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`Associate Professo
`Department of Obstetrics and
`
`Vickz V Baker; M.D.
`Associate Professor and Director, Division of Gynecologic Oncology,
`Department ofObstetrics, Gynecology, and Reproductive Sciences,
`The University ofTexas Medical School at Houston;
`Clinical Assistant Professor ofGynecology, and Clinical Assistant Gynecologist,
`Division ofSurgery, Department ofGynecologic Oncology,
`The University ofTexas M.D. Anderson Cancer Center, Houston, Texas
`
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`New York, Edinburgh, London, Madrid, Melbourne, Tokyo
`.-"1
`
`M I n v. Warner Chilcott
`|PR2015-00682
`
`y a we Ex. 2032, Pg- 1
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2032, Pg. 1
`
`

`
`Library of Congress Cataloging-in-Publication Data
`Gynecology and obstetrics : a longitudinal approach / edited by Thomas
`R. Moore
`[et al.].
`p.
`cm.
`Includes bibliographical references and index.
`ISBN 0-443-08811-X
`1. Moore, Thomas R.
`1. Gynecology. 2. Obstetrics.
`[DNLM: 1. Women’s Health. 2. Pregnancy. 3. Genital Diseases,
`Female. WQ 200 G997 1993]
`RG101.G937 1998 ‘
`618——-dc20
`DNLM/DLC
`for Library of Congress
`
`93-10566CIP
`
`© Churchill Livingstone Inc. 1993
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system,
`or transmitted in any form or by any means, electronic, mechanical, photocopying, recording,
`or otherwise, without prior permission of the publisher (Churchill Livingstone Inc., 650 Avenue
`of the Americas, New York, NY 10011).
`Distributed in the United Kingdom by Churchill Livingstone, Robert Stevenson House, 1-3
`Baxter’s Place, Leith Walk, Edinburgh EH1 SAF, and by associated companies, branches, and
`representatives throughout the world.
`Accurate indications, adverse reactions, and dosage schedules for drugs are provided in this
`book, but it is possible that they may change. The reader is urged to review the package infor-
`mation data of the manufacturers of the medications mentioned.
`The Publishers have made every effort to trace the copyright holders for borrowed material. If
`they have inadvertently overlooked any, they will be pleased to make the necessary arrange-
`ments at the first opportunity.
`
`Acquisidons Editor: Toni M. Tmcy
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`Copy Editor: Kamely Dahir
`Production Supervisor: Christina Hippeli
`Cover Design: jeanettejacobs
`
`Printed in the United States of America
`
`Firstpublished in 1993
`
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`4
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`|PR2015-00682
`Mylan v. Warner Chilcott
`WC EX. 2032, Pg. 2
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2032, Pg. 2
`
`

`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`II
`
`Fertility Control and
`Contraception
`
`Michael A. Thomas
`
`The use ‘of effective, reversible contraception allows
`sexually active couples to exercise control over their
`fertility. Indeed, approximately 90 percent of fertile
`couples will conceive within 1 year if no contraceptive
`method is used. A key role of women’s health care pro-
`viders is to provide patients with unbiased, objective
`information regarding the advantages and disadvan-
`tages of available contraceptive methods, taking into ac-
`count the couple’s individual social, religious, and polit-
`ical views. The patient’s medical history and risk profile,
`both for unwanted pregnancy and undesired side effects
`of contraception, should be fully considered.
`
`FERTILITY AND CONTRACEPTIVE
`
`CHOICE
`
`The fertility rate, or the number of live births per 1000
`women of reproductive age (15 to 44 years), reached its
`peak in the United States in 1910 (127 per 1000
`women). Subsequently there was a steady decline in
`childbearing until the “baby boom” period following
`World War II, when fertility rates again climbed up-
`Ward, reaching a secondary peak in 1960 (118 per 1000
`Women). With the introduction of oral contraceptive
`pills (OCPS) during the 1960s, fertility rates began again
`to decline, a trend that has continued until the present.
`With a wider array of contraceptive choices (barrier,
`hormonal, and surgical), couples now have increased
`Options in pregnancy prevention and therefore can bet-
`ter time) the occurrence of desired conceptions. This
`freedom, combined with the increased numbers of
`Women in the job force, have contributed to delayed
`' Tlllildbearing and smaller families. The fertility rate pres-
`fintly is 65 per 1000 women.
`According to a 1987 survey, of the 57.4 million
`Women of reproductive age in the United States,
`'72
`
`percent were at risk for pregnancy.‘ Only 93 percent of .
`the women at risk ever use a form of contraception, with
`more unmarried than married women falling into this
`category. The combination OCP is the most commonly
`used single form of pregnancy prevention (32 percent of
`women). Female and male sterilization combined is used
`
`by 36 percent of the population, making it the most
`common form of fertility control. Condoms and vaginal
`barrier methods account for only 20 percent of users.
`However, barrier contraceptives are currently increas-
`ing in popularity and use because of the fear of acquired
`immunodeficiency syndrome (AIDS) -and other sexually
`transmitted diseases. Use of the intrauterine device
`
`(IUD) has also increased as a result of the Food and Drug
`Administration (FDA)’s approval of a progesterone-
`containing device (Progestasert) -and an improved cop-
`per-containing device (ParaGard). It is currently un-
`clear what impact the newer subdermal methods (e.g.,
`the implantable levonorgestrel system [Norplant]) will
`have on contraceptive use patterns, although its conve-
`nience and low failure rate have resulted in a high rate of
`acceptance.
`
`CONTRACEPTIVE EFFECTIVENESS
`
`The ideal contraceptive agent would be one that is fully
`effective, easily reversible, free of both major and minor
`side effects, and acceptable to both partners and that has
`potential noncontraceptive health benefits and causes
`no reduction in fertility potential. Because no ideal con-
`traceptive exists for a sexually active couple, the clini-
`cian must help delineate the potential benefits and dis-
`advantages of a method or combination of methods that
`is most suitable for a particular couple’s level of under-
`standing and life-style.
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`
`l 86 Gynecology and Obstetrics: A Longitudinal Approach
`
`Actual and Theoretical Effectiveness
`The effectiveness of a contraceptive device is usually
`considered under two aspects, theoretical effectiveness
`and use effectiveness. The more important of the two,
`use effectiveness, measures failure rates in actual use,
`which always exceed those expected from the strictly
`theoretical effectiveness. Factors that may affect actual
`versus published rates include (1) individual motivation
`to use a method correctly and consistently; (2) the social,
`cultural, and economic background of the user; and
`(3) the degree of bias and level of competence of the
`investigators who planned and conducted the original
`effectiveness studies. Table 11-1 lists the lowest ex-
`pected and typical failure rates during the first year of
`use of common hormonal and nonhormonal contracep-
`“V6 agents‘
`
`Counseling and Contraceptive Selection
`.
`.
`.
`A woman’s contraceptive needs may vary significantly
`.
`.
`.
`over the course of her reproductive life. Contraceptive
`advice should therefore take account of the patient’s
`individual situation. Effectiveness statistics used in
`counseling should be carefully and objectively deter-
`mined from the literature and applied realistically. Data
`from the National Center for Health Statistics indicate
`that oral contraceptives are the most widely used form of
`contraception among women aged 15 to 34 years? while
`among women aged 35 to 44 years, sterilization is most
`popular (Fig. 11-1).
`There may be a tendency to overlook contraceptive
`issues in women 45 years of age or older, partly because
`' of the increase in certain contraceptive complications
`and side effects in this age group. However, since the
`risk of pregnancy-associated mortality is sharply in-
`80
`V
`
`Table l l-l . First—Year Contraceptive Failure Rates in the United
`Slates
`
`Mell‘°°l
`Chance
`Withdrawal
`Periodic abstinence
`caiendar
`Ovulation method
`SYmPt°the_Tmal
`Posholfulauon
`Spermlcldes
`Condoms
`Spffggcfus
`Nullipamus
`Diaphragm
`Cervical cap
`Intrauterine device
`pmgestasert
`ParaGard
`,
`,
`Contraceptive Pills
`Pmgestin only
`Combination
`Depot medmxyprogesterone
`acetate (Depo-Provera)
`Norplant
`Sterilization
`WOW?“
`Men
`
`'
`
`l0WeSf
`Expecled l%l
`85
`4
`
`TYPlC°l lo/°l
`85
`18
`20
`
`9
`3
`2
`1
`3
`2
`9
`6
`6
`6
`
`2
`0.8
`
`QL1")
`0.3
`
`0.04
`
`0-2
`0.1
`
`21
`12
`28
`18
`18
`18
`
`()_3
`
`0.04
`
`0-4
`0.15
`
`(Adapted from Trussell et al.,7 with permission.)
`
`creased in these patients (nearly 50 times greater for
`women 45 years or older and 10 times as great for
`women aged 40 to 44 years as comparedwitli women
`aged 20 to 24 years), it is important that every men-
`struating woman be offered contraceptive counseling.
`-
`
`
`
`
`
`Percentageusingcontraception
`
`60
`
`40
`
`20
`‘
`A
`O J 1 _.._ &.
`
`4
`
`Sterilization
`Female
`Male
`
`Oral
`contraceptive
`pill
`
`Intrauterine Diaphragm
`device
`
`Condom
`
`Other
`
`B 15-24
`
`25-34
`
`I 35-44
`
`.
`
`Figure l l-l . Contraceptive choices among sexually active women of various ages using contraception. (Data from
`i
`Mosher and Prattf‘).
`
`
`
`lPR2015-00682
`Mylan v. Warner Chilcott
`WC Ex. 2032, Pg. 4
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`.-.
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`1
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`L
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`Mylan v. Warner Chilcott IPR2015-00682
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`
`CONTRACEPTIVE METHODS
`
`Basal Body Temperature
`
`Fertility Control and Contraception
`
`l 87
`
`Natural Family Planning
`
`Periodic Abstinence
`
`Periodic abstinence methods, sometimes termed natu-
`ral family planning, reduce fertility by abstention from
`sexual intercourse during the periovulatory period. This
`:is accomplished by meticulously charting the menstrual
`cycle and observing certain physiologic changes that
`take place during the cycle (e.g., cervical mucus
`changes), from which the most likely time of ovulation is
`inferred. Charting methods include simple charting of
`the menstrual cycle (the so-called rhythm method), daily
`_ observations of basal body temperature (BBT) or cervi-
`cal mucus, or a combination of these methods (symp-
`tothermal charting). All
`these methods of “fertility
`awareness” require a highly motivated couple willing to
`abstain from sexual intercourse for specific portions of
`the cycle.
`Methods of periodic abstinence can be effective in
`preventing pregnancy, but in actual use the failure rate
`of such methods is high, owing to persistent risk taking
`and rule breaking, lack of motivation, dissatisfaction, or
`desire for another method.
`
`
`
`Calendar (Rhythm) Method
`
`‘
`
`The calendar method is the oldest and most widely prac-
`ticed form of natural family planning. Its effectiveness is
`predicated on the assumption that a woman’s most fer-
`tile period occurs 14 i 2 days before her subsequent
`menses. Other variables that influence effectiveness of
`
`the rhythm method are sperm potency duration (up to 2
`to 3 days) and oocyte survival (usually 24 hours). The
`earliest day of abstinence is calculated by subtracting 18
`days from the length of the woman’s shortest cycle; the
`latest day of abstinence is the length of her longest cycle
`minus approximately 11 days. For a typical 28- to 30-day
`cycle, the required abstinence period extends from day
`10 to 19. It is clear, then, that use of the rhythm method
`-eisoptimized by using baseline menstrual calendars for at
`least 8 months in predicting the expected lengths of the
`Cycles.
`
`_.
`
`.
`
`Daily charting of basal body temperature (BBT) involves
`recording body temperature each morning upon awak-
`ening, the time when the temperature of a healthy indi-
`vidual is lowest. In order to reliably and prospectively
`predict the time of ovulation, three to four BBT calen-
`dars should be reviewed. Ovulation is signified by a sub-
`tle drop in BBT, which typically precedes ovulation by
`about 12 to 24 hours. This is followed’ by a sustained
`elevation in temperature (0.5 to 0.7°C) for several days,
`which is thought to be due to the influence of ovarian
`progesterone on the thermoregulatory center of the hy-
`pothalamus. Unfortunately, many factors can alter the
`typical biphasic pattern of the BBT, including illness, jet
`lag, and interrupted sleep?’ Because of these atypical
`patterns and the fact that the rise occurs after ovulation,
`BBT monitoring alone is not the most accurate means" of
`predicting ovulation.
`'
`
`Cervical Mucus
`
`Immediately after menstruation, there is almost no cer-
`vical mucus evident at the external os. As the cycle pro-
`ceeds, usually by cycle day 7 to 9, the mucus becomes
`cloudy, sticky, and somewhat more abundant. During
`the ensuing preovulatory phase, the cervical mucus thins
`under the influence of rising plasma levels of estradiol
`produced by the dominant follicle. Abstinence should
`begin in this period. As ovulation approaches (approxi-
`mately on day 14), the mucus becomes clear, abundant,
`elastic, thin, and slippery, qualities that facilitate sperm
`penetration into the uterus. It is usually during this pe-
`riod that a ferning pattern can be observed when the
`mucus is spread on a microscope slide.
`Physically, periovulatory mucus can be stretched be-
`tween two slides to a distance of 6 cm or greater (spinn-
`barkeit). After ovulation, plasma progesterone levels
`rise, causing the mucus to thicken and become less pen-
`etrable by sperm; intercourse can resume approximately
`4 days later. Factors that may hamper normal cervical
`mucus production and therefore interfere with the re-
`liabilty of this method of natural family planning include
`intravaginal deposition of foreign substances (including
`semen), use of medications, and development of vaginal
`infections.-
`
`Symptothermal Charting
`
`Symptothermal charting combines cervical mucus mon-
`itoring and BBT calendars. A detailed diary of these
`observations must be maintained. Periovulatory absti-
`nence may be discontinued 4 days after peak elasticity in
`cervical mucus or 3 days followingtemperature eleva-
`tion, which is later.
`'
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`|PR2015-00682
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`WC Ex. 2032, Pg. 5
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`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2032, Pg. 5
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`

`
`l 88 Gynecology and Obstetrics: A Longitudinal Approach
`
`Caitus Interruptus
`
`Coitus interruptus (i.e., withdrawal of the penis from the
`vagina before ejaculation), is used as a primary method
`of contraception by 2 percent of couples in the United
`States, especially sexually active adolescents.‘ In other
`developed countries, particularly Turkey and Poland,
`the rate is as high as 30 percent.5
`This relatively unreliable contraceptive method (18
`percent rate of failure among typical users) can be used
`when sexual intercourse occurs unexpectedly and no
`other method of pregnancy prevention is available. Po-
`tential problems with its use include the following:
`
`1. Reliance on the male’s ability to control and time
`ejaculation
`2. Sexual dissatisfaction experienced by the female
`partner secondary to the abrupt termination of the
`act
`
`3. The danger of either premature ejaculation or
`pre-ejaculatory release of sperm in the urethral
`secretions
`
`4. The potential for transmitting or acquiring a com-
`municable disease
`
`Effectiveness of Natural Methods
`
`The first-year failure rate of the various methods of nat-
`ural family planning is approximately 20 percent, with
`the lowest rates in couples using a combination of these
`techniques.*"‘7 It is suspected that individuals who en-
`gage in risk-taking behaviors during their fertile period
`account for most of the “accidental” pregnancies rather
`than those who improperly interpret their records.
`
`Side Effects
`
`There are also data, in both animal and human studies,
`
`to suggest that the use of natural family planning predis-
`poses to a higher rate of fetal wastage and birth defects
`in failures.” In these studies it is theorized that post-
`ovulatory fertilization of an “older” oocyte increases the
`risk of polyspermia, early spontaneous abortions, and
`fetal abnormalities.
`
`Barrier Methods
`
`Condoms
`
`At this time the condom is the only reversible and effec-
`tive method of contraception available for males in the
`United States. Latex rubber condoms provide protec-
`tion against transmission of the human immunodefi-
`ciency virus (HIV) and other sexually transmitted dis-
`eases (STDs). The fear of AIDS and other STDs has
`spurred a 60 percent increase in condom sales over a
`recent 3-year period. Condom use among adolescent
`males more than doubled between 1979 and 1988 from
`21 to 58 percent.” Overall, it is estimated that over 40
`million couples in the world use condoms.
`
`.
`
`In order for the condom to i
`Device and Technique.
`work properly, it must be placed over the erect penis.
`_
`These devices range in length from 7.0 to 8.06 inches
`and in width from 1.75 to 2.13 inches. An empty space of
`approximately 1/2 inch must remain at the tip as a reser-
`voir for ejaculated sperm (some brands are made with a
`preformed reservoir tip). They can be tapered around
`the glans of the penis or straight, ribbed (to heighten
`vaginal stimulation) or smooth, lubricated or n0nlubri-
`cated, and colored, transparent, or white. The lubri-
`cants are made either from “dry” silicone oil, wetjellies,
`or dry powder. Some lubricants contain spermicides,
`which have been shown to be helpful in reducing the risk
`of transmission of the AIDS virus. The material used in 1
`
`percent of condoms sold is lamb intestinal cecum, but
`transmission of HIV through these condoms is possible
`because of the porous nature of this more “natural”
`material.
`
`Effectiveness. The average first-year failure rate for
`the typical condom user is about 12 percent,5 although
`some investigators believe that the first-year rate among
`more “perfect” users is 2 percent. Failure is most com-
`monly associated with condom breakage rather than
`with inadvertent spill of semen. Breakage occurs more
`commonly during anal intercourse (one condom rup-
`ture in approximately 105 acts of intercourse) than dur-
`ing vaginal intercourse (l in 165). Certain vaginal medi-
`cations or lubricants can weaken the composition of
`latex condoms and thereby predispose to breakage.“
`These include petroleum jelly, estrogen creams, anti-
`candidal products, and certain spermicides.
`
`The Female Condom
`
`Two different versions of the so-called female condom
`
`have been developed, but they are not in wide use
`currently. One model is fastened around the woman’s
`waist. A compacted condom is located in a pouch near
`the area of the vaginal introitus. When the penis enters
`the vaginal vault, it pushes the pouch up into the vagina.
`The other version of the female condom consists of a
`
`polyurethane cylinder with an inner ring that is inserted
`in the vagina (like a diaphragm) and an outer ring that is
`positioned against the labia.
`
`Vaginal Spermicides
`
`There are many spermicidal products (including creams,
`jellies, suppositories,
`film", and foam) on the market
`today, all of which can be purchased over the counter
`without a prescription. They are simple to use and medi-
`cally safe and can reduce STD transmission. The major-
`ity of these preparations contain nonoxynol-9, with 3
`few products in the United States containing 0Ct0XY1’l01'
`Both agents are surfactants, which destroy the sperm
`cell membrane and also act as a physical barrier to sperm
`penetration into the cervix. Depending on the agent and
`
`|PR2015-00682
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`WC Ex. 2032, Pg. 6
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`WC Ex. 2032, Pg. 6
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`
`Fertility Control and Contraception
`
`l89
`
`nol-9,14 no such effects have been documented in
`humans.
`
`Formerly, it was believed that spermicides might play
`a role in the development of fetal malformations. More
`recent studies have demonstrated no increase in either
`
`Down syndrome, hypospadias, limb reduction defects,
`neoplasms, neural tube defects, or trisomies associated
`with spermicide use.”''”‘
`
`The Diaphragm, Cervical Cap, and Sponge
`
`The vaginal diaphragm consists of a rubber dome that is
`circumferientially supported by a firm spring rim. Sper-
`micidal jelly or cream is applied to the internal surface
`and around the rim. The diaphragm is inserted into the
`vagina up to 2 to 3 hours before intercourse. The device
`should be positioned so that the posterior rim rests in
`the posterior fornix and the anterior rim is seated be-
`hind the pubic bone. It should be left in place for at least
`6 hours after intercourse before removal. Because these
`
`devices are avilable in a range of sizes (the size number
`corresponding to the rim diameter in millimeters), they
`must be fitted by a physician. If the disphragm is too '
`small, it will not stay in place; if it is too large, it will be
`uncomfortable when forced into place. Expulsion can
`occur if a Cystocele or uterine prolapse is present. The
`contraceptive effect of this device is dependent on both
`the spermicidal activity of the spermicide and on the
`barrier effect, which helps to reduce the access of sperm
`to the cervix. To optimize its contraceptive effect, the
`diaphragm should be left in place for at least 6 hours
`after intercourse.
`
`Four styles of diaphragms are currently available in
`the United States (Fig. 11-2). A flat or coil spring rather
`than the arcing spring may be effective in reducing the
`frequency of urinary tract infections among some nulli-
`gravid women with frequent cystitis.
`
`@ A
`
`rcing spring
`
`; <
`
` /
`
`Coil spring
`
`Wide seal rim
`
`
`
`Flat spring
`
`Figure l l-2. Types of diaphragms.
`
`|PR2015-00682
`Mylan v. Warner Chilcott
`WC Ex. 2032, Pg. 7
`
`its concentration, they can be used alone or with a dia-
`phragm or condom.
`
`In order to be optimally effective, the
`Technique.
`spermicide must be used with careful adherence to the
`manufacturer’s instructions. The clinician should be fa-
`miliar with aivariety of different products and have sam-
`ples available for patient instruction.
`
`Effectiveness. The first-year failure rate for the
`“typical” user is about 21 percent, but depending on the
`agent, can be as high as 36 percent. These high preg-
`nancy rates are primarily related to inconsistent use
`rather than to failure of the method during use.
`
`
`
`Significant protective action of spermicides against
`gonorrhea and Chlamydia infection has been reported in
`clinical studies. Jick and associates” found that nonox-
`ynol-9 was protective against acquisition of gonorrhea,
`with a relative risk of 0.7 5 (compared with 1.0 for non-
`users). This protective effect, although not infallible, is
`also evident with genital herpes, Trichomonas infection,
`syphilis, and HIV. Moreover, a study by Celentano and
`colleagues,” which controlled for behavioral factors
`such as age at first intercourse, smoking, frequency of
`Pap smears, and visits to gynecologists, found that vagi-
`nal spermicides conferred a significant protective effect
`against cervical cancer as compared with other contra-
`Ceptive methods.
`
`Irritation of the vulva, vagina, or penis
`Side Effects.
`18 a temporary side effect experienced by some sper-
`micide users. Changing to another agent should be
`- ‘attempted before abandoning this method of contra-
`Ception. Although there have been animal studies
`‘documenting liver toxicity and embryotoxic effects with
`hlgh doses of intravaginally administered nonoxy-
`
`Mylan v. Warner Chilcott IPR2015-00682
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`
`l 90 Gynecology and Obstetrics: A Longitudinal Approach
`
`The cervical capis a small, flexible, cup-like device,
`which is self-inserted around the base of the cervix. Prior
`
`to insertion one-third of the inner portion of the cap is
`filled with spermicide. When properly placed over the
`cervix, the cap, like the diaphragm, acts as a physical
`barrier to reduce cervical exposure to sperm. The sper-
`micide provides extra protection by destroying any
`sperm that traverse the protective barrier. The cap
`should be kept in place for at least 6 to 8 hours after
`intercourse before removal. It is not suitable for pro-
`longed wear because of problems with an odor after 72
`hours and because of the theoretical risk of toxic shock
`
`syndrome (discussed below).
`The only cervical cap approved for use in the United
`States by the FDA is the Prentif Cavity Rim cervical cap.
`The Prentif cap has a firm, rounded rim, which has a
`groove that is incorporated around the inner circumfer-
`ence to enhance the seal between the device and the
`
`cervix. Two other caps, Dumas and Vimule, are available
`in other countries.
`
`’ The contraceptive sponge is a small, pillow-shaped
`polyurethane device impregnated with nonoxynol-9. It
`is moistened with tap water and then inserted into the
`upper vagina with the concave dimple placed over the
`cervix. This dimple is designed to increase the chance of
`the sponge remaining in contact with the cervix. The
`other side of the sponge has a woven polyester loop to
`facilitate removal. Once in place, the sponge can provide
`adequate protection for as long as 24 hours. It works by
`releasing spermicide, by providing a barrier between
`sperm and the cervix, and by entrapping sperm in the
`sponge.
`
`
`
`Effectiveness. The effectiveness of the vaginal
`barrier methods is dependent primarily on the user’s
`
`
`
`ability to use the particular method consistently and
`correctly.
`-
`,
`Concurrent studies of the effectiveness of the dia-
`
`A
`
`phragm and cervical cap show no significant differences.
`Bernstein and associates” found the first-year failure
`rate for diaphragm users was 16.7 pregnancies per 100
`woman—years of use versus 17.4 for cervical cap users.
`Other studies have documented rates as low as 2.4 per
`100 woman—years of use with the diaphragm (established
`users).18
`The sponge has a higher failure rate than both the
`diaphragm and cervical cap. This higher rate may be due
`to the “one size fits all” philosophy of the manufacturer.
`McIntyre and colleagues” demonstrated a significantly
`higher pregnancy rate in parous than nulliparous
`sponge users (28.3 versus 15.9 per 100 woman—years of
`use).
`The use of a barrier method with a spermicide signifi-
`cantly reduces the risk of all STDs, including AIDS. One
`study showed that the risk of contracting pelvic inflam-
`matory disease (PID) and subsequent tubal infertility
`with barrier methods was equivalent to that with oral
`contraceptives and approximately half that recorded
`among women using no contraception.” Also, the dia-
`phragm has been shown to reduce the risk of cervical
`dysplasia and/or cancer.
`
`Complications. The use of vaginal barrier contra-
`ceptives is not without risk._Vaginal trauma and ulcer-
`ations have been noted with the diaphragm and cervical
`cap. The diaphragm has been linked to increased fre-
`quency of urinary tract infections, possibly via coloniza-
`tion of the bladder with Escherichia coli from the vagina
`and/or an effect on bladder or urethral competency
`during use.
`' “
`Toxic shock syndrome (TSS) has been reported in
`both diaphragm and sponge users. This is a rare condi-
`tion in which a toxin of some strains of Staphylococcus
`aureus causes a high fever, a sunburn-like rash, myalgias,
`and gastrointestinal symptoms. Death may ensue if toxic
`shock syndrome is unrecognized and untreated. How-
`ever, the studies linking these devices to TSS have many
`shortcomings and do not demonstrate a statistical in-
`crease in relative risk. Nevertheless, it is currently esti-
`mated that approximately 10 cases of TSS can be ex-
`pected for every 1 00,000 women using sponges,” with a
`similar rate theorized for diaphragm users.
`,1
`
`The Intrauterine Device
`
`Prior to 1986 the intrauterine device (IUD) was the con-
`traceptive of choice of 10 million American women, who
`comprised 10 percent of the reproductive-age women
`using contraceptive agents. However, near the end of
`1986 most manufacturers removed their products from
`the U.S. market because of fear of product liability suits
`associated with the extensive litigation among patients,
`
`|PR2015-00682
`Mylan v. Warner Chilcott
`WC Ex. 2032, Pg. 8
`
`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2032, Pg. 8
`
`

`
`necologists, and the manufacturer of the Dalkon
`Shield. Mounting evidence had accumulated in the 1975
`to 1985 period indicating a strong association between
`IUD use and serious pelvic infections resulting in infer-
`tility and/or hysterectomy. The Dalkon Shield was im-
`plicated most notably, possibly because its polyfilamen-
`mug string may have served as a wick for
`the
`introduction of pathogenic *'organisrns into the uterine
`cavity. The medical reports "stimulated extensive and
`frequently sensational media coverage,
`leading the
`manufacturers of other, more popular IUDs such as the
`- Lippes Loop and the Copper-7 to discontinue produc-
`tion. Despite its infamous reputation, the Dalkon Shield
`is believed by some investigators to have no greater asso-
`ciation with salpingitis and related pelvic infections”
`than other IUDs.
`
`A reanalysis of data from the Women’s Health Study,
`a-case control study comparing 657 women hospitalized
`for PID with 2,566 women hospitalized for nongyneco-
`logic conditions between 1976 and I978, revealed that
`women whoused the IUD did indeed have an elevated
`risk of PID as compared with women who used other
`gcontraceptive methods.” Moreover, most of the risk was
`associated with the Dalkon Shield. The reanalysis also
`showed that the relative risk of PID is more strongly
`related to behavior (particularly the number of sexual
`partners) than to the IUD per se. Today, only two. IUDs
`are approved by the FDA, the Progestasert (a progester-
`one-containing device approved for 1 year of use) and
`the ParaGard (a T-shaped copper device approved for 8
`years of use).
`
`Mechanism of Action
`
`Originally the contraceptive effect of the IUD was
`thought to be associated with its ability to produce in-
`flammatory changes in the endometrium, which inhibit
`implantation. However, more recent studies“ have doc-
`umented additional mechanisms by which the IUD ap-
`pears to work, including interference with sperm trans-
`port from the cervix to the fallopian tube and inhibition
`of sperm capacitation or survival. These effects may be
`linked to the unfavorable cervical mucus produced by
`progesterone-containing IUDs. Although some have
`suggested that the foreign body effect of the IUD within
`the uterus prevents or aborts blastocyst implantation,
`Serial measurements of human chorionic gonadotropin
`(hCG) concentrations in IUD users fail to demonstrate
`implantation. Thus it is doubtful that the IUD serves as
`an abortifacient.25
`‘
`
`The progesterone- and copper-containing IUDs alter
`the biochemical and cellular composition of cervical
`mucus, as well as that of endometrial and tubal secre-
`tions, without interfering with either ovulation or men-
`’ Strual cyclicity. These foreign devices in the uterus also
`result in significant increases in macrophages, lympho-
`Cytes, and plasma cells. The copper device causes an
`
`Fertility Control and Contraception
`
`l9l
`
`endome trial environment that impairs sperm capacita-
`tion and motility; the progesterone-releasing agents may
`alter tubal motility as well as sperm or egg viability in the
`fallopian tube.
`
`Effectiveness
`
`The contraceptive effectiveness of the IUD is based to a
`large degree on its size and shape and the presence of
`copper or progesterone. User characteristics, such as
`age, parity, and ability to detect expulsion, are also re-
`sponsible for differences in its effectiveness. The age
`and parity of the user correlate inversely with the failure
`rate. Patients who are unable to promptly detect partial
`or complete expulsion have higher pregnancy rates. The
`first-year failure rate is 3 percent; however, the lowest
`pregnancy rate with the Progestasert is 2 percent and
`that with the copper-T is 0.8 percent.“
`
`Complications
`
`Irreg-
`Spotting, Cramping, Bleeding and Anemia.
`ular uterine bleeding, severe enough to cause the pa-
`tient to request removal of the IUD, occurs in 15 per- '
`cent of users. Spotting and menorrhagia may result in
`significant anemia over time. Patients should be in-
`formed of this complication prior to initial insertion.
`Use of nonsteroidal anti-inflammatory agents perimen-
`strually provides symptomatic relief and reduces blood
`loss.
`
`Pelvic Infections. Uterine or pelvic infections initi-
`ated by IUD insertion are rare and usually develop in the
`first few weeks. Introduction of pathogenic vaginal or-
`ganisms into the uterine cavity is the primary mode of
`infection. This complication is usually avoided by proper
`patient selection, appropriate preinsertion culturing,
`use of prophylactic antibiotics with insertion in high-risk
`patients, and use of an antiseptic solution to cleanse the
`cervix. Because of the risks of salpingitis, peritonitis,
`abscess formation, and infertility, a suspected pelvic in-
`fection in a woman with an IUD should be agg