
`
`

`
`J. Errdrikcrt at oi‘. I Ctrrrtraception 64 (2001 J 99405
`
`a 23-day 20175
`
`I 21-day 20175
`
`5-?
`
`cycles
`
`Fig.
`
`I. Any intracyclic bleeding (W; of participants) (23-day regimen: 11 = 336: 2|-day regimen: n = 360).
`
`ence was significant {p <0.000l). The incidence of long
`withdrawal bleeding periods of >2 days or amenorrhea (0
`days) was negligible in both groups (Fig. 4).
`In the majority of the treatment cycles, the median num-
`ber of bleeding days was 4 days in the 23-day regimen
`group and 5 days in the 21-day regimen group (Fig. 5).
`Both treatments relieved symptoms of dysmenorrhea:
`58.2% (23-day regimen) and 56% (21-day regimen} of
`participants with dysmenorrhea at baseline showed im-
`provement.
`
`3. 3. Tot‘ernb:'.-'r't_v
`
`A total of 113 participants discontinued the study (23-
`day regimen, n = 64; 21-day regimen, n = 49) for various
`reasons. Twenty-four (6%. 23-day regimen) and lo (4%,
`21-day regimen) participants discontinued the study be-
`cause of adverse events (mainly headache, breast tension,
`and nausea).
`In addition to these events, other specific
`reasons for discontinuation included desire to have children,
`
`change of address. lack of efficacy. and loss to follow-up.
`The overall incidence of adverse events reported during the
`
`trial was low in both groups, as shown in Table 2. The most
`frequent events in the 23-day regimen and 21-day regimen
`group were headache (15.2% vs. 16.3%,
`respectively),
`breast tension (7% in both groups), and nausea (5.1% vs.
`4.4%. respectively). Other adverse events occurred in less
`than 5% of participants.
`In each treatment group, three serious (nonvascular) ad-
`verse events were reported. Only one case (spontaneously .
`reabsorbed ectopic pregnancy) was considered by the in-
`vestigator to be probably study drug reiated; all others were
`assessed by the investigators as not being related to the OC
`intake.
`
`-.
`
`The mean study group blood pressure values (systolic:
`117 mm Hg. diastolic: 72 mm Hg) did not noticeably
`change during treatment. However, slightly more partici-
`pants had an increase of >10 mm Hg at the end of study
`(systolic: 23-day regimen 10.6%, 2!-day regimen 11.4%:
`diastolic: 23-day regimen 8.1%, 21-day regimen 6.3%) than
`those with a decrease of ?IO mm Hg (systolic: 23-day
`regimen 8.9%. 21-day regimen 8.5%; diastolic: 23-day reg-
`imen 6.3%, 21-day regimen 5.1%).
`Body weight remained constant throughout the trial for
`
`".123-day 20:75 T-
`
`‘
`
`.1 21-day 20r?5i
`
`cycle
`
`Fig. 2.. Any iutracyclic bleeding (‘its of cycles).
`
`Mylan v. Warner Chilcott
`
`|PR2015-006
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2026, Pg. 6
`
`

`
`J’. Endri.l<aI at at‘. /‘ Crm.rr'ar.'e,o.ft'oii 64 (200!) 99—l'05
`
`Fig. 3. Percent of participants with I-4 withdrawal bleeding days {23—day regimen: n = 321: 2l—clay regimen: n = 352).
`
`most participants in both treatment groups. More than 75%
`of the participants in both groups either maintained constant
`body weight (1 2 kg) or lost weight.
`
`Neither appreciable changes in_mean laboratory values
`over the course of the study nor remarkable differences in
`
`the laboratory values between the two treatment groups
`were found.
`
`4. Discussion
`
`These study results indicate that both the 23-day and the
`21-day 20 gig ethinyl estradiolr".-*5 ,u.g gestodene regimens
`provide reliabie contraception and good cycle control. A
`large data pool
`that
`is available for the 21-day regimen
`_-substantiates these findings [I-35].
`in each treatment group, one pregnancy because of
`method failure was reported. This resulted in an uncorrected
`study Peari Index of 0.5 for each treatment.
`It should be
`
`noted that the total number of cycles in this single study was
`only about one quaiter of the number required to calculate
`ttreliable estimate of the Pearl Index. However, interesting
`
`findings on ovulation inhibition of the 23-day versus the
`21-day regimen were reported by Spona et al. [8]. He found
`superior ovarian suppression with the 23-day compared to
`the 2 [-day regimen. He claimed that shortening the pill-free
`interval could increase the contraceptive safety margin in
`women who use low-dose formulations. This slightly supe-
`rior ovarian activity suppression might not be highly rele-
`vant for compliant users. but could be of particular impor-
`tance for women who tend to miss at least two pills per
`cycle.
`Although the intracyclic hleeclings incidences for both
`regimens were equally low, we found that withdrawal
`bleeding periods were shorter with the 23-day regimen.
`Significantly [p <0.00{ll) more cycles where short with-
`drawal bleeding periods of [-4 bleeding days were reported
`for the 23-day regimen compared to the 21-day regimen. In
`the majority of 23-clay regimen treatment cycles, the median
`number of bleeding days was 4 days and in the 21-day
`regimen group 5 days. We believe that the shorter with-
`drawal bleeding periods would be welcomed by users, es-
`pecially by those who suffer from heavy and profuse with-
`drawal bleeding periods. Adclitionally, blood loss is reduced
`
`If2-3»-day 201751
`ll 21-day 20175
`
`Fig. 4. Length of withdrawal bleeding Hi: of Cycles I-6} t23—day regimen: EDIE: 2l—day regimen: 2|4*J}.
`
`days
`
`Mylan v. Warner Chilcott
`
`|PR2015-0068
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2026, Pg. 7
`
`

`
`J. Erm'r'ikm‘ er at’. I‘ CmI.r:'r:t‘r:_mfmt 64 f.?t'Jt'}i'} .99—H.35
`
`=..23-day_2fJ.F7T5‘
`T .1 21-day 20375
`
`Fig. 5. Length of withdrawal bleeding (Ce o|' Cycles 1-6].
`
`and iron deficiency might be less frequent. Similar findings
`were reported by the Gestodene Study Group 324 [9]. This
`group investigated a 24-day regimen with 15 gig ethinyl
`estradioll60 ,u.g gestodene compared to a 21-day regimen of
`20 gig ethinyl estt'adioli"l5[l ug desogestrel. Those findings
`also showed significantly shorter withdrawal bleeding pe-
`riod lengths, significantly lower bleeding intensity, and a
`significantly shorter time of onset of the withdrawal bleed-
`ing period in the pill-free interval with the prolonged intake
`regimen. Because the preparations used in that study were
`different in two variables tgestodene versus desogestrel. and
`I5 p.g versus 20 ug ethinyl estradiol), it is difficult to assess-
`the extent the prolongation of the intake regimen had on
`their results. Nevertheless,
`the Gestodene Study Group
`[9,l0] provided evidence that prolongation of length of
`intake might facilitate additional ethinyl estradiol and pro-
`gestin dose reductions.
`Virtually no cliffe1'ences between treatment groups were
`found in the safety parameters measured in the study (i.e.
`gynecological status, blood pressure, body weight, and lab-
`oratory parameters). Overall, T5‘/ca of participants in both
`groups maintained their body weight or lost weight during
`
`Table 2
`
`Percentages of subjects experiencing various adverse events for the lirst
`time during treatment (at least once]
`
`Adverse event
`
`I-leadaclie
`Breast tension
`Nausea
`Depressive moods
`Dizziness
`
`Vomiting
`Nervousness
`Change of li|Ji:.1o
`Acne
`EtJt:1't1t-.t
`
`Varicose complaints
`
`23—t|ay regimen
`in = 395,1
`
`2|—da_v regimen
`(n = 41!}
`
`I53
`'.-'.|
` . I
`2.8
`0.8
`
`3.3
`0.3
`0.8
`2.8
`0.5
`
`0.0
`
`I63
`7.0
`4.4
`L5
`L5
`
`4.4
`0.8
`{L5
`21.2
`[}.U
`
`0.2
`
`the seven treatment cycles. Clinicaliy relevant differences
`between the two regimens in the tolerabiiity analysis were
`not found. Therefore the hypothesis that reduced hormone
`concentration fiuctuations in the regimen with a shorter
`pill—Free interval could improve tolerability was not substan-
`tiated. At the same time, obvious increases in the frequency
`of adverse events because of the prolongation of the intake
`phase were not found.
`in conclusion, both the 23-day and the 2|-day low—dose
`OC regimen (20 pig ethinyl estradiolr'75 lug gestodene}
`provided reliable contraception. acceptable cycle control.
`and good tolerability. We found that the length of with-
`drawal bleeding period with the 23-day regimen was favor-
`ably shortened. The superior ovarian suppression of this
`regimen was investigated in another study [8]. Additional
`studies with prolonged intake regimens should examine
`whether this could be particularly advantageous for women
`who tend to miss tablet intake.
`
`Overall. these results indicate that the development of
`prolonged intake regimens for OCs is a promising option to
`further improve the acceptance of this modern form of
`contraception.
`
`Acknowledgments
`
`We especially thank Ms. Angelika Herzog and Ms. Bar-
`bel Wilke for their contributions and professional assistance
`in the conduct of this study.
`
`References
`
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`gation into efficacy. cycle control and lolerability of a new low—dtiHC
`monophasic oral contraceptive containing gestodene. Gynecol F.n:lo-
`crinol
`l‘-J96:l0:33—9.
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`[El Gast K. Gruhb G. A review of cycle control with a low-dose orill
`contraceptive containing 75 pg gestodene, and 20 ug ethinylestr:1-
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`|99li‘.|2(Sopp| 3):3I-1
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`Mylan v. Warner Chilcott
`
`|PR2015-006:‘
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2026, Pg. 8
`
`

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`[5| Basil S. Alvarado A. Cclis C. et al. Latin America experience with
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`[7] Hire RC. Banaicunerschult R. Fmt—Kuchenbccker P. Turck R. Bn'l| K.
`Large observational trial of .1 new |ow—dosc oral contraceptive con-
`taining
`20 Ug
`ctltinylestradlol
`and
`IUU Lfg
`Ievonorgcstrel
`(MlI'il110\'u‘F’l in Germany. EurJ Contracep Reprod Health Care I999;
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`Spuna J. Elstein M. Feichtinger W. et ul. Shorter pill-free interval in
`combined oral contraceptives decreases folliculenr tlevelopntcnt. Con-
`traception l99fi:S4:'Fl—7.
`
`Gestttdcne Study Group 324. Cycle control. safely and efficacy of a
`24-day regimen of gestudene 60 pgfetltittylcstrndiril
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`Contracept Reprod Health C(ll'C |999:~1[SLIpp| 2.1: |?—25.
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`
`Mylan v. Warner Chilcott
`
`|PR2015-0068
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2026, Pg. 9