1119 Journal of
`“plied Medicine
`1,; the Primary care
`physician
`
`l l&§!i~ir\'rn
`
`University of Wisconsin
`1305 Linden Dl'.,
`lvlndison, Wis, 53706
`
`SEP 23 1887
`
`Renal disease: Managing acute, renal failure 0 When is hematuria a
`cause for alarm? 0 Renal disease‘_r'e1sulting from too much uric acid
`_
`H
`-
`,
`_
`High-carbohydrate, hug‘fi5Fil:’ier'diet‘to‘r treating hyperlipldemia 0 How to
`
`
`
`control persistent nosebleed 0 Oral contraceptives: Who, which,
`
`when, and why? 0 Loss of function in the frail elderly 0 Breast cancer
`
`presenting as periostitis 0 Sportsrelated CNS injuries in children
`Complete contents beginning page 5
`
`Carbohydrates and fiber: Modifying diet to reduce heart disease
`
`--.4
`
`Mylan v. Warner Chilcott |PR2015-00682
`WC Ex. 2014, Pg.1
`
`Editorial
`The rooter man taught
`-me about charging for
`after-hours service
`
`Renal disease
`1947-‘i987
`APGM retrospective by
`H. E. de Wardener, MD, FRCP
`
`Coming in the next issue:
`APGM symposium on
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`Mylan v. Warner Chilcott IPR2015-00682
`WC Ex. 2014, Pg. 1
`
`

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`
`CONTENTS
`
`POSTGRADUATE MEDICINE
`The Journal of Applied Medicine for the Primary Care Physician
`
`SEPTEMBER 15, 1987
`VOLUME 82
`NUMBER 4
`
`
`EDITORIAL
`13
`THE ROOTER MAN TAUGI-IT ME ABOUT CHARGING
`FOR AFTER-HOURS SERVICE
`Glen C. Griffin, MD
`
`Service with a smile, for a price
`
`AT-LARGE
`
`19
`
`HURRAH FOR THE PATIENT!
`J. Mostyn Davis, MD
`
` PHYSlGIAN-
`
`A cheer for those who endure pain, suffering, and the medical
`system
`
`HIGH-FIBER
`DIET FOR
`HYPERLIPIDEMIA
`
`40
`
`HIGH-CARBOHYDRATE, HIGH-FIBER DIET: IS IT
`PRACTICAL AND EFFECTIVE IN TREATING HYPEFILIPIDEMIA?
`James VII. Anderson, MD, Nancy J. Gustafson, MS, RD
`Reduction of coronary artery disease risk through diet
`
`EPISTAXIS
`
`59
`
`EPISTAXIS: HOW TO CONTROL THE PEFISISTENT NOSEBLEED
`Stanton A. Enivin, MD
`
`Methods the physician can use to stop bleeding refractory to home
`[I
`remedies
`I
`__1 I
`ORAL '
`66
`ORAL CONTRAGEPTIVES: WHO. WHICH, WHEN, AND WHY?
`I
`GONTRACEPTIVES
`Edward L. Marut, MD
`'
`
`OPINION
`
`GERIATRIC
`ASSESSMENT
`
`13
`
`75
`
`Answers to questions about "the pill” and discussion of benefits
`
`DEGEPTION
`Selig J. Kavka, MD
`A thought—provoking medical fish story
`
`,
`
`LOSS OF FUNCTION IN THE FRAIL ELDERLY: A METHOD
`FOR DETERMINING THE UNDERLYING CAUSES
`Gerald K. Goodenough, MD, MSPH, Lawrence J. Lutz, MD, MSPH
`
`DESIPRAMINE
`TOXICITY
`
`’
`
`86
`
`DESIPRAIIIIINE-INDUCED OONDUGTION DISORDER
`MIMICKING MYOCARDIAL INFARCTION (Case Report)
`Douglas B. Smith, MD, John W Tyznik, MD
`
`A new electrocardiographic finding associated with desipramine
`toxicity
`’
`
`' T '
`‘J I
`*0
`
`POSTGRADUATE MEDIClNE® (ISSN 0032-5481) is published monthly, with additional issues in February. May, September, and November Executive, editorial. circulation,
`and advertising ofticos: 4530 W 77th St, Minneapolis, MN 55435. Telephone: 612-535-3222. Second class postage paid at New York, NY, and additional mailing offices; post-
`age paid at Winnipeg. MB (registration No. 9459).
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`Copyright 1987 by McGraw-Hill, Inc, all rights reserved. Where necessary, permission is granted by the copyright owner for libraries and others registered with the Copyright Clearance
`Center (CCC) to photocopy any article herein for the base tee of $2.35 per copy of the article. Payment should be sent directly to the CCC: 21 Congress St. Salem, MA 01970. Copying
`done for other than personal or internal reference use without the express permission of McGraw-Hill is prohibited. Requests for special permission or bulk orders should be addressed to
`the publisher. ISSN 0032-5481/87 $2.35. POSTMASTER: Please send address changes to POSTGRADUATE MEDICINE, 4580 W 77th St, Minneapolis. MN 55435.
`continued on page 7
`
`VOL 82/NO 4/SEPTEMBER 15. 1987/POSTGRADUATE MEDICINE
`
`5
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`(cid:3) (cid:55)(cid:75)(cid:76)(cid:86)(cid:3)(cid:80)(cid:68)(cid:87)(cid:72)(cid:85)(cid:76)(cid:68)(cid:79)(cid:3)(cid:80)(cid:68)(cid:92)(cid:3)(cid:69)(cid:72)(cid:3)(cid:83)(cid:85)(cid:82)(cid:87)(cid:72)(cid:70)(cid:87)(cid:72)(cid:71)(cid:3)(cid:69)(cid:92)(cid:3)(cid:38)(cid:82)(cid:83)(cid:92)(cid:85)(cid:76)(cid:74)(cid:75)(cid:87)(cid:3)(cid:79)(cid:68)(cid:90)(cid:3)(cid:11)(cid:55)(cid:76)(cid:87)(cid:79)(cid:72)(cid:3)(cid:20)(cid:26)(cid:3)(cid:56)(cid:17)(cid:54)(cid:17)(cid:3)(cid:38)(cid:82)(cid:71)(cid:72)(cid:12)(cid:3)
`
`Mylan v. Warner Chilcott IPR2015-00682
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`
`according to their manufacturers,
`are physiologic or more natural
`than their fixed-dose counter-
`
`parts. In my opinion, this is a fal-
`lacy, because the purpose of
`« oral contraceptives is nonphysio-
`logic, ie, to block ovulation and
`prevent conception.
`What multiphasics should
`provide is a reduction in proges-
`tin-related side effects. How-
`
`ever, the total hormone dose per
`cycle is lower for some fixed—dose
`products than for multiphasics.
`ln everyday usage, the inflexibili-
`ty of the preplanned dosage of
`multiphasics makes intracycle
`adjustments more difficult and
`proper use somewhat trickier
`than with fixed-dose oral contra-
`
`ceptives. Although the multi-
`phasics are said to cause less
`breakthrough bleeding than the
`standard fixed—dose counterpart,
`this may not be the case.“
`
`When should the pill cycle be
`started?
`Considerable flexibility is allowed
`in starting oral contraceptive
`use. Manufacturers’ directions
`
`range from starting on day 1 of
`the menstrual cycle to starting
`on the first Sunday of the cycle (to
`avoid subsequent weekend
`menses). The patient can gener-
`ally begin taking the pills on
`any day up to the sixth day of
`her cycle, presuming a normal
`period and a cycle length of at
`least 28 days. If the usual cycle
`
`length is less than 28 days, use
`of the pills must be started earlier
`or a backup method of contracep-
`tion must be used. Because the
`follicle destined to ovulate is
`selected seven days before ovula-
`tion, the pill cycle can be ini-
`tiated up to day 6. If ovulation
`occurs before day 14, the dom-
`inant follicle may go on to ovulate
`unless the patient begins taking
`the pills before the selection
`process occurs.
`When to start oral contracep-
`tive therapy after early termina-
`tion of pregnancy (elective or
`spontaneous], after delivery, or
`after nursing depends on when
`ovulation is likely to resume
`in each situation. After a first-
`trimester abortion or miscar-
`
`riage, oral contraceptive therapy
`should be started Within six
`
`days——just as in a regular men-
`strual cyc1e—since some women
`ovulate about two weeks after
`
`the termination of pregnancy.
`For a pregnancy loss in the
`second or third trimester when
`lactation is suppressed by bromo-
`criptine (Parlodel), the pill should
`be started within two weeks,
`since ovulation may occur three
`to four weeks later. This is also
`
`true for a premature or full-term
`delivery when bromocriptine has
`been administered, since the
`reduction in prolactin levels re-
`sults in a faster return to regular
`cyclicity.
`A woman who breast-feeds
`
`should not use combination oral
`
`contraceptives until nursing is
`well established, since the milk
`supply may be decreased by
`immediate postpartum use. How-
`ever, ovulation may resume in a
`mother who is breast-feeding
`but has reduced suckling epi-
`sodes. Therefore, an alternative
`method of contraception should
`be used by all nursing mothers as
`soon as they resume sexual
`activity post partum. (Although
`small amounts of hormone are
`excreted in breast milk“ “ and the
`
`absolute safety to the infant is
`not established, the American
`Academy of Pediatrics“ approves
`use of oral contraceptives by
`breast-feeding mothers.)
`
`When is worryjustified?
`Warning signs of potential major
`complications of oral contracep-
`tives must be heeded. These
`
`complications are mostly cardio-
`vascular: thromboembolism.
`cerebrovascular accidents, myo-
`cardial infarction, and hyperten-
`sion.2'5 A patient with symptoms
`referable to these complications
`(table 3] should seek medical
`advice immediately. Abdominal
`pain is included in table 3 be-
`cause of the risk of hepatocellular
`adenoma associated with use of
`oral contraceptives. This disease
`is rare (3 to 4/ 100,000 long-
`term users] but potentially fatal.
`The absolute risk in most
`
`women taking oral contracep-
`continued
`
`VOL B2/NO 4/SEPTEMBER 15. 1987/POSTGRADUATE MEDICINE 0 ORAL GONTRAGEPTIVES
`
`
`
`67
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`Side effects related
`to either progestin or
`estrogen in oral
`contraceptives may
`be alleviated by
`adjusting the appro-
`priate component.
`
`
`
`Table 1. Contraindications to use
`of oral contraceptives
`
`Table 2. Relative effects of
`progestins at similar doses
`
`Absolute contraindications
`Cardiovascular or thromboembolic
`disease
`Estrogen—dependent neoplasm
`Liver neoplasm
`Active liver disease
`Persistent hypertension
`
`Strong relative contraindications
`Migraine or vascular headaches
`Diabetes
`Gallbladder disease
`Hemoglobin S-3 or S-C disease
`Immobilization or leg injury
`Age over 40 yr and second risk
`factor for cardiovascular disease
`Age over 35 yr and history of heavy
`smoking
`
`Possible relative contraindications
`Family history of absolute or strong
`relative contraindications
`Previous cholestatic disease or
`recent liver disease
`Lactation
`Psychiatric disease
`Varices
`Asthma
`Seizure disorder
`Leiomyomata uteri
`
`Androgenic
`Norethynod rel
`Ethynodiol diacetate
`Norethindrone
`Norethindrone acetate
`Norgestrel
`Levonorgestrel
`
`Progestational
`Norethindrone
`Norethynod rel
`Norethindrone acetate
`Ethynodiol diacetate
`Norgeslrel
`Levonorgestrel
`
`O
`1.0
`1.6
`2.5
`7.5
`15.0
`
`1.0
`1.1
`2.0
`15.0
`30.0
`60.0
`
`Table 3. Warning signs of major
`complications with oral
`contraceptive use
`
`Abdominal pain
`Chest pain or dyspnea
`Headache or neurologic symptoms
`Visual or speech problems
`Leg pain or weakness
`
`tives is low. A British study‘ es-
`tablished that the excess annual
`cardiovascular mortality for
`women taking the pill is 1/77,000
`for nonsmokers under 35 years
`of age, 1/10,000 for smokers un-
`der 35, 1 /6,700 for nonsmokers
`between 35 and 40, and 1/2,000
`for smokers between 35 and 40.
`
`When should the regimen be
`changed?
`A woman who experiences
`breakthrough bleeding while
`taking low-dose combination oral
`contraceptives usually finds
`that it disappears after a few cy-
`cles. lfthe breakthrough bleeding
`persists, the first option is to
`
`add estrogen (10 to 20 ug of ethi-
`nyl estradiol or equivalent) for
`the remainder of the cycle. Often
`this is enough to stabilize the
`endometriurn. If breakthrough
`bleeding recurs, changing to a
`50—ug preparation for several cy-
`cles may be useful.
`Amenorrhea with use of oral
`
`contraceptives is also caused by
`the effect of a low level of estro-
`
`gen on the endometrium. This is
`unsettling but not dangerous.
`A woman who is amenorrheic
`
`while properly taking the pill can
`be reassured, but a pregnancy
`test may be necessary to relieve
`anxiety.
`Estrogen may be added for
`breakthrough bleeding to obtain
`some endometrial proliferation,
`but increasing the estrogen con-
`tent of the pill seems unwise
`for long-term use because of the
`increased likelihood of side ef-
`
`fects. Manipulating the progestin-
`estrogen ratio by lowering the
`amount of progestin may be use-
`ful in breakthrough bleeding
`and amenorrhea, since both are
`caused by a relative insufficiency
`of estrogen.
`Nuisance side effects related to
`
`progestin or estrogen may be
`alleviated by adjusting the appro-
`priate component. With low-
`dcse combination pills, these ef-
`fects are fortunately uncommon.
`If side effects are androgenic [eg.
`acne, weight gain], the relative
`
`68
`
`ORAL CONTHACEPTIVES ' VOL B2/NO 4/SEPTEMBER 15. 1987/POSTGRADUATE MEDICINE
`
`Mylan v. Warner Chilcott |PR2015-00682
`WC Ex. 2014, Pg. 5
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`Mylan v. Warner Chilcott IPR2015-00682
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`
`

`
`Evidence supports a protective effect of oral
`contraceptives against endometrial and
`ovarian malignancy, benign breast disease,
`and infection of the upper genital tract.
`
`Replacement parts
`for your prescribing
`armamentarium
`
`<
`
`,x~
`
`_ J
`
`'1
`. y /
`
`
`
`Sta.
`,-"5;
`
`\ k
`
`,§;/
`
`Soma“
`Compound
`
`(carisoprodol 200 mg and
`aspirin 325 mg tablets, USP)
`
`(‘fl WALLACE LABORATORIES
`
`Division of Carter-Wallace Inc.
`Cranbury, New Jersey 0512
`
`Edward L. Marut
`Dr Marut is director division of
`reproductive endocrinology and
`infertility, department of obstet-
`rics and gynecology Michael
`Reese Hospital and Medical
`Center, Chicago, and assistant
`professor of obstetrics and
`gynecology, University of Chica-
`go Pritzker School of Medicine.
`
`
`
`androgenic effect of the proges-
`tins [table 2] should be considered
`so that appropriate adjustments
`can be made. If side effects are
`
`progestational (cg, headaches,
`depression), the relative progesta-
`tional potency of the progestins
`(table 2) should likewise be con-
`sidered. Estrogen side effects
`include fluid retention, nausea,
`and headache. Keeping the estro-
`gen content below 50 pg should
`minimize these side effects.
`
`(Whether ethinyl estradiol and
`rnestranol are equivalent in es-
`trogenicity is still contmversial.
`However. since all pills with less
`than 50 pg of estrogen contain
`
`ethinyl estradlol, this may not be
`a critical point.)
`
`Why should women take the
`pill‘?
`Besides the obvious contraceptive
`benefit of the combination pill—
`an effectiveness superiorto
`that of all other nonsurgical
`forms of contraception-the
`many noncontiaceptive benefits
`are good reasons to select oral
`contraceptives.
`The mechanism by which oral
`contraceptives act [ie, suppres-
`sion of gonadotropins and, thus,
`of the ovaries) results in men-
`strual regulation, decreased men-
`continued
`
`VOL B2[NO 4/SEPTEMBER 15, 1987/POSTGRADUATE MEDlClNE 0 ORAL COHTRACEPTIVES
`
`
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`
`strual flow: and prevention of
`functional ovarian cysts. 12 Evi-
`dence also supports a protective
`effect of the pill against endomo-
`trial and ovarian malignancy,
`most likely by its progestational
`effect on the endometrial lining
`and its suppressive effect on
`the ovaries. The risk of these neo-
`
`plasms is reduced by one half in
`women who have used ora:
`contraceptives. 13
`Most studies indicate no in-
`creased risk of breast cancer in
`
`women taking oral contracep-
`tives, and there is agreement that
`the pill has a protective effect
`against benign breast disease,
`again by eliminating the cyclicity
`of ovarian steroids. Similarly,
`suppression of androgen secre-
`tion by the ovaries can improve
`hirsutism and acne, if either
`is present. Premenstrual symp-
`toms and dysmenorrhea, when
`functional, are often blunted by
`smoothing the usual hormonal
`cyclicity.
`‘
`Interestingly, use of oral con-
`traceptives may protect against
`infection of the upper genital
`tract [salpingitis, pelvic inflam-
`matory disease). W5 The reasons
`for this protection include a
`decrease in menstrual effluent,
`which is a potential culture medi-
`um for bacteria, and thickening
`of cervical mucus, which may
`prevent microorganisms from
`ascending the genital tract.
`
`Summary
`
`The risks of oral contracep-
`tives are very small, and they
`cluster in a subset of users,
`although warning signs of car-
`diovascular complications
`must be heeded. The best
`choice of an oral contraceptive
`is one with an estrogen content
`of 30 to 35 pg. A greater (50 pg]
`content may be necessary
`if breakthrough bleeding or
`amenorrhea persists beyond a
`few t1'eatrnent cycles. The
`starting date for the pill can be
`up to the sixth day of the cycle.
`Noncontraceptive benefits
`of the pill may include a pro-
`tective effect against endomo-
`trial and ovarian malignancy,
`
`benign breast disease, and
`infection of the upper genital
`tract. Both the contraceptive
`and noncontraceptive benefits
`of low-dose combination oral
`contraceptives are desirable.
`They far outweigh the risks
`in women who require a high-
`efficacy. reversible contracep-
`tive and who have no signifi-
`cant contraindication to use of
`the pill. Rivl
`
`Presented at the 71st annual Scientific
`Assembly of the Interstate Postgraduate
`Medical Association. held in San Diego.
`
`Address for correspondence: Edward L.
`Marut. MD. Division of Reproductive
`Endocrinologyand Infertility. Michael
`Reese Hospital and Medical Center,
`Lake Shore Dr at 31 st St, Chicago, IL
`60616.
`
`References
`1. Royal College of General Practitioners. Oral
`contraceptivesand health: report of Royal College of
`General Practitioners. London: Pitrnan Medical, i974-
`2. Jick H. Dinan B. Rothman KJ. Oral contraceptivs
`and nonfatal myocardial infarction. JAMA 1 978;
`2391 141: 1 403-6
`3. Layde PM, Ba-nl V, Kay CR. Further analyses of
`mortality in oral contraceptive users. Lancet 1981:
`lfMar 7):5r11e
`4. Petittt DB, Wingerd J, Pellegrln F. et al. Risk of
`vascular disease in women: smoking. nral contracep-
`tives, nuncontraceptive estrogens. and other factors.
`JAMA l979:242[1 l]:l 150-4
`5. Shapiro S, Slone D. Micttlnen OS, etal. Oml
`contraceptive use in relation to myomi-dial infarction.
`Lancet 1979;1[a119);743-7
`6. Tlkkanen MJ. Nikkila EA. Kane! '1‘. etsl. High
`density llpopmtern-2 and hepatic lipase: reciprocal
`changes produced by estrogen and nnrgestrel. J Clin
`Enclocrinol Metab l 982;54{6]: l 1 13-7
`7. Tikkanen MJ. Nikkila EA. Knnal T. etnl. Reluc-
`tlnn of plasma high-density lipopmtein cholesterol
`and increase of postlreparin plasma hepatic lipase
`activityduring prcgestin treatment. Clin Chim Acta
`l981:ll5(l]:63-71
`
`8. Hitcher RA. Guest F, Stewart F, at Al. Combined
`oral wnti-aceptives. Ln: Williams NB. ed. Contraceptive
`tcchnologi 1986-1987. New York: lrvingtnn Publishers.
`1 9861147-9
`9. Nilsson S, Nygren KG, Johnnsson ED. 'I‘ransferof
`estradiol to human milk. Am J Obstet Gyneoul 1978;
`l32(6]:653-7
`ll). lbdrlywalla VS. Joshl L. Vlrhr K. Effectof
`contraceptive steroids on human lactation. Am J Obstel
`Gynecol l977;127[3]:245-9
`1 1. American Academy ofPediatrics. Breastfeeding
`and contiaceptlcn. Pediatrics 198] :68[ 1]: 133-40
`12. Attitudes toward contraception. Princeton, NJ:
`Gallup Organimtian. 1985 Mar 1
`13. Rubin GL, Peterson I-113. Oral contraceptive use
`and cancer. Contraceptive Tbchnol Update 1985:6
`(Jan): 1- l 4-
`14. OryHW. The noncontraceptive health benefits
`fmm oral contraceptive use. Fam Plann Perspect l9B2:
`l4[4);l82-4
`15. Sennnayake P. Kramer DG. Contraception and
`the etiulogr of pelvic inflammatcrydisease: new
`perspectives. Am J Obstet Gynewl 1980: 138[7 Pt 21-’
`852-60
`
`70
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