GASTROENTE RDLDGY 1997;112:1817-1822
`
`Famotidine for Healing and Maintenance in Nonsteroidal Anti-
`inflammatory Drug—Associated Gastroduodenal Ulceration
`
`NICHOLAS HUDSON,* ALI S. TAHA,+ ROBIN I. RUSSELL,T PENELOPE TRYE,§ JEREMY COTTRELL,§
`STEPHEN G. MANN.§ ANTHONY J. SWl'SiNELL,H ROGER D. STURROCK,T
`and CHRISTOPHER J. HAWKEY*
`* Division of Gastroenterology. University Hospital, Nottingham, England: *Department of Gastroenterology and Rheumatology. Glasgow
`Royal Infirmary, Glasgow. Scotland; Elvlerclt Research Laboratories UK. Hoddesdon. Herts, England; and "Department of Rheumatology.
`University and City Hospitais. Nottingham. England
`
`See editorial on page 2143.
`
`Bacgground & Aims: Nonsteroidal anti-inflammatory
`drugs (NSAIDs) are strongly associated with gastroduo—
`denal ulceration. How to manage patients with NSAID-
`associated ulcers is a common clinical dilemma. High-
`dose famotidine in the healing and maintenance of
`NSAID-associated gastroduodenal
`ulceration was
`therefore evaluated. Methods: One hundred four pa-
`tients with rheumatoid or osteoarthritis who had gastro-
`duodenal ulceration received famotidine, 40 mg twice
`daily. Sixteen patients stopped and 88 continued their
`NSAID treatment. Ulcer healing was assessed endo~
`scopically at 4 and 12 weeks. Seventy-eight NSAID
`users with healed ulcers were then randomized to re
`
`ceive 40 mg twice daily famotidine or placebo and un-
`
`derwent endoscopy at 4, 12. and 24 weeks. Results:
`Cumulative ulcer healing rates at 12 weeks were 89.0%
`(95% confidence interval [CI]. 82.3%—95.7%l for pa-
`tients who continued NSAID treatment and 100% (95%
`Cl, 82.9%—100.0%) for those who stopped. The subse-
`quent estimated cumulative gastroduodenal ulcer re-
`lapse over 6 months for NSAID users who took placebo
`was 53.5% (95% CI. 36.6%—70.3%). This was reduced
`to 26.0% (12496—39396) in patients taking famotidine
`(P = 0.011). Conclusions: Highdose famotidine is ef-
`fective ulcer healing therapy in patients who stop or
`continue NSAID treatment and significantly reduced
`the cumulative incidence of gastroduodenal ulcer recur-
`rence compared with placebo when given as mainte-
`nance therapy.
`
`onsteroidal anti—inflammatory drugs (NSAIDS) are
`Nstrongly associated with gastroduodenal ulceration
`and the complications 0F ulcer hemorrhage and perfora-
`tion.'Ti These risks seem to be increased in patients with
`a history of gastroduodenal ulceration?’H Use of the pros—
`taglandin analogue misoprostol for prophylaxis against
`development of NSAID-associated ulceration is well es-
`
`tablishedf' ” but there is very little evidence about ulcer
`healing.'2 Treatments that suppress acid are better toler—
`ated, but high doses are needed to prevent acute mucosa!
`injurydj'” Because management 0F patients presenting
`with ulceration represents the most common dilemma
`in the management of such patients, we conducted a
`study to assess the efficacy of high-dose famotidine, an
`H3 antagonist, in both the healing of NSAID-associated
`gastroduodenal ulceration and the subsequent prevention
`of ulcer relapse when given as maintenance therapy. This
`enabled us to compare ulcer development rates with those
`observed in a study of primary prophylaxis conducted to
`an identical design, at the same time,
`in a cohort of
`patients drawn from the same population.
`
`Patients and Methods
`
`Design
`
`The study consisted of two phases: an open study of
`Famotidine, 40 mg twice daily, in the healing of endoscopically
`proven gastroduodenal ulceration and, in patients with success-
`ful ulcer healing, a prospecrive randomized double-blind pla-
`ceborcontrolled maintenance study of famotidine, 40 mg twice
`daily, as secondary prophylaxis against endoscopically detected
`recurrent gastroduodenal ulceration.
`
`Patients
`
`Adult patients (aged 218 years) with rheumatoid ar—
`thritis or osteoarthritis were recruited from the rheumatology
`and orthopedic clinics, provided they had been receiving an
`NSAID within the range of standard recommended dosage For
`at least
`1 month before endoscopy. Patients were not consid-
`ered For the study if they had been taking antiulccr drugs
`other than antacids <7 days before study entry or were taking
`steroids at a dosage equivalent 27.5 mg prednisolone daily,
`methotrexate, or antineopiastic drugs. The other main exclu-
`
`Abbreviations used in this paper: CI, confidence interval; HAQ,
`Health Assessment Questionnaire.
`fl 1997 by the American Gastroenterological Association
`0016-5085/97/53.00
`
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`

`1818 HUDSON ET AL.
`
`GASTROENTEROLOGY Vol. 112. N0. 6
`
`sion criteria were lactation, child-bearing potential, renal fail-
`ure, diabetes, or clinically significant prestudy laboratory ab—
`normalities.
`
`Recruitment Procedures
`
`Recruitment was performed by two gastroenterologists
`who attended the Rheumatology and Orthopedic Clinics and
`approached all potentially suitable arthritic patients regardless
`of dyspeptic symptoms. Patients who accepted the invitation
`to participate underwent screening endoscopy. At endoscopy,
`ulcers, erosions, and intramucosal hemorrhages were recorded
`separately for the esophagus, gastric body, gastric antrum,
`duodenal bulb, and second part of the duodenum.
`
`Definitions and Assessments
`
`An ulcer was defined as an excavated mucosal break
`
`>3 mm in diameter, measured using biopsy forceps or a cus-
`tom-made measuring device. Erosions (defined as superficial
`mucosal breaks) and intramucosal hemorrhages (defined as
`hemorrhagic lesions without an overlying mucosal break), to-
`gether with any ulcer in each of the target areas, were used to
`derive Lanza scoresm Helimfimter pyfrm' status was determined
`by CLO test and gastric antral histology. Before commence-
`ment of the study.
`the two endosc0pists (A.S.'I'. and NH.)
`attended each other's endoscopic sessions and reviewed still
`and video images as a process of standardization of reporting
`criteria for ulcers and other lesions. Both studies were approved
`by the Nottingham and Glasgow Hospital ethics committees.
`
`Healing Phase
`
`Patients with ulcers were entered into the healing
`Study and invited to discontinue their NSAID therapy. Pa-
`tients without ulceration entered a prophylaxis study, reported
`elsewhere.17 Patients received two ZO-mg fiamotidine tablets
`twice daily.
`In addition. antacid tablets (Maalox; Rhone~
`Poulenc Rorer, Eastbourne, East Sussex, England) were pro~
`vided for relief of dyspepsia as required. Patients underwent
`endoscopy after 4 weelG oftreatment and, if the ulcer remained
`unhealed. underwent a repeat endoscopy at 12 weeks. Patients
`who were unhealed at 12 weeks were designated as treatment
`failures.
`
`Maintenance Phase
`
`Patients who wished to continue NSAID therapy and
`whose ulcers had healed successfully during the study or during
`the following 4 weeks were invited to enter the maintenance
`study. These patients were randomized to receive either famotiu
`dine, 40 mg twice daily, or placebo in a double~blind fashion
`and underwent further endoscopy at 4, 12, and 24 weeks or
`until ulcer relapse during the study.
`
`Nonendoscopic Assessments
`
`Patients were assessed routinely at baseline and at the
`time of each subsequent endoscopy. In addition to endoscopy,
`the following assessments were performed: NSAID and other
`drug usage, arthritis-related physical disability measured by
`
`the Health Assessment Questionnaire (HAQ), vital signs, com-
`plete physical examination (baseline and end ofsrudy), urinaly-
`sis, hematology, and biochemistry. Antacid use and abdominal
`symptoms were recorded daily on specific diary cards. Compli-
`ance with study drugs was assessed by tablet count and adverse
`events by open questioning at each visit.
`
`End Points
`
`The primary end point ofthe healing study was healing
`of gasttoduodenal ulceration at the 4- or 12-week endoscopy.
`The primary end point ofthe maintenance study was the cumu-
`lative incidence of gastroduodenal ulcer relapse as assessed at
`followup endoscopies (at 4, 12, and 24 weeks). The main
`secondary end points were the corresponding findings related
`to gastric and duodenal ulcers separately, Ianza scores for lesser
`degrees of gastroduodenal injury, abdominal pain, and antacid
`consumption. The main safety analyses included assessment
`of adverse events, arthritis, HAQ, physical examination, and
`laboratory results.
`
`Statistical Methods
`
`The study was designed to be pragmatic rather than
`explanatory. Efficacy data in both the healing and maintenance
`study were therefore subjected to a primary "all patients
`treated" analysis. Product limit (Kaplan—Meier) estimates of
`the cumulative incidence of ulceration, the primary end point,
`were made for each endoscopy visit. Comparisons between
`treatment groups were made using the log rank test to allow
`For those withdrawn for reasons other than ulceration. The
`
`cumulative incidence of gastric ulceration and duodenal ulcer-
`ation were also similarly analyzed separately. Similar per-proto-
`col analyses of efficaCy were also performed on assessable pa-
`tients. Assessable patients were defined as those who satisfied
`the inclusion and exclusion criteria, consumed >80% of both
`the prescribed NSAID and study drugs, did not consume addiu
`tional fullndose salicylates, and had their enduof-study end05u
`copy performed no more than 5 days after the end of study
`treatment. Secondary efficacy end points were also analyzed
`using “all patients treated" as the primary analysis and a per“
`protocol approach as the secondary analysis. The Mantel—
`Haenszel test or Kruskal—Wallis test were used where appro-
`priate. Comparisons were considered significant at P values of
`<01]?
`
`regression
`Prognostic factors. A Cox proportional
`model was constructed to assess the effects of 26 potential
`prognostic factors on cumulative ulcer incidence. The potential
`prognostic factors were identified before the study. These fac-
`tors were added to or removed From the model in a stepwise
`regressive procedure. based on a threshold P value (<O.l
`to
`be added or >U.l to be removed), with the effect of treatment
`group being included at each stage. The prognostic variables
`included the following; recruiting center, age, sex, smoking
`habit, alcohol use, type of NSAID, duration of prior NSAID
`use, rheumatological diagnosis. duration of arthritis, history
`of peptic ulceration. time to ulcer healing. presence of erosions
`or hemorrhagic lesions at screening endoscopy, ulcer size at
`
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`June 1997
`
`FAMOTIDINE AND NSAIDS 1819
`
`Table 1. Patient Characteristics in Healing and
`Maintenance Study ("All Patients Treated"
`Population)
`
`Maintenance
`
`Ulcer healing
`(n = 104)
`
`Farnutidine 40 mg
`{n = 39)
`
`Median age (yr. range)
`M/F
`Smokers {96]
`Alcohol consumption (RS)
`Rheumatoid/osteoarmritis
`PfEViOUS PUD ($5:
`Second-line therapy (95)
`Mean HAQ score {SD}
`NSND type
`Naproxsn (as)
`Indomethacin (95)
`DichIerlac E96]
`omer r95]
`PUD. peptic ulcer disease.
`
`53 [31-39)
`32/72
`32 [31)
`45 [4-3)
`32/22
`26 (25)
`25 [24].
`1.4 [0.8)
`
`31 (30)
`19 [13)
`14 [13}
`40 [38)
`
`53 (32-79)
`14,125
`13 133)
`17 {44}
`34/5
`12 (31)
`12 {31}
`1.5 [0.8)
`
`14 (36)
`3 (a;
`6 (15}
`16 {41}
`
`Placebo
`in = 39)
`
`55 [35-391
`12,127
`12 [31)
`18 [46]
`3376
`11 (28)
`1o [18)
`1.5 (0.8}
`
`11 (28)
`9 [23)
`4 [10)
`15 [39)
`
`endoscopy, abdominal pain at baseline, HAQ score, second—
`line antirheurnatoid agent prednisolone, total leukocyte count,
`hemoglobin. and platelet count.
`
`Results
`
`Five hundred seventy patients (Glasgow, n : 299;
`Nottingham, [1 : 271) were invited to enter the study,
`ofwhom 389 accepted (Glasgow, n = 235; Nottingham,
`11 = 154). Of these, 104 had gastroduodenal ulcers at
`screening endoscopy (gastric ulcers, n = 76; duodenal
`ulcers, n = 42', and both, I] = 14) and were entered into
`the healing study; 69 (66%) were recruited from Glasgow
`and 3-5 (54%) from Nottingham. H. pylori status was
`established (histology and urease test) in 93 patients.
`The patients with no ulcer at screening participated in
`a primary prophylaxis study run concurrently. As shown
`in Table 1, patients were well matched for age, sex,
`smoking status, alcohol usage, underlying arthritis, ulcer
`history, ftCQuency of joint pain, HAQ score, and use of
`individual NSAIDS or disease—modifying drugs. Eighty—
`two patients had rheumatoid arthritis and 22 had osteoe
`arthritis. Sixteen patients agreed to stop their NSAID
`therapy during the course of the healing study, and 88
`continued NSAID therapy.
`
`Ulcer Healing Study
`
`At 4 weeks, 65.9% (95% confidence interval {CI},
`56.0%—7 5.8%) of patients who continued and 81.3%
`(95% CI, 54.4%—96.0%) who discontinued NSAID
`therapy had successfully healed ulcers on “all patients
`treated" analysis. Two patients unhealed at 4 weeks were
`not assessed further (see below). At 12 weeks, the cumu—
`lative healing rate was 89.0% (95% CI, 82.3%—95.7%)
`in patients who remained on NSAID therapy and 100%
`(95% CI, 82.9%—100.0%} in those who discontinued
`
`NSAID slapped
`___-__---_s——i.
`
`NSAID continued
`
`
`4
`Weeks
`3
`12
`
`
`
`at.healed a
`
`Figure 1. Proportion of patients with uicers healed with famotidine,
`40 mg twice daily, at 4 and 12 weeks in those who continued or
`discontinued NSAID therapy.
`
`NSAID therapy. Differences in healing rates were not
`significant at either 4 or 12 weeks (Figure 1). Ulcers
`failed to heal in 9 patients after 12 weeks of therapy, all of
`whom continued NSAID therapy. For the corresponding
`results per protocol, the cumulative healing rates were
`67.6% (95% CI, 56.7%—78.5%) vs. 76.9% (95% CI,
`54096—99896) at 4 weeks and 91.2% (95% CI, 84.4%—
`97.9%) vs. 100% (95% CI, 79.4%—100.0%) at 12
`weeks in NSAID users and nonusers, respectively.
`Of the prognostic variables, only ulcer size was sig
`nificantly and inversely correlated with ulcer healing.
`Nonetheless, the 12-week cumulative healing rate for 49
`ulcers that were >5 mm in diameter was 81.6% (95%
`
`CI, 70.7—92.5). Healing occurred in 85.7% (95% CI,
`76.6%—94.8%) of patients who were H. pylori negative
`and 95.0% (95% CI, 86.4%799696) of those who were
`H. pylori positive. When healing rates for gastric and
`duodenal ulcer were analyzed separately, the cumulative
`healing rates For gastric ulcers in 63 patients who contin-
`ued NSAID therapy were 63.5% (95% CI, 51.6%—
`75.4%) at 4 weeks and 86.7% (95% CI, 78.2%—95.2%)
`at 12 weeks. For duodenal ulcers, healing rates were
`75.7% (95% CI, 61.9%—89.5%) and 97.0% (95% CI,
`91.1%—100.0%), respectively. Similar results were ob—
`tained from the pereprotocol analysis.
`
`Maintenance Study
`
`Seventy—eight patients who continued to use
`NSAIDs agreed to enter the maintenance study, although
`1 patient did not undergo repeat endoscopy. Patient char-
`acteristics are shown in Table 1. On “all patients treated"
`
`Weeks
`:1
`12
`24
`
`
`‘rfk———_ _
`l a
`——___‘I
`
`Eamohdine
`""19 ”a
`'— — Placebo
`
`a: = 100
`
`.E .g
`'a 3!
`E E 5"
`ire E D
`
`Figure 2. Life table of cumulative incidence of ulcer recurrence rates
`at 4. 12. and 24 weeks in patients taking maintenance iamotidine.
`40 mg twice daily. compared with placebo.
`
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`

`1820 HUDSON ET AL.
`
`GASTROENTEROLOGY Vol. 112. N0. 6
`
`Table 2. Prognostic Variables for Ulcer Relapse During
`Maintenance Phase
`
`Cumulative relative risk
`
`
` (95% Cl) P value
`
`Famotidine 40 mg twice daily
`Duodenal ulcer in healing study
`Length of time to healing
`HAO score
`Use of ketoprofen
`Shorter duration of arthritis
`Model with H. pylori included
`Famotidine 40 mg twice daily
`Shorter duration of arthritis
`Baseline H. pylori status
`
`0.093 (0025—034)
`4.919 (133—1816)
`4.944 (125—1953)
`3.361 (1.41—8.01)
`8.06? (03141.39)
`0.935 (0.87—1.01)
`
`0.290 (0108—0774)
`0.953 (0893—1017)
`2.08 (059676.218)
`
`0.0003
`0.01?
`0.023
`0.006
`0.061
`0.071
`
`0.013
`0.149
`0.190
`
`analysis, the estimated cumulative incidence of gastrodu-
`odenal ulceration over the following 24 weeks for the 39
`patients taking placebo was 55.5% (95% CI, 36.6%—
`70.3%) compared with 26.0% (95% CI, 12.1%—39-9%)
`(P = 0.011) in patients taking famotidine, 40 mg twice
`daily (Figure 2). The crude ulcer incidence at 4 weeks
`was 54.2% (95% CI, 19.1%—49.3%) in the placebo
`group vs. 12.8% (95% CI, 2.5%—23.3%) in the famoti—
`dine group, and at 12 weeks was 49.9% (95% Cl,
`33.3%—66.5%) for placebo vs. 20.5% (95% CI, 7.8%—
`33.2%) for famotidine. Similar results were obtained
`following the per-protocol analysis.
`Famotidine also significantly reduced the incidence of
`gastric ulceration at 24 weeks when analyzed separately,
`from 41.4% (95% Cl, 24.0%758.7%) in the placebo
`group to 19.1% (95% CI, 6.3%—31.9%) in the famoti-
`dine group (P = 0026). For duodenal ulcers, the esti-
`mated rate was 16.7% (95% CI, 2.8%—50.6%) com—
`pared with
`7.9% (95% CI, 0.0%—16.5%) with
`famotidine (P = 0.31). Similar results were obtained
`following the per-protocol analysis.
`
`Risk Factors
`
`The Cox proportional regression analysis (Table
`2) confirmed the efficacy of famotidine. Famotidine, 40
`mg twice daily, was associated with an estimated condi—
`tional risk ratio of 0.093 (95% CI, 0025—0337) com-
`pared with placebo (P < 0.0003). Other significant ad-
`verse prognostic factors were as follows: not having a
`duodenal ulcer in the healing study, long time to ulcer
`healing, longer duration of arthritis,
`low HAQ score,
`and use of ketoprofen.
`included H.
`A similar analysis was performed that
`mien? status as a prognostic variable. In this analysis,
`baseline H. pylori infection was associated with a 2.08
`(range, 0.70—6.22) cumulative relative risk of relapse,
`although this did not reach statistical significance (P =
`0.19; Table 2). Estimated cumulative relapse rates in
`
`patients taking placebo were 63.6% (range, 43.5%—
`83.7%) in patients who were H. pylori positive (n = 25)
`and 23.8% (range, 0%—52.8%) in those who were H.
`pylori negative (n 2 10). For famotidine, the figures were
`25.1% (range, 3195—43095) for H. pylori—positive pa—
`tients (n = 18) and 21.4% (range, 4796—50396) for H.
`pylori—negative patients (n = 14).
`
`Secondary Efficacy Analyses
`
`Gastric mucosal injury expressed as a Lanza score
`was significantly lower in the famotidine group compared
`with placebo at the 4-week endoscopy in both the healing
`and maintenance study (P = 0.042). Data for later endo-
`scopies could not be analyzed directly because they were
`confounded by selective dropout of ulcer patients. Dififer—
`ences between the treatment groups for abdominal pain
`scores, mean daily antacid consumption, and arthritic
`pain scores were not significant, and there was no correla-
`tion between abdominal pain and the presence or absence
`of ulceration.
`
`Safety and Withdrawals
`
`In the ulcer healing study, 1 patient died of bron-
`chopneumonia and multisystem disorder and 1 of pancre-
`atic cancer after completing the study. One patient With—
`drew because of nausea and vomiting. In the maintenance
`study, 4 patients in the famotidine group and 7 in the
`placebo group were withdrawn for reasons other than
`ulcer relapse. One patient
`in each group was lost
`to
`follow—up evaluation, and 3 patients in the placebo group
`were unwilling to continue. There were three withdraw—
`als in both the famotidine and placebo groups because
`of adverse events; none of them were drug related.
`Famotidine was well
`tolerated as both healing and
`maintenance therapy. In the healing study, 10.6% of
`patients appeared to have drug—related adverse events,
`and 1 patient withdrew.
`In the maintenance study,
`28.2% of patients taking famotidine had adverse events,
`of which 12.8% were believed to be drug related, and
`35.9% of those in the placebo group had adverse events,
`of which 12.8% were also believed to be drug related.
`
`This study shows that famotidine, 40 mg twice
`daily, heals ulcers in arthritic patients who continue
`NSAID therapy and reduces subseqent relapse when con—
`tinued after successful healing. There was no significant
`retardation of healing in patients who continued NSAID
`therapy compared with those who stopped. Although
`relatively few patients stopped NSAID therapy and we
`cannot completely exclude the possibility that retarda-
`tion in those who continued was missed, this is unlikely
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`

`June 1997
`
`FAMOTIDINE AND NSAIDS 1821
`
`to be a major effect because the healing rate in this group
`was high and similar to that previously reported for ome—
`prazole, 40 mg daily.” Famotidine was effective in heal-
`ing both gastric and duodenal ulcers and in those who
`were either H. pylori positive or negative and seemed to
`be effective for larger as well as smaller ulcers. Subgroup
`analysis of the relapse data must be more guarded because
`of the possibility of confounding due to the differential
`relapse rate and because numbers were small. It seems
`clear that famotidine was able to prevent gastric ulcer
`relapse. In our study, there were too few duodenal ulcers
`to know whether the relapse rate was truly reduced.
`However, there was a trend in this direction, and previous
`studies have shown that duodenal ulcers are easier to
`
`prevent than gastric ulcers using standard doses of 1—12
`antagonists under primary prophylaxis conditions?”J Re-
`lapse rates in patients taking famotidine were similar
`whether patients were H. pylori positive or negative, but
`small numbers limit the confidence of this conclusion.
`
`Whether H. pylori eradication would affect the clinical
`course of NSAID users is unknown and is currently the
`subject of investigation. However, epidemiological data
`suggest that the risk of NSAID-associated ulcer compli-
`cations may not be substantially influenced by H. pylori
`status.20
`
`We used a high dose of famotidine because previous
`work has suggested that healing rates with standard doses
`of H2 antagonists are reduced if NSAID therapy is con-
`tinued
`zl'fl but
`that this effect
`is abolished if a more
`
`profound effect with proton pump inhibitors is used.1H
`We have also found that only the higher dose of famoti-
`dine, when used as primary prophylaxis, was capable of
`reducing significantly the incidence of gastric ulcer.17
`Our data are compatible with earlier evidence that more
`profound acid suppression can overcome the retardation
`of healing by NSAID therapy.” These data are also sup-
`ported by short-term studies in volunteers that show that
`proton pump inhibitors or high doses of famotidine are
`more effective than standard doses ong receptor antago-
`|.—I
`1‘
`5 and more
`nists in preventing acute gastric erosions
`recent evidence, reported in abstract form, concerning
`large trials of the proton pump inhibitor omeprazole.”
`Previous studies have examined the use of both rani-
`
`tidine and misoprostol in the prevention of NSA ID-asso-
`ciated gastroduodenal ulcerations—7’” Misoprostol ap-
`pears to confer protection against both gastric and
`duodenal ulcers, whereas standard doses of tanitidine pre—
`vented duodenal ulcers but were relatively ineffective
`in preventing gastric ulcers. However, in most of these
`studies, patients with ulceration at baseline endoscopy
`were either excluded from entry or a mixed group was
`studied and H. pyfari' status was not established. Epidemi—
`
`ological evidence suggests that patients with a history of
`peptic ulcer disease are at greater risk of subsequent
`ulceration and ulcer complications.“ This phenomenon
`was also observed in previous studies in that the rate of
`ulceration observed endoscopically was greater in patients
`with an ulcer history” or in those in whom ulcers were
`healed before entry.“ Our study directly establishes the
`importance of ulceration detected during NSAID use as
`a risk factor for further ulceration, because the placebo
`relapse rate was 52.3%, significantly higher than the
`25.8% we found in patients who did not have ulcers at
`baseline endoscopy and who were studied under primary
`prophylaxis conditions.17 We are confident that this dif—
`ference is likely to be genuine for a variety of reasons.
`Patients in the two studies were drawn from the same
`
`populations and studied concurrently to an identical pro-
`tocol. All examinations were conducted by two endoscop—
`ists, each of whom agreed on criteria for ulcer diagnosis,
`thereby avoiding the large interobserver variation in the
`assessment of NSAID—associated gastroduodenal lesions
`that is likely to characterize other large studies conducted
`in multiple centers.25 The high subsequent relapse rate
`associated with detection of an ulcer in NSAID users has
`
`important implications for management and reinforces
`the notion that this is a group in whom maintenance
`treatment should be considered if the NSAID therapy
`cannot be stopped. Our data suggest that treatment with
`famotidine, 40 mg twice daily, would be appropriate to
`consider for these patients.
`
`References
`
`1. Griffin MR. Piper JM, Daugherty JR, Snowden M, Ray WA. Noni
`steroidal anti-inflammatoryr drug use and increased risk for peptic
`ulcer disease in elderly persons. Ann Intern Med 1991:1142
`25? —263.
`2. Guess HA, West R, Strand LM, Helstcn D, Lydiclt EG. Bergman
`U. Wolski K. Fatal upper gastrointestinal heemorrhage or perfora-
`tion among users and nonusers of antiinflammatory drugs in
`Saskatchewan. Canada. 1983. J Clin Epidemiol 1988;41:35—
`45.
`3. Hawkey CJ. Non-steroidal anti-inflammatory drugs and peptic ul-
`cers. Facts and figures multiply, but do they add up? Br Med J
`1990: 300:278— 284.
`4. Langman MJS, Weil J, Wainwright P, Lawson DH, Rawlins MD,
`Logan RFA, Murphy M, Vessey MP, Colin—Jones 06. Risk of
`bleeding peptic ulcer associated with individual non steroidal
`anti-inflammatory drugs. Lancet 1994;343:1075—1078.
`5. Ehsanullah RSB, Page MC. ‘l’rldesley G. wood JR. Prevemion of
`gastroduodenal damage induced by nonisteroidal antiiinflamma
`tory drugs: controlled trial of ranitidine. Br Med J 1988:297:
`1017—1020.
`6. Graham DY, White RH, More-land LW, Schubert T. Kat: R, Jaszew-
`ski R. Duodenal and gastric ulcer prevention with misoprostol in
`arthritic patients taking NSAIDs: Misoprostol Study Group. Ann
`Intern Med 1993;119:257-262.
`7. Fries JF. Williams GA, Bloch DA, Michel BA. Nonsteroidal anti-
`inflammatory drug—associated gastropathy: incidence and risk
`factor models. Am J Med 1991;91:213—222.
`
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`1822 HUDSON ET AL.
`
`GASTROENTEROLOGY Vol. 112. N0. 6
`
`Laporte J—R. Carme X. Vidal X. Moreno V. Juan J. Upper gastroin—
`testinal bleeding in relation to previous use of analgesics and
`non-steroidal anti—inflammatory drugs. Lancet 1991; 337:85—89.
`Graham DY, Agrawal NM, Roth SH. Prevention of NSAID-induced
`gastric ulcer with misoprostol: multicentre. double blind, placebo
`controlled trial. Lancet 1988;2:12??—1280.
`Agrawal NW. Roth S, Graham DY. White RH. Germain B. Brown
`JA, Stromatt SC. Misoprostol compared with sucralfate in the
`prevention of non steroidal anti-inflammatory drug induced gas-
`tric ulcer: a randomised controlled trial. Ann Intern Med 1991;
`115:195—200.
`Silverstein FE, Graham DY. Senior JR. Davies Hw. Struthers BJ.
`Bittman RM. et al. Misoprostol reduces serious gastrointestinal
`complications in patients with rheumatoid arthritis receiving non
`steroidal anti-inflammatory drugs: a randomised. double blind
`placebo controlled trial. Ann Intern Med 1995: 123:241—249.
`Roth 5, Agrawal N, Mahowald M. Montoya H. Robbins D, Miller
`S. Nutting E. Woods E. Crager M, Nissen C. Swabb E. Misoprostol
`heals gastroduodenal injury in patients with rheumatoid arthritis
`receiving aspirin. Arch Intern Med 1989;149:775—779.
`Daneshmend TK. Pritchard PH. Bhaskar NK. Millns P. Hawkey
`CJ. Use of microbleeding and an ultrathin endoscope to assess
`gastric mucosal protection by famotidine. Gastroenterology
`1989; 9? :944—949.
`Daneshmend TK. Stein AG, Bhaskar NK. Hawkey CJ. Abolition
`by omeprazole of aspirin induced gastric mucosal
`injury in hu-
`mans. Gut 1990;31:514—517.
`Cole AT, Brundell S, Hudson N. Hawthorne AB. Mahida YR.
`Hawkey CJ. Ranitidine: differential effects on gastric bleeding
`and gastric mucosal damage induced by aspirin. Aliment Pharma-
`col Ther 1992:6:707—715.
`Lanza FL. A double blind study of the prophylactic effects of
`misoprostol on lesions of the gastric and duodenal mucosa in-
`duced by oral administration of tolmetin in healthy subjects. Dig
`Dis Sci 1986;31(Suppl):131—136.
`Taha AS, Hudson N. Trye P, Cottrell J. Mann 5, Wannell AJ. Trye
`PN. Cottrell J. Mann 86. Simon TJ. Sturrock RD. Russell RI.
`Prevention of NSAID related gastric and duodenal ulcers by fa—
`motidine: a placebo controlled double blind study. N Engl J Med
`1996; 334:1435— 1439.
`Walan A. Bader J—P. Glassen M. Lammern CB. Piper DW. Effect
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`17.
`
`18.
`
`of omeprazole and ranitidine on ulcer healing and relapse rates
`in patients with benign gastric ulcer. N Engl J Med 1989:320:
`69— 75.
`Robinson MG. Griffin Jw. Bowers J. Kogan FJ, Kogut DG. Lanza
`FL. Warner CW. Effect of ranitidine on gastroduodenal mucosal
`damage induced by non steroidal anti-inflammatory drugs. Dig
`Dis Sci 1989;34:424—428.
`Cullen DJE, Hawkey GM, Humphries H, Cave R. Sheperd V. Logan
`RFA. Hawkey CJ. Role of non steroidal anti-inflammatory drugs
`and Helicobacter pylori in bleeding peptic ulcer (abstr). Gastroen-
`terology 1994;106:A66.
`Lancaster-Smith MJ, Jaderberg MR, Jackson DA. Ranitidine in
`the treatment of non-steroidal anti-inflammatory drug associated
`gastric and duodenal ulcers. Gut 1991;32:252—256.
`Bank 5. Greenberg RE, Zucker S. Ranitidine and non steroidal
`anti-inflammatory drug (NSAID) associated gastric and duodenal
`ulceration. Gut 1991;32:963—964.
`Hawkey OJ. Swannell AJ, Eriksson S. Walan A. Lofberg I. Taure
`E. Wicklund I. Yeomans ND. Benefit ofomeprazole over misopros—
`tol in healing NSAID associated ulcers labstr). Gastroenterology
`1996: 1102A131.
`Elliot SD. Yeomans ND. Buchanan RRC, Duckham ML. Boyden
`KN. Newnham RG. Smallwood RA. Long term effects of misopros-
`tol on gastropathy induced by non steroidal anti-inflammatory
`drugs (NSAIDs) (abstr). Gastroenterology 1990;98:A40.
`Hudson N. Everitt S. Hawkeyr CJ. Inter observer variation in the
`endoscopic classification of NSAID associated gastric lesions.
`Gut 1994;35:1030—1032.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`
`25.
`
`Received June 19. 1996. Accepted February 4. 1997.
`Address requests for reprints to: Christopher J. Hawkey. M.D..
`F.R.C.P.. Division of Gastroenterology, University Hospital. Notting-
`ham NG? 2UH. England. Fax: {44) 0115-9422232.
`This study was developed in collaboration with Merck Research
`Laboratories UK following an approach from the academic investiga
`tors and was funded by Merck Research Laboratories UK.
`The authors thank Dr. G. Birnie. Dr. D. H. Bossingham. and Dr.
`J. K. Lloyd-Jones for their help in recruiting patients to the study. and
`David Thompson of Applied Statistics for performing the statistical
`analysis.
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`GASTROENTE RDLDGY 1997;112:1817-1822
`
`Famotidine for Healing and Maintenance in Nonsteroidal Anti-
`inflammatory Drug—Associated Gastroduodenal Ulceration
`
`NICHOLAS HUDSON,* ALI S. TAHA,+ ROBIN I. RUSSELL,T PENELOPE TRYE,§ JEREMY COTTRELL,§
`STEPHEN G. MANN.§ ANTHONY J. SWl'SiNELL,H ROGER D. STURROCK,T
`and CHRISTOPHER J. HAWKEY*
`* Division of Gastroenterology. University Hospital, Nottingham, England: *Department of Gastroenterology and Rheumatology. Glasgow
`Royal Infirmary, Glasgow. Scotland; Elvlerclt Research Laboratories UK. Hoddesdon. Herts, England; and "Department of Rheumatology.
`University and City Hospitais. Nottingham. England
`
`See editorial on page 2143.
`
`Bacgground & Aims: Nonsteroidal anti-inflammatory
`drugs (NSAIDs) are strongly associated with gastroduo—
`denal ulceration. How to manage patients with NSAID-
`associated ulcers is a common clinical dilemma. High-
`dose famotidine in the healing and maintenance of
`NSAID-associated gastroduodenal
`ulceration was
`therefore evaluated. Methods: One hundred four pa-
`tients with rheumatoid or osteoarthritis who had gastro-
`duodenal ulceration received famotidine, 40 mg twice
`daily. Sixteen patients stopped and 88 continued their
`NSAID treatment. Ulcer healing was assessed endo~
`scopically at 4 and 12 weeks. Seventy-eight NSAID
`users with healed ulcers were then randomized to re
`
`ceive 40 mg twice daily famotidine or placebo and un-
`
`derwent endoscopy at 4, 12. and 24 weeks. Results:
`Cumulative ulcer healing rates at 12 weeks were 89.0%
`(95% confidence interval [CI]. 82.3%—95.7%l for pa-
`tients who continued NSAI