Wt AM493
`v.et
`1991
`N0.3
`c.ot--------SEQ: A2443SOOO
`Tl: AMERICAN JOURNAL OF
`MEDICINE
`
`POLICY WATCH
`
`I' Number13
`; li•1iC•,Olt11
`, ; !09 GI Dlsea1e and NSAID Use-Pincus and Griffin
`/
`
`CLINICAL STUDIES
`
`'; 213 NSAID-Assoclated Gastropathy-Fries ET AL
`, ; 223 Risk of GI Bleeding with Corticosteroids-Carson
`ET AL
`: 229 Weekly Erythropoletln Corrects Uremic Anemia-
`, Zappaco~ta ET AL
`: 233 Natrlure11c Effect of Nlfedlplne-Cappuccio ET AL
`. !39 Cllnlcal ~bservatlons on Niacin Therapy-Henkin
`: ETAL
`
`, 147 CAD Assciclated with Diagonal Earlobe Crease(cid:173)
`Elliott and Karrison
`: 155 DNR Orders: Physician and Patient
`Decision-Waking-Ebel! ET AL
`, i/61 Oral Ofloxacln for Acute Bacterial Pneumonia(cid:173)
`Sanders ET AL
`
`SPECIAL ARTICLE
`
`: l67 Elevated CSF Pressure In Cryptococcal
`Menlngltl1-Denning ET AL
`IU•lilMI
`: 173 Double Trouble-Kreisberg
`
`IHJ1itl#dilttHM*i•11•Wiii1
`, 76 In a Stew-Lacombe
`1111,11
`, i79 Aortoesop/lageal Fistula-Hollander and Quick
`188 Stroke Pnventlon In Women-Hershey
`
`19it1t1•1Mi=l•11•iaas,wa1;11~111
`
`· ~3 CPC/Septc Polyarthrltls and Acute Renal Failure
`
`,ASE REPORTS
`
`, 00 Severe Skin l>lsease, Eoslnophllla In Patients with
`1 HTLV-11-Kcplan ET AL
`
`ION M. fortultun as Asymptomatic Enlarging Pulmonary
`odule-Pe,ce ET AL
`
`,r Complete Tlble of Co t
`
`n ents, See Pages A4, AS, Al4, .
`
`l\d A20.
`
`.
`
`Page 1 of 18
`
`Patent Owner Ex. 2014
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`The
`American
`Journal of
`Medicine®
`
`ADVERTISING SALES .OFFICES
`
`New York
`Michael A. Pepper (212) 463-6468
`Robert C. Weidner (212) 463-6469
`249 West 17th Street
`New York, NY 10011
`
`Des Plaines
`Wyman Carey (708) 635-8800
`1350 East Touhy Avenue
`P.O. Box 5080
`Des Plaines, IL 60017-5080
`
`Japan
`Kaoru Hara
`Dynaco International, Inc.
`Suite 1003, Sun-Palace Shinjuku
`8-12-1 Nishishinjuku Shinjuku-ku
`Tokyo 160, Japan
`Tel: (03) 366-8301
`Fax: (03) 366-8302
`
`For advertising sales in Austria, Benelux, Eastern
`Bloc Countries, West Germany, France, Italy,
`Scandinavia, Switzerland, and the United King(cid:173)
`dom, please contact Cahners Publishing Compa(cid:173)
`ny, 27 Paul Street, London EC2A, 4JU England;
`Telephone 1-44 1 628-7030; telex 914911; fax
`1-44 1 839-6626.
`
`Production Manager: Marty Schlessel
`(212) 463- 6546
`Contracts Coordinator: Luz Mejia
`lndlvldual Author Reprints: (800) 323-4958
`Corporate Bulk Reprints: (212) 463-6437
`Director of Art Department: Barrie Stern
`
`Questions regarding subscriptions can be directed to
`1-800-327-9021 (in Colorado, call [303] 388-4511) or
`write The American Journal of Medicine, P.O. Box
`173377, Denver, CO 80217-3377.
`
`1•
`
`MAXAIR.
`
`pirbuterol acetate inhalatioii'aeio'soi'
`Bronchodilator Aerosol
`For Inhalation Only
`BRIEF SUMMARY
`INDICATIONS AND.USAGE: MAXAIR Inhaler. ls Indicated for the prevenUon and.reversal of bronchospasm In
`patients with reversible bronchospasm Including asthma. It may be used with or without concurrent theophylline
`and/or steroid therapy.
`CONTRAINDICATIONS: MAXAIR is contraindicated in patients with a history of hypersensitivity to any of Its
`Ingredients.
`WARNINGS: As with other beta adrenergic aerosols, MAXAIR should not be used In excess. Controlled clinical
`studies and other clinical experience have shown that MAXAIR like other Inhaled beta adrenergic agonists can
`produce a signfficant cardiovascular effect In some patients, as measured by pulse rate, blood pressure
`symptoms, and/or ECG changes. As with other beta adrenergic aerosols, the potential for paradoxical broncho'.
`spasm (which can be life.threateningl should be kept in mind. If it occurs, the preparation should be discontinued
`Immediately and alternative therapy nst1tuted.
`Fatalities have been reported In association with excessive use of Inhaled sympathomimetic drugs.
`The contents of MAXAIR Inhaler are under pressure. Do not puncture. Do not use or store near heat or open
`flame. Exposure to temperature above 120°F may cause bursting. Never throw container Into fire or incinerator.
`Keep out of reach of children.
`PRECAUTIONS: General - Since pirbuterol is a sympathomimetic amine, It should be used with caution In
`patients with cardiovascular disord.ers, Including lschemicheartdisease, hypertension, orcarqiacarrhythmias, in
`patients with hyperthyro1d1sm or d.1abetes mellltus, and In patients who are unusuallY, resppnsive to sympathoml(cid:173)
`met1c amines or who have convulsive disorders. S1gmficant changes In systolic and diastolic blood pressure could
`be expected to occur in some patients atter use of any beta adrenergic aerosol bronchodilator.
`Information for Patients- MAXAIR effects may last up to five hours or lonqer. It should not be used more often
`than recommended and the patient should not Increase the number of inhalations or frequency of use without first
`asking the physician. If symptoms of asthma get worse, adverse reactions occur, or the patient does not respond
`to the usual dose, the patient should be Instructed to contact the physician immediately. The patient should be
`advised to see the Illustrated Directions for Use.
`Drug Interactions - Other beta adrenerglc aerosol bronchodllators should not be used concomitantly with
`MAXAIR because they may have additive effects. Beta adrenergic agonlsts should be administered with caution to
`patients being treated with monoamine oxldase Inhibitors or tricyclic antidepressants, since the action of beta
`adrenerglc agonlsts on the vascular system may be potentiated.
`Carcinogenesis, Mutagenesls and Impairment of Fertlllty- Pirbuterol hydrochloride administered In the diet
`to rats for 24 months and to mice for.18 months was fre~ of carcinogenic ai,tlvlty at doses corresponding to 200
`times the maximum human Inhalation dose. In add1t1on, the Jntragastnc Intubation of the drug at doses
`corresponding to 6250 times the maximum recommended human daily inhalation dose resulted In no Increase In
`tumors In a 12-month rat study. Stud.ies with pirb.uterol revealed no evidence of mutagenesis. Reproduction
`studies in rats revealed no evidence of impaired fertility.
`Teratogenic Effects - Pregnancy Category C- Reproduction stud.ies have been penormed In rats and rabbits
`by the inhalation route at doses up to 12 times (rat) and 16tlmes (rabbit) the maximum human Inhalation dose and
`have revealed no significant findings. Animal reproduction studies In rats at oral doses up to 300 mg/kg and In
`rabbits at oral doses up to 100 mg/kg have shown no adverse effect on reproductive behavior, fertility, litter s~e.
`pen- and postnatal viability or fetal development. In rabbits at the highest dose level given, 300 mg/kg, abortions
`and fetal mortality were observed. There are no adequate and well controlled studies In rregnant women and
`MAXAIR should be used during pregnancy only H the potential benefit Justifies the potentla risk to the fetus.
`Nursing Mothers- It is not known whether M(IXAIR Is excreted In human milk. Therefore, MAXAIR should be
`used during nursing only H the potential benefit Jusltties the possible nsk to the newborn.
`Pediatric use - MAXAIR Inhaler is not recommended for patients under the age of 12 years because of
`Insufficient clinical data to establish safety and effectiveness.
`ADVERSE REACTIONS: .The followl_ng rates of adverse reactions to pirbuterol are based on single and multiple
`dose clinical trials involving 761 patients, 400 of whom received multiple doses (mean duration of treatment was
`2 5 months and maximum was 19 months).
`· The following were the adverse reactions reported more frequently than 1 in 100 patients: CNS: nervousness
`(6.9%), tremor (6.0%), headache (2.0%l, dizziness (1.2%). Cardiovascular: palpitations (1.7%), tachycardia
`(1.2%). Respiratory: cough (1.2'/,). Gas rolntestlnal: nausea (1.7%).
`.
`The following adverse reactions occurr,ed less !requentlV than 1 In 100 patients and there may be a causal
`relationship with pirbuterol: CNS: depression, anxiety, confusion, Insomnia, weakness, hyperkinesla, syncope.
`tardlovascular. hypotenslon, skipped beats, chest pain. Gastrointestinal: dry mouth, glossitis, abdominal
`pain/cramps anorexia, diarrhea. stomatitis, nausea and vomiting. Ear, Nose and Throat smell/taste changes
`sore throat. Dermatological: rash, pruritus. Other. numbness in extremities, alopecla, bruising, fatigue, edema:
`weight gain, flushing.
`Other adverse reactions were reported with a frequency of less than 1 In 100 patients but a causal relationship
`between pirbuterol and the reaction could not be determined: migraine, productive cough, wheezing, and
`dermatitis.
`.
`h
`d
` •
`The following rates of adverse reactions dunng three-mont controlle c in1cal trials Involving 310 patients are
`noted. The table does not include mild reactions.
`PERCENT OF PATIENTS WITH MODERATE TD SEVERE ADVERSE REACTIONS
`Plr1Juterol
`Metaproterenol
`Plr1Juterol Metaproterenol
`N=157
`N=153
`N=157
`N=153
`
`Reaction
`Central Nervous System
`tremors
`nervousness
`headache
`weakness
`drowsiness
`dizziness
`tanllovascular
`palpitations
`tachycardia
`Respiratory
`chest pain,1ightness
`cough
`
`1.3%
`4.5%
`1.3%
`.0%
`.0%
`0.6%
`
`1.3%
`1.3%
`
`1.3%
`.0%
`
`3.3%
`2.6%
`2.0%
`1.3%
`0.7%
`.0%
`
`1.3%
`2.0%
`
`.0%
`0.7%
`
`1.3%
`1.3%
`1.3%
`.0%
`
`.0%
`.0%
`
`2.0%
`0.7%
`1.3%
`0.7%
`
`0.7%
`1.3%
`
`Reaction
`Gastrointestinal
`nausea
`diarrhea
`dry mouth
`vomiting
`Oennatologlcal
`s~n reaction
`rash
`Other
`0.6%
`.0%
`bruising
`0.6%
`.0%
`smell/taste change
`.0%
`0.7%
`backache
`.0%
`0.7%
`fatigue
`.0%
`0.7%
`hoarseness
`.0%
`0.7%
`nasal congestion
`OVERDOSAGE: The expected symptoms with overdosage are those of excessive beta-stimulation and/or any of
`the symptoms listed under adverse reactions, e.g., angina, hypertension or hypotension, arrhythmias, nervous(cid:173)
`ness. headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia.
`Treatment consists of discontinuation of pirbuterol together with approprtate symptomatic therap)'.
`The oral acute lethal dose In male and female rats and mice was greater than 2000 mg base/kg. The aerosol
`acute lethal dose was not determined.
`CAUTION: Federal law prohibits dispensing without prescription.
`Store between 15' and 30'C (59' to 86'F).
`For full prescribing Information, see package insert.
`PIR-4
`
`C 3M Phamnaceulicals-1991
`
`2300-2585
`
`l<PI CAHNERS PUBLISHING COMPANY
`
`249 West 17th Street, New York, NY 10011
`
`APRIL 1990
`
`Page 2 of 18
`
`Patent Owner Ex. 2014
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`The
`American
`Journal of
`Medicine.
`
`EDITOR-IN-CHIEF
`J. Claude Bennett, M.D.
`Birmingham, Alabama
`
`ASSOCIATE EDITORS
`William E. Dismukes, M.D.
`Birmingham, Alabama
`Robert A. Kreisberg, M.D.
`Birmingham, Alabama
`Richard M. Allman, M.D.
`Birmingham, Alabama
`Michael A. LaCombc, M.D.
`Norway, Maine
`
`SENIOR MANAGING EDITOR
`Monica K. Schmidt
`New York, New York
`
`ASSISTANT MANAGING EDITOR
`Rose Mary Piscitelli
`New York, New York
`
`PRODUCTION EDITOR
`Ann M. Breen
`New York, New York
`
`SENIOR EDITORIAL ASSISTANT
`Charmaine M. Clarke
`New York, New York
`
`EDITORIAL ASSISTANTS
`Carolyn Thomley
`Birmingham, Alabama
`Loretta H. Campbell
`New York, New York
`
`V.P./GROUP PUBLISHER
`Joseph L. Navitsky
`New York, New York
`
`PUBLISHER
`Steven V. Claps
`New York, New York
`
`EDITORIAL BOARD
`
`JAMES E. BALOW, M.D.
`National Institutes of Health
`Bethesda, Maryland
`
`ROBERT J. MA YER, M.D.
`Dana Farber Cancer Institute
`Boston, Massachusetts
`
`GIDEON BOSKER, M.D.
`Good Samaritan Hospital and Medical Center
`Portland, Oregon
`
`GUY M. McKHANN, M.D.
`Johns Hopkins Medical Institutions
`Baltimore, Maryland
`
`PAUL CALABRESI, M.D.
`Roger Williams General Hospital
`Brown University
`Providence, Rhode Island
`
`THOMAS R. CUPPS, M.D.
`Georgetown University Medical Center
`Washington, D.C.
`
`DAVID R. DANTZKER, M.D.
`Long Island Jewish Medical Center
`New Hyde Park, New York
`
`RAJK. GOYAL, M.D.
`Harvard Medical School
`Beth Israel Hospital
`Boston, Massachusetts
`
`ROLF GUNNAR, M.D.
`Loyola University of Chicago
`Stritch School of Medicine
`Maywood, Illinois
`
`WILLIAM R. HAZZARD, M.D.
`Bowman-Gray School of Medicine
`Winston-Salem, North Carolina
`
`JEROME M. HERSHMAN, M.D.
`University of California, Los Angeles,
`School of Medicine
`Los Angeles, California
`
`MARC C. HOCHBERG, M.D.
`Welch Center for Prevention, Epidemiology &
`Clinical Research
`The Johns Hopkins Medical Institutions
`Baltimore, Maryland
`
`ROBERT NARINS, M.D.
`Temple University Hospital
`Philadelphia, Pennsylvania
`
`JEROME B. POSNER, M.D.
`Memorial Sloan-Kettering Cancer Center
`New York, New York
`
`JARRETT RICHARDSON, M.D.
`Mayo Clinic
`Rochester, Minnesota
`
`JOEL E. RICHTER, M.D.
`University of Alabama at Birmingham
`Birmingham, Alabama
`
`RICHARD K. ROOT, M.D.
`University of California, San Francisco
`San Francisco, California
`
`EUGENE R. SCHIFF, M.D.
`Veterans Administration Hospital
`University of Miami
`Miami, Florida
`
`MARK SIEGLER, M.D.
`University of Chicago
`Chicago, Illinois
`
`JAMES C. WADE, M.D.
`University of Maryland Cancer Center
`Baltimore, Maryland
`
`BABETTE B. WEKSLER, M.D.
`Cornell University Medical College
`New York, New York
`
`SANFORD B. KRANTZ, M.D.
`Vanderbilt University School of Medicine
`Nashville, Tennessee
`
`DOUGLAS P. ZIPES, M.D.
`Indiana Medical Center
`Indianapolis, Indiana
`
`CONSULTING ASSOCIATE EDITORS
`Hematology/Oncology
`Edwin C. Cadman, M.D.
`Yale University School of Medicine
`New Haven, Connecticut
`Nephrology
`Thomas F. Ferris, M.D.
`University of Minnesota
`Minneapolis, Minnesota
`Gastroenterology
`Norton J. Greenberger, M.D.
`University of Kansas Medical Center
`Kansas City, Kansas
`
`Cardiology
`Joseph C. Greenfield, M.D.
`Duke University Medical Center
`Durham, North Carolina
`Health Services Research/Epidemiology
`Harold C. Sox, Jr., M.D.
`Dartmouth-Hitchcock Medical Center
`Hanover, New Hampshire
`
`THE AMERICAN JOURNAL OF MEDICINE® (ISSN 0002-9343) (GST 123397457), September
`1991, Vol. 91, No. 3
`
`years $175, 3 years $250; Canada/Mexico, I year $110, 2 years $193 3 years $27 5. all
`$1~~- countries (prices include air-speeded delivery), I year $150, 2 yiars $263, 3 yiars
`
`Not re'.pon~ible for replacing Journal issues unless Circulation Department is notified of
`Member American Business Press and Audit Bureau of Circulations. Published three
`nonrece,pt ".''thin _3 months _of issue date. S~bscribers agree that no article or any part
`times in April, May, July, and September, two times in February, March, June, and Augu_st,
`thereof p~blished ,n any ed,t,ons of t_he American Journal of Medicine received under this
`and one time in January, October, November. and December by the Cahners Publishing
`subscription agreement may _be c_op,ed,_ recorded, or reproduced in any form or by any
`Company, a Division of Reed Publishing USA. 275 Washington Street Newton, MA 02158-
`means. electronic or me.chanical, inclu_d,ng, among oth_ers, photocopy',ng or the storing of
`1630. Terrence M. McDermott, President; Frank Sibley, Executive V,c~-Pre_s,dent; Robert
`part or. all of such articles o~ any 1nformat1on retrieval system, without the written
`T. Brawn, Senior Vice-President/General Manager; Jerry D. Neth, Senior V1ce-Pres1dent/
`perm1ss1on of the Publisher .. Pnces for bulk reprints of articles available on request.
`Publishing Operations; J. J. Walsh. Senior Vice-President/Finance; Thomas J. Dellamaria,
`The Publisher assumes no liability tor any material published in the Journal All statements
`Senior Vice-President/Production & Manufacturing; Ralph Knupp, Vice-President/Human
`are the responsibility of the author(s).
`·
`Resources. Printed in Easton, PA.
`.
`Circulation records are maintained at 44 Cook Street, Denver, co ao205.58oo. Second
`SUBSCRIPTIONS: Solicited only from internists and other physicians. Publisher reser~es
`class postage paid at Denver, CO, and at additional mailing offices. Printed In U.S.A. The
`the right to refuse unqualified subscription requests. Address correspondence regarding
`American Journal of M~dlclne"' Is a registered trademark of Reed Properties Inc., used
`subscriptions and changes of address to: American Journal of Medicine, P.O. Box 173377,
`Denver, co 80217-3377; Telephone (1-800)327-9021; In CO, (303)388-4511. Please
`under llcens~. © Copyright 1991 by Reed Publishing USA; Ronald G. Segel, Chairman and
`Chief Executive Officer; Robert L. Krakoff, President and Chief Operating Officer· William M.
`include your zip code and, for changes of address, copy of old address label.
`. .
`Platt, Senior Vice-President.
`'
`Single copy prices: regular issues $10; symposium and special issues $12. Subscription
`MANUSCRIPTS_: _All manuscripts should be addressed to the Editorial Office, American
`Rates: lnd1v1dual: United States, (new) I year $19.90, (renewals) I year $57, 2 years $58,
`J~urnal of Med1c1ne, Department o_f Medicine,. Unive'.sity of Alabama at Birmingham,
`3 years $59; Canada/Mexico, 1 year $85, 2 years $149, 3 years $213; all other countries
`Diabetes Bu1ld1ng, Room _420_H, Un1v~rs1ty Station, Birmingham, AL 35294; telephone
`(prices include air-speeded delivery), I year $125, 2 years $21_9, 3 years $313. Students
`and residents United States only, I year $9.95. lnst,tut,ons: United States, 1 year $100, 2
`(205) 934-3189. For detailed information for authors, see page 324.
`Postmaster: Send address changes to the American Journal of Medicine, P.O. Box 173377, Denver, CO 80217-3377.
`Cahners Publishing Company, a Division of Reed Publishing USA o Speci~lized Business.Mag~zines for Building_ & Construcfon o Research o Technology o Electronics o Computing o
`Printing O Publishing O Health Care o Foodservice o Packaging o Environmental Engineering o Manufacturing o Entertainment o Home Furnishings O Interior Design O Specialized
`Consumer Magazines for Child Care, Boating and Wedding Planning
`A2
`September 1991 The American Journal of Medicine Volume 91
`
`Page 3 of 18
`
`Patent Owner Ex. 2014
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`The .
`American
`Joumalof
`Medicine®
`
`POLICY WATCH
`
`I
`Number 13
`
`209
`Gastrointestinal Disease Associated with Nonsteroidal Anti(cid:173)
`Inflammatory Drugs: New Insights from Observational Studies
`and Functional Status Questionnaires
`Theodore Pincus, Marie Griffin
`
`CLINICAL STUDIES
`
`213
`Nonsteroidal Anti-Inflammatory Drug-Associated
`Gastropathy: Incidence and Risk Factor Models
`James F. Fries, Catherine A. Williams, Daniel A. Bloch, Beat A. Michel
`The individual clinical variables appearing to be predictive of serious
`GI events in this study included age, disability, NSAID dose, previous
`GI hospitalization, prior GI complaints with NSAIDs, and use of
`prednisone, antacids, or H2-antagonists.
`
`223
`The Low Risk of Upper Gastrointestinal Bleeding in Patients
`Dispensed Corticosteroids
`Jeffrey L. Carson, Brian L. Strom, Rita Schinnar, Amy Duff, Ellen Sim
`This study demonstrates that the incidence of bleeding in patients
`exposed to corticosteroids is very low and suggests that prophylactic
`therapy should be reserved for high-risk patients, if it is to be used at
`all.
`
`Page 4 of 18
`
`Patent Owner Ex. 2014
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`CONTENTS
`
`H
`b.
`R
`229
`Weekly Subcutaneous ecom mant uman Erythropoietin
`Corrects Anemia of Progressive Renal Failure
`Anthony R. Zappacosta, Susan T. Perras, Alisa Bell
`Subcutaneous :Hu~PO adm~nistered. wee.kly ~as found to corr~ct
`anemia in pred~alys1s and ~entoneal d1alys1s patients. Weekly dosmg
`is more convenient for patients and may be less costly for Medicare
`providers.
`
`233
`' S d'
`• d Ch
`Acute and Sustame
`anges m o mm Balance During
`Nif edipine Treatment in Essential Hypertension
`Francesco P. Cappuccio, Nirmala D. Markandu, Giuseppe A. Sagnella, Donald
`R.J. Singer, Michelle A. Miller, Martin G. Buckley, Graham A. MacGregor
`The GITS formulation of ni~edipine was shown not only to cause a
`reduction in blood pressure m patients with essential hypertension
`but to cause an acute increase in both sodium and water excretion with
`significant declines in plasma ANP, significant increases in PRA and
`aldosterone, and a significant weight loss. After 1 month of treatment,
`nifedipine was withdrawn, causing significant sodium and water re(cid:173)
`tention, a significant weight gain, and a return of hormone levels to
`baseline.
`
`239
`Niacin Revisited: Clinical Observations on an Important but
`Underutilized Drug
`Yaakov Henkin, Albert Oberman, David C. Hurst, Jere P. Segrest
`The authors examine their experience with niacin, alone and in com(cid:173)
`bination with oth~r ~rugs, in the treatment of 82 dyslipidemic pa(cid:173)
`tients. Although macm was generally well tolerated and efficacious,
`they report a high incidence of hyperglycemia in heart transplant
`recipients, as well as a high incidence of hepatitis associated with
`sustained-release preparations. The authors conclude that the avail(cid:173)
`ability of sustained-release niacin as a nonprescription drug is unjusti(cid:173)
`fied and should be reexamined.
`
`247
`Increased All-Cause and Cardiac Morbidity and Mortality
`Associated with the Diagonal Earlobe Crease: A Prospective
`Cohort Study
`William J. Elliott, Theodore Karrison
`The finding that patients with diagonal ELCs may have higher cardi(cid:173)
`ac morbidity and mortality rates could be useful in identifying pa(cid:173)
`tients who need further screening for cardiac disease, or who may need
`further control of modifiable cardiac risk factors. This may be particu(cid:173)
`larly helpful in the case of identifying those who might otherwise have
`"sudden death" as the first symptom of CAD.
`
`255
`The Do-Not-Resuscitate Order: A Comparison of Physician
`and Patient Preferences and Decision-Making
`Mark H. Ebell, David J. Doukas, Mindy A. Smith
`A comparison of the decision-making and preferences regarding DNR
`orders of a group of family physicians with a group of outpatients from
`a family practice center shows that there are significant similarities
`and differences in the way physicians and patients make these deci(cid:173)
`sions.
`
`Page 5 of 18
`
`Patent Owner Ex. 2014
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`CONTENTS
`
`261
`Oral Ofloxacin for the Treatment of Acute Bacterial
`Pneumonia: Use of a Nontraditional Protocol to Compare
`Experimental Therapy with "Usual Care" in a Multicenter
`Clinical Trial
`W. Eugene Sanders, Jr., James F. Morris, Paul Alessi, Alex T. Makris, Richard
`V. McCloskey, Gordon M. Trenholme, Paul lannini, Marvin J. Bittner
`The clinical and microbiologic successes reported in this study rein(cid:173)
`force the need for meticulous attention to detail to ensure optimal
`therapeutic outcome and support the concept that an exclusively oral
`regimen-in this case ofloxacin-may be substituted for parenteral
`therapy in selected patients with pneumonia.
`
`SPECIAL ARTICLE
`
`267
`Elevated Cerebrospinal Fluid Pressures in Patients with
`Cryptococcal Meningitis and Acquired Immunodeficiency
`Syndrome
`David W. Denning, Robert W. Armstrong, Bradley H. Lewis, David A. Stevens
`
`273
`Double Trouble, Boil and Bubble
`Robert A. Kreisberg
`
`MEDICINE SCIENCE AND SOCIETY
`
`276
`In a Stew
`Michael A. Lacombe
`
`279
`Aortoesophageal Fistula: A Comprehensive Review of the
`Literature
`Judd E. Hollander, Gary Quick
`
`288
`Stroke Prevention in Women: Role of Aspirin Versus
`Ticlopidine
`Linda A. Hershey
`
`Cl.:INICOPATHOLOGIC CONFERENCE
`
`293
`Septic Polyarthritis and Acute Renal Failure in a
`57-Year-Old Man
`
`Continued on page A16
`
`Page 6 of 18
`
`Patent Owner Ex. 2014
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`CONTENTS
`
`CASE REPORTS
`
`300
`Syndrome of Severe Skin Disease, Eosinophilia, and
`Dermatopathic Lymphadenopathy in Patients with HTLV-11
`Complicating Human Immunodeficiency Virus Infection
`Mark H. Kaplan, William W. Hall, Myron Susin, Savita Pahwa, S. Zaki
`Salahuddin, Conrad Heilman, James Fetten, Maria Coronesi, Bruce F. Farber,
`Sharon Smith
`
`310
`Mycobacterium fortuitum Presenting as an Asymptomatic
`Enlarging Pulmonary Nodule
`Richard R. Pesce, Susan Fejka, Stephen M. Colodny
`
`BRIEF CLINICAL OBSERVATIONS
`
`313
`Procainamide-Induced Pleural Fibrosis
`Shabbir Sheikh, Joram S. Seggev
`
`315
`Phenazopyridine-Induced Sulfhemoglobinemia: Inadvertent
`Rechallenge
`Sheila M. Halvorsen, William L. Dull
`
`317
`Treatment of Cyclic Neutropenia with Very Low Doses of
`GM-CSF
`Razelle Kurzrock, Moshe Talpaz, Jordan U. Gutterman
`
`tit•idd:J.1a11~i,14~M:i
`319
`Delayed Diagnosis of HIV-Related Tuberculosis
`A. Ross Hill
`Reply: Francoise Kramer, Peter F. Barnes
`
`320
`Intravenous Immunoglobulin Treatment of Chronic Fatigue
`Syndrome
`Frederick L. Brancati
`Reply: Stephen E. Straus, Andrew Lloyd, Ian Hickie, Denis Wakefield,
`John Dwyer
`
`Continued on page A20
`
`Page 7 of 18
`
`Patent Owner Ex. 2014
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`CONTENTS
`
`321
`Overprescribing of Benzodiazepine Hypnotic Drugs in the
`Elderly
`Nicholas J. Belitsos
`Reply: Ronald I. Shorr, C. Seth Landefeld, Steven F. Bauwens
`
`321
`Pulse Cyclophosphamide Therapy for Wegener's
`Granulomatosis
`·
`John S. Cowdery
`Reply: Gary S. Hoffman, Randi Y. Leavitt, Anthony S. Fauci
`
`322
`Neuroleptic Malignant Syndrome Versus Malignant
`Hyperthermia
`Cecelia Hard
`Reply: James T. Lane, Robert J. Boudreau, William B. Kinlaw Ill
`
`324
`Information for Authors
`
`Al3, A19
`Classified Advertising
`
`Page 8 of 18
`
`Patent Owner Ex. 2014
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`_____ __,I CLINICAL STUDIES
`:Nonsteroidal Anti-Inflammatory Drug-Associated
`Gastropathy: Incidence and Risk Factor Models
`JAMES F. FRIES, M.D., CATHERINE A. WILLIAMS, M.A., DANIEL A. BLOCH, Ph.D.,
`~EAT A. MICHEL, M.D., Stanford, California
`
`PURPOSE: The most prevalent serious drug tox(cid:173)
`jcity in the United States is increasingly recog(cid:173)
`Jlized as gastrointestinal (GI) pathology associ(cid:173)
`ated with the use of nonsteroidal
`anti-inflammatory drugs (NSAIDs). The inci(cid:173)
`dence of serious GI events (hospitalization or
`death) associated with NSAID use was therefore
`prospectively analyzed in patients with rheuma(cid:173)
`toid arthritis (RA) and patients with
`osteoarthritis.
`PATIENTS, METHODS, AND RESULTS: The study
`consisted of 2,747 patients with RA and 1,091 pa(cid:173)
`tients with osteo~rthritis. The yearly hospital(cid:173)
`ization incidence during NSAID treatment was
`1.58% in RA patients and was similar in all five
`populations studied. The hazard ratio of patients
`taking NSAIDs to those not taking NSAIDs was
`5.2. The incidence in osteoarthritis may be less.
`The risk of GI-related death in RA patients was
`0.19% per year with NSAIDs. Multivariate anal(cid:173)
`yses assessing risk factors for serious GI events
`were performed in the 1,694 (98 with an event)
`RA patients taking NSAIDs at the predictive
`visit. The main risk factors were higher age, use
`of prednisone, previous NSAID GI side effects,
`prior GI hospitalization, level of disability, and
`NSAID dose. A rule is presented that allows esti(cid:173)
`mation of the risk for the individual patient with
`RA.
`CONCLUSION: Knowledge of the risk factors for
`NSAID-associated gastropathy and their inter(cid:173)
`relationships provides a tool for identification of
`the patient at high risk and for initiation of ap(cid:173)
`propriate therapeutic action.
`
`From the Division of Immunology and Rheumatology, Depar~men~ of
`Medicine, Stanford University School of Medicine, Stanford, California.
`This work was supported by a grant from the National Institutes of
`Health (AR21393) to ARAMIS (the Arthritis, Rheumatism, and Aging
`Medical Information System) and in part by a grant from Searle
`Laboratories.
`Requests for reprints should be addressed to James F. Fries, M.D.,
`1000 Welch Road, Suite 203, Palo Alto, California 94304.
`.
`.
`Manuscript submitted November 30, 1990, and accepted m revised
`form March 18, 1991.
`
`G astrointestinal (GI) pathology associated with
`
`the use of nonsteroidal anti-inflammatory
`drugs (NSAIDs) is increasingly recognized as the
`most prevalent serious drug toxicity in the United
`States, resulting in an estimated 2,600 deaths and
`24,000 hospitalizations annually in patients with
`rheumatoid arthritis (RA) alone [1,2]. The predom(cid:173)
`inant syndrome consists of antral prepyloric ulcers,
`which may eventuate in GI hemorrhage or perfora(cid:173)
`tion, although events in the duodenum, small bow(cid:173)
`el, and the large bowel are also seen. Ulcerations
`visible on endoscopy have a point prevalence of 10%
`to 25%, and severe erosions are seen in additional
`patients [3-5]. The risk of GI hospitalization has
`been estimated at 1 % to 1.5% per year in persons
`taking NSAIDs [1], and the risk of death is approxi(cid:173)
`mately 0.13% per year in individuals treated with
`NSAIDs [1,6,7]. The importance of the syndrome
`has been emphasized by gastroenterologists [3,8,9],
`rheumatologists [2,5,10], and the Food and Drug
`Administration (FDA) [11].
`Important information required for estimation of
`the magnitude of the problem and for development
`of strategies for resolution, however has been lack(cid:173)
`ing. For example, the prevalence of c~mplications in
`conditions other than RA, such as osteoarthritis,
`has not been established. Generalizability of the
`observations to different practice sites has not been
`presented. Quantitation of likely risk factors such
`as prior bleeding has not been reported, and the
`frequency of deaths has not been confirmed by pro(cid:173)
`spective study. Most importantly while individual
`risk factors have been suggested by a number of
`investigators [l,12,13], no multivariate risk factor
`model that permits estimation ofrisk in the individ(cid:173)
`ual patient has been presented.
`This report addresses these issues in two steps:
`(1) with descriptive analyses of 2,747 patients with
`RA followed prospectively for an average of 4 years
`at fi~e ARAMIS (Arthritis, Rheumatism, and Aging
`Medical Information System) data bank centers
`[14,15] and 1,091 patients with osteoarthritis and
`(2) with risk factor analyses based on the 1,694 of
`these RA patients taking NSAIDs at the predictive
`visit.
`
`September 1991 The American Journal of Medicine Volume 91
`
`213
`
`Page 9 of 18
`
`Patent Owner Ex. 2014
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`NSAID-ASSOCIATED GASTROPATHY / FRIES ET AL
`
`TABLE I
`Rheumatoid Arthritis Gastrointestinal (GI) Hospitalization by Center
`
`Number of patients
`Person-years of observation
`Person-years taking NSAIDs
`
`GI hospitalizations
`Number of patients
`Rate per person-year(%)
`Number taking NSAIDs
`Rate per year while taking NSAIDs (%)
`Number of years of observation after 1st
`hospitalization
`Number of additional GI hospitalizations
`while taking NSAIDs
`Rate for at least one more GI hospitaliza-
`tion per year while taking NSAIDs (%)
`Number of patients with upper GI hospi-
`talizations
`Rate of upper GI hospitalizations per year
`while taking NSAIDs (%)
`Number of patients with lower GI hospi-
`talizations
`Rate of lower GI hospitalizations per year
`while taking NSAIDs (%)
`
`All
`Centers
`
`2,747
`9,525
`6,741
`
`Santa
`Clara
`
`302
`1,632
`1,122
`
`Center
`
`Saskatoon
`
`Phoenix
`
`Stanford
`
`Wichita
`
`679
`2,468
`1,712
`
`307
`1,016
`720
`
`379
`1,318
`903
`
`1,080
`3,091
`2,284
`
`116
`1.22
`107
`1.58
`201
`
`10
`
`4.98
`
`95
`
`1.41
`
`12
`
`0.18
`
`13
`0.80
`13
`1.16
`24
`
`2
`
`8.33
`
`13
`
`1.16
`
`0
`
`0
`
`34
`1.38
`30
`1.75
`73
`
`4
`
`5.48
`
`27
`
`1.58
`
`3
`
`0.18
`
`14
`1.38
`13
`1.81
`22
`
`0
`
`0.00
`
`11
`
`1.53
`
`2
`
`0.30
`
`16
`1.21
`15
`1.66
`27.5
`
`2
`
`7.27
`
`13
`
`1.44
`
`2
`
`0.22
`
`39
`1.26
`36
`1.58
`54.5
`
`2
`
`3.66
`
`31
`
`1.36
`
`5
`
`0.22
`
`PATIENTS AND METHODS
`Two thousand seven hundred and. forty-seven
`patients with RA consecutively enrolled and fol(cid:173)
`lowed at five ARAMIS centers, for a total of 9,525
`years of observation, were available for study (Ta(cid:173)
`ble I). The Santa Clara County population of 302
`patients represents a community population re(cid:173)
`cruited by advertisement. The other populations
`were formed by consecutive patient accrual at the
`site. The 679 Saskatoon patients are believed to
`make up the great majority of patients in Northern
`Saskatchewan province, the 307 Phoenix patients
`were drawn from a rheumatology private practice,
`as were the 1,080 Wichita patients, and the 379
`Stanford patients were enrolled from a tertiary care
`referral center. Data are collected in two modes.
`First, all routine clinical data including diagnosis,
`symptoms, signs, demographics, past history, labo(cid:173)
`ratory tests, and treatment are entered for each
`patient encounter and hospitalization. Second, pa(cid:173)
`tients complete the Health Assessment Question(cid:173)
`naire (HAQ) [1,16-18] at 6-month intervals, provid(cid