American Journal of Therapeutics 7, 115-121 (2000)
`
`Gastrointestinal Complications of Prescription and
`Over-the-Counter Nonsteroidal Anti-inflammatory Drugs:
`A View from the ARAMIS Database
`
`
`
`Gurkirpal Singh
`
`More than 30 million people worldwide consume prescription nonsteroidal anti-inflammatory
`drugs (NSAIDs) on a daily basis. Gastrointestinal (GI) toxicity owing to the use of NSAIDs is a
`well-recognized clinical problem, with approximately 25%of all reported adverse drug, reactions
`being attributed to prescription NSAID use.In addition to prescription NSAIDs, the use of over-
`the-counter (OTC) formulations of these products is common. Althoughit has been suggested that
`OTC doses of NSAIDs may notleadto significant GI toxicity, the data confirming this have been
`lacking. Data on the GI risks of OTC doses ofaspirin, ibuprofen, naproxen, paracetamol, and no
`drug from 4164 consecutively diagnosed patients with rheumatoid arthritis from eight ARAMIS
`(Arthritis, Rheumatism, and Aging Medical Information System) centers in North America are
`presented. Serious GI events were defined as GI bleeds and otherclinically significant GI events
`requiring hospitalization. Relative risks were standardized for potential demographic confounders
`using Cox proportional hazard models. Althoughtherelative risk of OTC doses of NSAIDs(3 to4)
`is less than the previously published risk of prescription doses (6 to 7), it remains clinically signifi-
`cant and a matter of serious concern because of the widespread use of these medications and an
`underappreciation of the true risk. Paracetamol was notassociated with increased risk of Gl com-
`plications and should be consideredfirst-line therapy.
`
`Keywords: paracetamol, acetaminophen,gastrointestinal toxicity, over-the-counter dose, nonsteroi-
`dal anti-inflammatory drug.
`
`
`INTRODUCTION
`
`Aspirin and the other nonsteroidal anti-inflammatory
`drugs (NSAIDs) are considered to be one of the most
`frequently used class of drugs, with more than 30 mil-
`lion people using them on a daily basis, Despite their
`popularity, these drugs do carryrisks. It is now well
`recognized that they are associated with significant
`adverse effects on the gastrointestinal (GI) tract, that
`these are the most prevalent category of adverse drug
`reactions,’ and that they lead to significant morbidity
`
`and mortality.” In recent years, there has been much
`research interest in the area of Gl-related complica-
`tions. The aim ofthis paperis to put these GI compli-
`cations into clinical perspective using information
`gained from the studies of the ARAMIS (Arthritis,
`Rheumatism, and Aging Medical Information System)
`database. To this end, we briefly review the literature
`and update previously published ARAMIS informa-
`tion from the prescription setting as well as newin-
`formation relating to the use of over-the-counter
`(OTC) analgesics.
`
`The Department ofMedicine, Division of Immunology and Rheu-
`matology, Stanford Liniversity School of Medicine, Palo Alto,
`California, USA,
`:
`;
`;
`Address for correspondence: ARAMIS Post-Marketing Surveil-
`lance Program, Stanford University, 1000 Welch Road, Suite 203,
`Palo Alto, CA, USA.
`;
`
`THE ARAMIS DATABASE
`
`ARAMISis
`,
`aH
`i
`is a
`prospective observational noninterven-
`i
`ROPER
`tional cohort 5tudy that has systematically collected
`data on individuals with chronic rheumatic diseases.
`It provides a means with which physician- and pa-
`
`1075-2765 © 2000 Lippincott Williams & Wilkins, Inc.
`
`Page 1 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`Page 1 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`116
`
`tient-reported data can be systematically collected and
`analyzed. Funded primarily by grants from the Na-
`tional Institutes of Health, the ARAMIS database has
`now amassed detailed clinical outcome information
`on more than 36,000 patients with rheumatic diseases
`from 17 centers in the United States and Canada who
`have been followed for more than 300,000 patient-
`years. The ARAMIS Post-Marketing Surveillance
`(PMS) Program has prospectively followed patient
`outcome status, drug side effects, and economic im-
`pactof illness in a cohort of more than 12,000 consec-
`utively enrolled osteoarthritis (OA) and rheumatoid
`arthritis (RA) patients from eight patient populations
`(Stanford, CA; Santa Clara County, CA; Wichita, KS;
`Phoenix, AZ; Cincinnati, OH; Baltimore, MD; Saska-
`toon, Saskatchewan, Canada; and Montreal, Quebec,
`Canada).* These data provide a large body of infor-
`mation that can be used to evaluate various aspectsof
`the epidemiology of NSAID-related GI side effects.
`Patient characteristics, study design, and data collec-
`tion methods are described in detail elsewhere,*°
`
`NSAID-RELATED
`GASTROINTESTINAL
`COMPLICATIONS
`
`NSAID-related GI complications cover a number of
`different disorders that can be divided into three main
`categories ranging from nuisance symptoms to endo-
`scopically determined mucosallesions and serious GI
`complications.°
`
`Nuisance symptoms, including dyspepsia
`Nuisance symptoms, suchas heartburn, nausea, dys-
`pepsia, and abdominalpain, affect approximately 10%
`to 20%of patients after taking an NSAID,°*although
`this may range from 5%to 50%, depending on factors
`
`SINGH
`
`such as study design, patient populations, drugs, dos-
`ages, and durationof use.* Such symptomscan have a
`great impact on NSAID compliance. Indeed,
`it has
`been noted that, among patients with OA on NSAID
`treatmentafter 1 year, only 15% to 20%werestill tak-
`ing the same drug.”
`
`Endoscopically determined mucosallesions
`
`NSAID-induced mucosal lesions can range from mi-
`nor gastroduodenal lesions to serious GI complica-
`tions such as bleeding and perforation. Acute hemor-
`rhages and erosions occur within several hours to
`minutesof taking NSAIDsand canbeseen in as many
`as 80%of patients treated with NSAIDs.'° Theseulcers
`are usually asymptomatic andwill heal and redevelop
`over time. Endoscopic evidence of mucosal damage
`can be seen without the patient reporting any symp-
`toms; similarly a patient may report symptoms with-
`out any evidence of mucosal damage; and serious GI]
`complications can occur withoutthe patient reporting
`any symptoms or there being any endoscopic evi-
`dence of mucosal damage.""
`
`Serious gastrointestinal complications
`
`Serious GI complications resulting in hospitalization
`occur annually in 1%to 2%of individuals taking
`NSAIDsregularly.'* Werecently reported the data on
`the incidence of serious GI complicationsresulting in
`hospitalization among patients with RA and OA
`(Table 1),° showing that, when compared with previ-
`ously published data,°'*° the rate of hospitalization
`for NSAID-related serious GI complications may have
`decreased in recent years. This decline may be ac-
`counted for by twofactors, namely,the establishment
`of morestringentcriteria for hospitalization in a man-
`aged-care setting and physician-education campaigns,
`which emphasize increased use of newer, less GI-toxic
`
`Table 1. Gastrointestinal complications in osteoarthritis and rheumatoid arthritis.OOOeee
`OA
`RA
`
`
`
`Hospitalizations
`Hospitalizations Deathseeee
`Number of patients
`2921
`3883
`1283
`Person—years of observation
`12,224
`19,961
`3234
`Person—years taking NSAIDs
`8471
`15,638
`2199
`Number of GI events
`25
`228
`19
`Numberof GI events while taking NSAIDs
`19
`205
`16
`Rate per year while taking NSAIDs (%)
`0.22
`1.31
`0.73
`Rate per year while not taking NSAIDs (%)
`0.05
`0.19
`0.29
`Relative risk while taking NSAIDs
`
`
`6.772.51 4.21eeeeeeeaaeaaeeeeE=SP————————
`Adapted from ref. 3.
`
`American Journal of Therapeutics (2000) 7(2)
`
`Page 2 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`Page 2 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`GI COMPLICATIONS OF PRESCRIPTION AND OTC NSAIDS: A VIEW FROM THE ARAMIS DATABASE
`
`ily
`
`NSAIDs and non-NSAID analgesics, such as paracet-
`amol, in high-risk populations.””
`
`THE BURDEN OF NSAID-RELATED
`GASTROINTESTINAL
`COMPLICATIONS
`
`MANY CONSUMERS DO NOT
`RECOGNIZE THE SERIOUSNESS
`OF THE PROBLEM
`
`A survey conducted in 1998 by Roper-Starch, the
`American Gastroenterological Association, and G.D.
`Searle & Co. revealed that limited consumer knowl-
`edgeplus a lack of concern contribute to the problem
`of NSAID-related GI complications. Some 807 indi-
`viduals were included in the analysis, which revealed
`that almost half (45%) took NSAIDs for 5 days or
`longer at least once a month.’ Furthermore, nearly
`40% of individuals combined OTC and prescription
`NSAIDs. Of great concern wasthe revelation that of
`those consumers whoregularly used NSAIDs, nearly
`75% did not know about or were unconcerned about
`NSAID-related GI complications (Fig. 2). In addition,
`almost two thirds believed they would get warning
`signs in advance of a serious NSAID-induced compli-
`cation (Fig. 3). Yet other studies showed that only 20%
`of people who have a serious GI complication will
`have any warning sign.°
`
`ARE THERE WARNING SIGNS FOR
`SERIOUS GASTROINTESTINAL
`COMPLICATIONS?
`
`Approximately 10%to 15% of cases of hospitalizations
`for upperGI bleeding results in death.'° In our previ-
`ously published ARAMIS data, we reported 26 GI
`deathsin 12,224 patient-years of exposure to NSAIDs.*
`Of these deaths, 19 could be attributed to NSAIDs,
`giving a GIdeath rate of 0.22%per year, and a relative
`risk of 4.21.
`It could be argued that this may not seem signifi-
`cant. However, given the high usage of these prod-
`ucts, often on a chronic basis, the lifetime risk and
`health care burden may be substantial. Based on these
`conservativefigures and ARAMISdata, the number of
`hospitalizations for serious GI complications per year
`is estimated to be 103,000, which, at a conservative
`estimated cost of US$15,000 to 20,000 per hospitaliza-
`tion,amounts to an annualcost in excess of US$2 bil-
`lion.”
`Among RA and OApatients, data are even more
`startling. It has been conservatively estimated that
`16,500 NSAID-related deaths occur in these patients
`every year in the United States (Fig. 1). When com-
`Whereas dyspeptic symptoms are commonin patients
`pared with some other commoncauses of death in the
`on NSAIDs, there is little correlation between these
`United States during 1997,’” it becomes apparentthat
`symptomsand serious GI complications. For example,
`NSAIDs may be responsible for almost as many
`we previously reported that in a prospective cohort
`deaths as AIDS and significantly more deaths than
`evaluation of 1921 patients, the overall incidence of
`asthma, cervical cancer, and Hodgkin’s disease.°
`
`Numberof deaths from selected causes, US population (1997)
`
`
`
`
`
`25,000
`
`20,000
`
`15,000
`
`10,000
`
`5,000
`
`Number
`of deaths
`
`04
`
`Leukemia
`
`HIV
`
`NSAIDs GI Multiple
`myeloma
`Cause of Death
`
`Asthma
`
`Cervical
`cancer
`
`Hodgkin's
`disease
`
`Fig. 1. Number of deaths
`associated with NSAID-in-
`duced gastrointestinal dam-
`age compared with other
`causes (U.S. population).'”
`From ref. 3, with permis-
`sion.
`
`Page 3 of 8
`
`American Journal of Therapeutics (2000) 7(2)
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`Page 3 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`cause oTc
`
`users
`
`users
`
`Dual
`users
`
`m Aware of
`complications
`but unconcerned
`
`m Unaware of
`complications
`NSAIDs can
`
`SINGH
`
`constant over time. Somebelieve that if patients are
`going to bleed, they will do so early in the course of
`therapy. Therefore, it is postulated that those patients
`whocontinue with NSAID therapy may have become
`tolerant and thus will have a reduced risk of develop-
`ing serious GI complications. Our studies, which have
`followed cohorts for as long as 15 years, suggest that
`the risk of GI bleed (the hazard function) remains con-
`stant.* Oneof the waysof understandingthis is to use
`the analogy of a game of darts. The probability of
`hitting the center of a dartboard is dependent on the
`number of darts thrown—the more darts that are
`thrown, the greater the odds. Similarly, the longer a
`patient takes NSAIDs, the greater the odds of a GI
`bleed. But, based on chancealone,thefirst dart can hit
`the center, or the second onecan, or the third one can
`and similarly, a patient can bleed from just one tablet,
`or the second tablet, or the third one.
`The single most important risk factor for an NSAID-
`related bleed is the duration of NSAID therapy; how-
`ever, currently available risk factor models do not con-
`sider this exposure. Through ARAMISit has been pos-
`sible to develop Cox proportional hazard models
`based onlife-table analysis that enable us to estimate
`the true risks associated with various patient charac-
`teristics. These have now evolved into a simple point-
`based, risk-factor algorithm called the Gl SCORE
`(Standardized Calculator of Risks for Events) that may
`be used: to assess a patient’s risks from NSAID
`therapy.’ The SCORE program has been well vali-
`dated and is available from the author should more
`information be needed.'**! It is hoped thatthis simple
`scoring system will aid physicians in making in-
`formeddecisions regarding the prescription of NSAID
`therapy, the use of prophylactic therapy, and the fre-
`quencyof patient monitoring, all of which would help
`to reduce the incidence of serious NSAID-induced GI
`complications.’
`
`OVER-THE-COUNTER NSAIDs: AN
`UNDERESTIMATED PROBLEM
`
`In the United States in 1998, 16.1 billion tablets of OTC
`NSAIDs were sold compared with only 2.9 billion of
`prescription NSAIDs. Of the more than 30 million
`people who regularly take NSAIDs, 40% take both
`prescription and OTC NSAIDsat the same time, and
`nearly one third of people who take prescription
`NSAIDs consume more than the maximum recom-
`mended doses.Yet, as demonstratedearlier, there is a
`perception among the general public that because
`these drugs are available OTC, they do not carry any
`significant risk.
`
`Fig. 2. Percentage of people who are unaware of NSAID-
`related complications in a cohort of regular NSAID users.
`Rx, prescription. From ref. 3, with permission.
`
`NSAID-related GI side effects was 15%, with a 2.2%
`incidence ofserious GI complications requiring hospi-
`talization® and that as many as 81% of patients who
`had serious GI complications had no prior GI symp-
`toms.°
`
`WHO IS AT GREATESTRISK FOR
`SERIOUS GASTROINTESTINAL
`COMPLICATIONS?
`
`Owing to the largely asymptomatic nature of GI side
`effects, determining risk factors is important. Data
`from manystudies established a variety of risk factors
`including advanced age,'*-** higher NSAID doses,2?°
`pgae of GI problems(eg, peptic ulcer and GI bleed-
`ing),“*°° concomitant corticosteroid use,?*?”?* dura-
`tion of therapy,'****° and concomitant anticoagulant
`use.”*Despite the consistent results from these stud-
`ies, many are based on univariate analyses and do not
`take into accountthe interaction among multiple fac-
`tors (eg, an older patientis also likely to have a longer
`duration of disease and is perhaps sicker with more
`comorbidities).
`One importantissuein this respect is the questionof
`whether the risk for NSAID-related gastropathy is
`
`Rx users
`
`OTC users
`
`ep
`
`Don’t Expect Warning Signs
`Expect Warning Signs
`
`Fig. 3. Percentage of regular NSAID users who expect to
`experience a warning sign before a serious gastrointes-
`tinal complication. From ref. 3, with permission.
`
`American Journal of Therapeutics (2000) 7(2)
`
`Page 4 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`Page 4 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`GI COMPLICATIONS OF PRESCRIPTION AND OTC NSAIDS: A VIEW FROM THE ARAMIS DATABASE
`
`119
`
`and 6.2% of controls, nor was there an increased GI
`The association of prescription NSAIDs with serious
`risk for those using paracetamol and alcohol.
`GI complications has been established primarily from
`Blot and McLaughlin recently presented a detailed
`case-control studies. Most of these studies are based
`analysis of the ACG bleed registry and association
`on analysis of computer databases of Medicare, Med-
`with OTC NSAIDs.*4 Overall, 27% of bleeders were
`icaid, or managedcare records. Although these retro-
`taking OTC doseaspirin compared with 12.0%of con-
`spective studies document that prescriptions have
`trols. The corresponding numbers with OTC dose ibu-
`been dispensed, actual consumption cannotbe deter-
`profen were 10,1% and 5.8%, respectively, and those
`mined, and the prevalence of OTC NSAIDuse cannot
`be assessed.
`with OTC dose paracetamol were 4.5% and 6.3%, re-
`spectively. The oddsratios for a serious GI bleed with
`There are several case series demonstrating the as-
`OTC dose aspirin and ibuprofen were 2.7 and 2.3—
`sociation of prescription NSAIDs with upper GI hem-
`both representingastatistically significant increase in
`orrhage, but few have specifically looked at OTC
`risk. The odds ratio for paracetamol was 0.9, repre-
`NSAIDs. In a prospective study, Wilcox and col-
`senting a risk not statistically different from back-
`leagues showed that in a large U.S. county hospital,
`ground. The oddsratios were related to the dose: ibu-
`56% of 421 upper GI bleeds during 1990 to 1992 were
`profen doses of <600 mg/day hadaratio of 1.7. This
`associated with the use of NSAIDs.” Of the NSAID-
`increased to 3.4 in patients who took 600 to 1200 mg/
`related bleeds, 63%were associated with OTC aspirin
`day, and to 3.5 in those who took >1200 mg/day.
`use and 16% with OTC nonaspirin NSAID use. They
`state:
`There was a strong interaction between alcohol con-
`sumption and OTC NSAID use. Although alcohol use
`doubled the risk for a GI bleed, when alcohol was
`combined withaspirin, the risk increased to fourfold.
`In patients who took OTC ibuprofen and alcoholto-
`gether, the risk increased to 7.1.
`There are several studies on the risk of aspirin, al-
`though many do not differentiate between prescrip-
`tion and OTC use. In a case-control study, Levy and
`colleagues reported that the relative risk of occasional
`aspirin use (presumably OTC)in causing major upper
`GI bleeds was 5.6 (CI 2.7-12.0).*° There was no in-
`creased risk with the use of paracetamol. Weil and
`colleagues estimate that approximately twothirds of
`the 10,000 episodesof ulcer bleeding in people aged 60
`years and older every year in England and Wales are
`related to the use of NSAIDs.°° Of these, 46%are re-
`lated to aspirin use, two thirds of which is givenfor
`prophylactic purposes. According to the authors, no
`dose of aspirin was safe: the relative risks for daily
`doses of 75 mg, 105 mg, and 300 mg were 2.3, 3.2, and
`3.9, respectively. In a recent study, Cryer and Feldman
`reported that even 10 mg aspirin substantially re-
`duced gastric mucosal prostaglandin levels to ap-
`proximately 40%of the baseline value and caused sig-
`nificant gastric injury.”
`
`In our experience, when a patient is asked generically
`concerning medication use, consumption of OTC
`preparations is often not volunteered as patients con-
`sider these OTC agents as not a drug perse. In addi-
`tion, some patients consume non-aspirin NSAIDs as
`an “aspirin substitute” but are unaware of their po-
`tential gastrointestinal
`toxicity. Given the apparent
`frequency with which these OTC NSAIDsare used,
`these products may represent an important health
`hazard, particularly in patients with ulcer disease.
`
`How important the health hazard is was brought
`out clearly in a recent study conducted by the Ameri-
`can College of Gastroenterology (ACG)** to assess de-
`mographics, management strategies, and outcomes
`for patients with GI bleeding. All ACG members and
`Fellows were requested to send information on as
`many as ten bleeding patients and for ten procedure-
`matched controls. A total of 635 bleeders and 600 con-
`trols was studied. Among the 635 bleeders, 56.9%
`were taking NSAIDs and of these, 84% were taking
`OTC NSAIDs, with the vast majority using aspirin.
`Alcohol intake was also recorded. Overall, 47.6% of
`bleeders were taking OTC aspirin or NSAIDs com-
`pared with only 19.4%of controls. Of note is the fact
`that 84%of the NSAID-related GI bleeds occurred
`among, patients taking OTC NSAIDs. These authors
`estimated that the odds ratio for use of OTC NSAIDs
`was 2.76 (confidence interval [CI] 2.03-3.74) and that
`of alcohol use was 2.07 (CI 1.48-2.88). When OTC
`NSAIDsand alcohol were used together, the relative
`risk increased dramatically to 4.47 (CI 2.73-7.32),
`showing a significant interaction. In this study, the
`authors showed that paracetamol did not have any
`significant risk, being used by only 4.4%of bleeders
`
`ARAMIS INVESTIGATION OF
`OVER-THE-COUNTER
`DOSE NSAIDs
`
`Using the ARAMIS database, we conducted a pro-
`spective observational noninterventional study in a
`large group of RA patients taking OTC doses of
`
`American Journal of Therapeutics (2000) 7(2)
`
`Page 5 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`Page 5 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`120
`
`SINGH
`
`toxicity of aspirin,
`NSAIDs. Westudied serious GI
`ibuprofen, and naproxen in OTC doses, comparing
`these drugs with the non-NSAID analgesic paraceta-
`mol and nodrug therapy in 4164 patients with 6279
`patient-years of observation. Of these, 2064 patients
`were taking OTC NSAIDs, 721 taking paracetamol,
`and 1379 were not taking any medication during the
`study. Serious GI events were defined as GI bleeds
`and other clinically significant GI events requiring
`hospitalization.
`
`ARAMIS RESULTS
`AND CONCLUSIONS
`
`There was no difference in the incidencerates of seri-
`ous GI complications among,
`those patients taking
`paracetamolandthosenot on anydrug therapy. How-
`ever, patients taking OTC doses of NSAIDs had an
`incidence rate of 0.58 per 100 patient-years, statisti-
`cally significantly higher than the rate among patients
`on paracetamol (0.16; P < .05) or not on any therapy
`(0.17; P < .05). Relative risks were standardized for
`potential demographic confounders using Cox pro-
`portional hazard models. Because this was an obser-
`vational study, there were systematic differences in
`people on different analgesics. For example, patients
`on paracetamol tended to be older and had morese-
`vere disease (and thus more likely to have a Gl ad-
`verse event) compared with patients on OTC NSAIDs.
`Cox proportional hazard models were used to control
`for confounders such as age, duration of therapy, and
`disease severity. Standardized relative risks of differ-
`ent therapies were comparedwith patients not on any
`therapy. Therelative risk of paracetamol did not differ
`significantly from background, whereas the OTC
`doses of NSAIDs hadarelativerisk of 3.92 (P < .01).
`Theindividual NSAID risks wereas follows: aspirin,
`4.14 (P < .01); ibuprofen, 3.5 (P < .05); and naproxen,
`3.42 (p < .05).
`Although the relative risks observed for the OTC
`doses of NSAIDsare, as expected, lowerthan thosefor
`prescription doses, theyare clinically meaningful and
`statistically significant. These data lead us to conclude
`that even the lower doses of NSAIDs available OTC
`are not without GI risk. However, it should be noted
`that these data were derived from patients with RA,
`andtwothirdsof the patients in our study were taking
`OTC NSAIDsregularly and not in an occasional fash-
`ion.
`
`CONCLUSIONS
`
`The seriousness of NSAID-related GI ulcer complica-
`tions (eg, bleeding and perforation) are well docu-
`
`American Journal of Therapeutics (2000) 7(2)
`
`mented. Unfortunately and of great concern, many pa-
`tients are unaware of these potential complications. In
`the vast majority of cases, serious GI complications are
`not preceded by any symptoms or signs. Patients and
`physicians need to be awareof the risk factor profiles
`that predisposepatients to serious GI problems, using
`tools such as the GI] SCOREto their advantagein this
`respect.
`Therisk of OTC NSAIDs remains a matter of serious
`concern becauseof the widespread useof these medi-
`cations and an underappreciation of the truerisk. Al-
`though consistent data are beginning to emerge on
`problems caused by OTC doses,thereis still a need for
`further information on therisks involved.
`
`REFERENCES
`
`|. Butt JH, Barthel JS, Moore RA: Clinical spectrum of the
`upper gastrointestinal effects of nonsteroidal anti-
`inflammatory drugs. Natural history, symptomatology,
`andsignificance. Am ] Med 1988;84:5-14,
`2. Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal
`toxicity of nonsteroidal antiinflammatory drugs. N Engl
`J Med 1999;340:1888-1899,
`3. Singh G, Triadafilopoulos G: Epidemiology of NSAID
`induced gastrointestinal complications.
`J Rheumatol
`1999;26:18-24.
`
`4, Singh G, Fries JF, Spitz P, Williams CA: Toxiceffects of
`azathioprine in rheumatoid arthritis. A national post-
`marketing perspective. Arthritis Rheum 1989;32:837—
`843,
`
`5. Singh G, Fries JF, Williams CA, et al: Toxicity profiles of
`disease modifying antirheumatic drugs in rheumatoid
`arthritis. J] Rheumatol 1991;18:188-194,
`6. Singh G, Ramey DR, Morfeld D, et al: Gastrointestinal
`tract complications of nonsteroidal anti-inflammatory
`drug treatment in rheumatoid arthritis. A prospective
`observational cohort study, Arch Intern Med 1996;156:
`1530-1536,
`
`7. Hardin JG, Longenecker GL: Handbook of Drug Therapyin
`Rheumatic Disease: Pharmacology and Clinical Aspects.
`Little, Brown, Boston, 1992.
`8. Goldenberg DL, Cohen AS: Drugs in the Rheumatic Dis-
`cases. Grune and Stratton, New York, 1986,
`9. Scholes D, Stergachis A, Penna PM, et al: Nonsteroidal
`antiinflammatory drug discontinuation in patients with
`osteoarthritis. J Rheumatol 1995;22:708-712.
`10, Ehsanullah RS, Page MC, Tildesley G, WoodJR: Preven-
`tion of gastroduodenal damage induced by non-
`steroidal anti-inflammatory drugs: controlledtrial of ra-
`nitidine. BMJ 1988;297:1017-1021,
`11. Graham DY, Smith JL: Gastroduodenal complications of
`chronic NSAID therapy. Am J Gastroenterol 1988;83:
`1081-1084.
`
`Page 6 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`Page 6 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`GI COMPLICATIONS OF PRESCRIPTION AND OTC NSAIDS: A VIEW FROM THE ARAMIS DATABASE
`
`121
`
`12,
`
`13,
`
`14.
`
`15.
`
`16.
`
`7,
`
`18.
`
`19F
`
`20.
`
`21.
`
`po
`
`23:
`
`24,
`
`25.
`
`26.
`
`Cryer B: Nonsteroidal anti-inflammatory drug gastroin-
`testinal toxicity, Curr Opin Gastroenterol 1999;15:473—
`480.
`Singh G, Ramey DR,Balise R, Triadafilopolous G: Epi-
`demiology of NSAID-related GI complications in pa-
`tients with osteoarthritis (OA): a 13 year prospective
`study [abstract]. Arthritis Rheum 1998;41:5180.
`Fries JF, Ramey DR, Singh G, et al: A reevaluation of
`aspirin therapy in rheumatoid arthritis. Arch Intern Med
`1993;153:2465-2471.
`Singh G: Recent considerations in nonsteroidal anti-
`inflammatory drug gastropathy. Am J Med 1998;105:
`315-385,
`Armstrong CP, Blower AL: Non-steroidal anti-
`inflammatory drugs and life threatening complications
`of peptic ulceration, Gut 1987;28:527-532.
`National Center for Health Statistics: 1998, Hyattsville,
`MD.
`Bjorkman DJ: Nonsteroidal anti-inflammatory drug-
`induced gastrointestinal injury. Am J Med 1996;101:255—
`328.
`Longstreth GF: Epidemiology of hospitalization for
`acute upper gastrointestinal hemorrhage: a population-
`based study. Am J Gastroenterol 1995;90:206-210.
`Greene JM, Winickoff RN: Cost-conscious prescribing of
`nonsteroidal anti-inflammatory drugs for adults withar-
`thritis. A review and suggestions. Arch Intern Med 1992;
`152:1995-2002.
`Gabriel SE, Jaakkimainen L, Bombardier C: Risk for se-
`rious gastrointestinal complications related to use of
`nonsteroidal anti-inflammatory drugs. A meta-analysis.
`AnnIntern Med 1991;115:787-796.
`Griffin MR, Piper JM, Daugherty JR, et al: Nonsteroidal
`anti-inflammatory drug use and increased risk for pep-
`tic ulcer disease in elderly persons. Ann Intern Med
`1991;114:257-263.
`!
`LangmanMJ, Weil J, Wainwright P, et al: Risks of bleed-
`ing peptic ulcer associated with individual non-steroidal
`anti-inflammatory drugs. Lancet 1994;343:1075—-1078.
`Garcia RL, Jick H: Risk of uppergastrointestinal bleed-
`ing and perforation associated with individual non-
`steroidal anti-inflammatory drugs. Lancet 1994;343:769—
`772.
`Hallas J, Lauritsen J, Villadsen HD, Gram LF: Nonste-
`roidal anti-inflammatory drugs and uppergastrointesti-
`nal bleeding, identifying high-risk groups by excess risk
`estimates. Scand J Gastroenterol 1995;30:438-444,
`Nielsen JC, Bjerring P, Arendt-Nielsen L: A comparison
`
`273
`
`28.
`
`29,
`
`of the hypoalgesic effect of paracetamol in slow-release
`and plain tablets on laser-induced pain. Br J Clin Phar-
`macol 1991;31:267-270,
`Hochain P, Berkelmans I, Czernichow P, et al: Which
`patients taking non-aspirin non-steroidal anti-
`inflammatory drugs bleed? A case-control study. EurJ
`Gastroenterol Hepatol 1995;7:419-426.
`Piper JM, Ray WA, Daugherty JR, Griffin MR: Cortico-
`steroid use and peptic ulcer disease: role of nonsteroidal
`anti-inflammatory drugs. Ann Intern Med 1991;114:735—
`740.
`
`Silverstein FE, Graham DY,SeniorJR, et al: Misoprostol
`reduces serious gastrointestinal complications in pa-
`tients with rheumatoid arthritis receiving nonsteroidal
`anti-inflammatory drugs. A randomized, double-blind,
`placebo-controlled trial. Ann Intern Med 1995;123:241-
`249,
`
`o2s
`
`33,
`
`. Shorr RI, Ray WA, Daugherty JR, Griffin MR: Concur-
`rent use of nonsteroidal anti-inflammatory drugs and
`oral anticoagulants places elderly persons at high risk
`for hemorrhagic peptic ulcer disease. Arch Intern Med
`1993;153:1665-1670.
`1. Singh G, Ramey DR, Triadafilopolous G, et al: GI
`SCORE: A simple self-assessment instrument to quan-
`tify the risk of serious NSAID-related GI complications
`in RA and OA[abstract]. Arthritis Rheum 1998;41:S75.
`Wilcox CM, Shalek KA, Cotsonis G: Striking prevalence
`of over-the-counter nonsteroidal anti-inflammatory
`drug use in patients with upper gastrointestinal hemor-
`rhage. Arch Intern Med 1994;154:42-46,
`Peura DA, Lanza FL, Gostout CJ, Foutch PG: The Ameri-
`can College of Gastroenterology Bleeding Registry: pre-
`liminary findings [abstract]. Am J Gastroenterol 1997;92:
`924-928,
`. Blot W, McLaughlinJ: GI bleeding in relation to analge-
`sic use [abstract]. Digestion 1998;59:207.
`. Levy M, Miller DR, Kaufman DW,et al; Major upper
`gastrointestinal tract bleeding. Relation to the use of as-
`pirin and other nonnarcotic analgesics. Arch Intern Med
`1988;148:281-285.
`Weil J, Colin-Jones D, Langman M,et al: Prophylactic
`aspirin and risk of peptic ulcer bleeding. BMJ 1995;310:
`827-830.
`
`36,
`
`37,
`
`Cryer B, Feldman M:Effects of very low dose daily,
`long-term aspirin therapy on gastric, duodenal, and rec-
`tal prostaglandin levels and on mucosal
`injury in
`healthy humans. Gastroenterology 1999;117:17-25.
`
`Page 7 of 8
`
`American Journal of Therapeutics (2000) 7(2)
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`Page 7 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Page 8 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`Page 8 of 8
`
`Patent Owner Ex. 2046
`Mylan v. Pozen
`IPR2017-01995
`
`