Misoprostol Compared with Sucralfate in the Prevention
`of Nonsteroidal Anti-inflammatory Drug-induced Gastric
`Ulcer
`
`A Randomized, Controlled Trial
`
`Naurang M. Agrawal, MD; Sanford Roth, MD; David Y. Graham, MD;Richard H. White, MD;
`Bernard Germain, MD; Jeffry A. Brown, MD; and Scott C. Stromatt, MD
`
`™@ Objectives: To compare the efficacy and frequency
`of adverse experiences of misoprostol and sucralfate in
`the prevention of gastric ulcers in patients receiving
`nonsteroidal anti-inflammatory drug (NSAID) therapy.
`@ Design: A prospective, randomized, single-blind,
`multicenter trial.
`@ Patients: Patients with osteoarthritis receiving treat-
`ment with ibuprofen, piroxicam, or naproxen and expe-
`riencing abdominal pain were eligible.
`@ Interventions: Patients who were expected to re-
`ceive at least 3 months of NSAID therapy and who did
`not have a gastric ulcer at the time of the initial
`screening endoscopy were randomized to receive mi-
`soprostol, 200 jg four times a day, or sucralfate, 1g
`four times a day. A gastric ulcer was defined as a lesion
`of the gastric mucosa 0.3 cm or greater in diameter.
`Patients were followed clinically, and repeat endosco-
`pies were performed after 4, 8, and 12 weeks.
`@ Main Measurement: The development of a gastric
`ulcer, which was regarded as a prophylaxis failure.
`@ Results: Two hundred fifty-three patients were eval-
`uable for efficacy analysis. A gastric ulcer developed in
`2 of the 122 (1.6%, 95% Cl, 0.3% to 6.4%) patients on
`misoprostol, compared with 21 of 131 patients on
`sucralfate (16%, Cl, 10.4% to 23.7%). The difference in
`ulcer rates was 14.4% (Cl, 10.4% to 19.5%; P < 0.001).
`@ Conclusion: In patients receiving chronic NSAID
`therapy for osteoarthritis, treatment with misoprostol
`for 3 months was associated with a significantly lower
`frequency of gastric ulcer formation, compared with
`treatment with sucralfate (P < 0.001).
`
`Annals of Internal Medicine. 1991;115:195-200.
`
`From Tulane University School of Medicine, New Orleans,
`Louisiana; Arizona Arthritis Research & Education, Ltd.,
`Phoenix, Arizona; Baylor College of Medicine/Veterans Affairs
`Medical Center, Houston, Texas; University of California, Da-
`vis and Sacramento, California; University of South Florida,
`Tampa, Florida; University of Illinois, Chicago, Illinois; and
`University of Health Sciences/Chicago Medical School, Chi-
`cago, Illinois. For a list of additional study investigators and
`for current author addresses, see end of text.
`
`Nonsteroidal anti-inflammatory drugs (NSAIDs) are an
`integral part of the therapy of rheumatic diseases. These
`drugs can damage the gastrointestinal
`tract and have
`been implicated as a cause of peptic ulceration and
`life-threatening bleeding (1-4). The inhibitory effect of
`NSAIDs on the endogenous biosynthesis of prostaglan-
`dins is thought
`to be the major mechanism for the
`therapeutic properties of NSAIDs in the treatment of
`inflammatory arthritis, although other mechanisms have
`recently been proposed (5). Prostaglandins play a sig-
`nificant role in the defense of gastrointestinal mucosa
`(6, 7). Prostaglandins of the E series have gastric an-
`lisecretory and mucosal protective properties, and
`NSAID-induced inhibition of gastric mucosal prosta-
`glandin synthesis is thought to be responsible for much
`of the gastrointestinal
`tract
`toxicity associated with
`these agents (3, 6-8).
`Misoprostol, a synthetic prostaglandin E, analog, has
`been shownto be effective in the prevention of NSAID-
`induced gastric ulcers in patients with arthritis (9). This
`agent has also been shown to prevent the development
`of NSAID-induced duodenal lesions both in normal sub-
`jects (10, 11) and in arthritic patients (12). The benefi-
`cial effects of misoprostol on the gastrointestinal tract
`are not accompanied by a compromise ofthe antirheu-
`matic effects of the NSAID (13, 14).
`Sucralfate is an effective anti-ulcer drug that has been
`shown to increase the release of endogenous prostaglan-
`dins from the gastric mucosa (15, 16), suggesting that
`stimulation of prostaglandin synthesis may be a mech-
`anism for its action. Despite the fact that sucralfate is
`widely used to prevent NSAID-induced gastrointestinal
`mucosal damage, no study has evaluated the efficacy of
`sucralfate in the prevention of NSAID-induced mucosal
`damage in chronic NSAID users.
`We compared misoprostol and sucralfate in the pre-
`vention of NSAID-induced gastric ulcer in a large co-
`hort of patients with osteoarthritis who were experienc-
`ing upper gastrointestinal pain in association with the
`use of NSAID therapy.
`
`Methods
`
`Patients were recruited from private practice offices and
`clinics, Veterans Affairs clinics, health maintenance organiza-
`tions, and academicinstitutions. Patients were eligible to enter
`the study if they had osteoarthritis and were experiencing
`upper abdominal pain that was thought to be caused by one of
`three NSAIDs: ibuprofen, piroxicam, or naproxen. In addition,
`
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`it was required that all patients be expected to receive
`NSAIDs for at least 3 additional months. Women had to be
`postmenopausal, surgically sterilized, or practicing adequate
`contraception. Women of child-bearing potential were in-
`formed of the possibility that use of misoprostol could result in
`a miscarriage. A pregnancy test was done 72 hours before
`receiving the first dose of study medication; if the pregnancy
`177
`179
`Patients, n
`test was positive, the patient was excluded. Exclusion criteria
`
`Median age, (range) y 60 (30 to 82)=60 (29 to 82)
`included a history of recurrent peptic ulcer disease, active
`Women:men, %
`56:44
`59:41
`bleeding ulcer, upper gastrointestinal malignancy or metastasis
`Race, %
`to the upper gastrointestinal tract, pyloric or duodenal obstruc-
`White
`tion, acute hepatitis, pancreatitis, inflammatory bowel disease.
`Nonwhite
`bleeding diathesis, upper gastrointestinal surgery within 30
`NSAID* used, %
`days, or severe renal impairment. Patients taking antineoplas-
`41
`35
`Ibuprofen
`tic drugs, anticoagulants, or anti-ulcer drugs, other than the
`i
`40
`Naproxen
`study drugs, were excluded.
`28
`25
`Piroxicam
`15
`Smokers (> 10 cigarettes/d),% 14
`23
`Alcohol use, %
`18
`80
`Previous antacid use, %
`84
`10.1
`Duration of osteoarthritis, y
`9.4
`1.4
`Duration of NSAID use, y
`1.7
`
`History of ulcer disease, % 26.6 22.4
`
`
`Table 1. Demographic and Clinical Characteristics of the
`Intent-to-Treat Cohort (All Randomized Patients)
`
`Characteristic
`
`Misoprostol
`Group
`
`Sucralfate
`Group
`
`89
`11
`
`&4
`16
`
`Study Design
`
`The study was a prospective, randomized, single-blind, mul-
`ticenter comparison of misoprostol, 200 yg given four times a
`day (with meals and at bedtime) and sucralfate, 1 g four times
`a day (30 minutes before meals and at bedtime). Patients were
`referred for abdominal pain that was thought by the investiga-
`tors to be due to NSAID therapy. Patients were entered con-
`secutively into the study.
`Eligible patients underwentan initial screening upper gastro-
`intestinal endoscopy. Patients in whom a gastric or duodenal
`ulcer was found were excluded from the study, Patients with-
`out a gastric ulcer were randomized and started on a study
`drug within 72 hours of the entry endoscopic examination.
`Patients continued to take NSAIDs at the same dose that was
`administered before the study.
`Although the patients in the study could have possibly rec-
`ognized their study medication, the endoscopists were blinded
`to the medications being taken by the patients.
`In addition,
`patients were instructed not to discuss their study medications
`or symptoms with the endoscopists.
`The gastric mucosa was examined by fiberoptic endoscopy
`after 4 weeks (+ 3 days), 8 weeks (+ 5 days), and 12 weeks
`(+ 5 days) after randomization. Patients were allowed to take
`up to four aluminum hydroxide antacid tablets per day, during
`the first week only, for relief of upper gastrointestinal pain.
`Patients were instructed to take the study medication the night
`before the endoscopy and not to take the next dose until after
`the procedure was completed. Noncompliance was defined as
`failure to take at least 75% of prescribed medication and was
`determined at 4, 8, and 12 weeks by counting pills not taken,
`The protocol was approved by an institutional review board,
`and each patient gave written, informed consent,
`
`End Point
`
`The primary end point of the study was the development of
`a gastric ulcer at the time of any of the follow-up endoscopic
`procedures. A gastric ulcer was defined as a circumscribed
`break in the gastric mucosa of 0.3 cm in diameter or greater.
`Additionally,
`the frequency of adverse experiences was as-
`sessed by the clinical investigator.
`
`Statistics
`
`Treatment group comparability at bascline was assessed by
`evaluating the hypothesis of equivalent treatment group means
`using analysis of variance for the following factors: age, height,
`weight,
`temperature, heart
`rate, and blood pressure. This
`method was also used to compare the mean change from
`baseline at the end of the trial between the treatment groups,
`with respect to each of the continuous laboratory variables.
`The Pearson chi-square test or Fisher exact test was used to
`compare the proportion of patients in the two treatment groups
`who developed a gastric ulcer during trial participation, with
`respect to both intent-to-treat and evaluable patient groups.
`The gastric ulceration rate was analyzed using survival meth-
`ods, Life-table estimates of the ulcer-free rate were computed
`and the log rank test was used to compare treatments. Addi-
`tionally, ulcer rates were analyzed by size at
`the 12-week
`
`* NSAID = nonsteroidal anti-inammatory drug.
`
`period using the Fisher exact test. The time until gastric ulcer
`occurrence was analyzed by fitting a Cox proportional hazards
`regression model with the following factors included as cova-
`riates:
`treatment group, aluminum hydroxide use, NSAID
`type, baseline erosion, baseline gastritis, baseline abnormal
`mucosa, history of ulcer disease including gastritis, history of
`ulcer disease excluding gastritis, and history of gastritis.
`The frequency of endoscopically abnormal mucosa, “‘gastri-
`tis,” and erosions was analyzed at each time point using the
`chi-square test. Statistical significance was assessed at the 0.05
`level. All reported P values are two-sided.
`
`Results
`
`Four hundred three patients underwent baseline en-
`doscopy screening, of whom 47 (11.7%) were found to
`have an active ulcer and were excluded from the study.
`However, the screening data possibly under-report the
`point prevalence of gastric ulcers because several inves-
`tigators were screening patients for other trials. Of the
`remaining 356 patients, 179 (S0%) were randomized to
`receive misoprostol and 177 (50%) were randomized to
`receive sucralfate. A total of 352 patients took at least
`one dose of the study medication (176 in each group)
`and therefore qualified for analysis of the frequency of
`adverse experiences. Three patients in the misoprostol
`group and one patient in the sucralfate group did not
`take any medication after randomization. One hundred
`twenty-two of the 179 patients randomized to receive
`misoprostol and 131 of the 177 randomized to the su-
`cralfate group were evaluable for efficacy analysis.
`Among the patients who were randomized (the intent-
`to-treat cohort), there were no statistically significant
`differences between the study groups with respect to
`demographic or clinical characteristics (Table 1). The
`median age for all study participants was 60 (range 29 to
`82 years), with two thirds of the patients over 55 years
`of age. Fifty-eight percent were women and 86% were
`white. Approximately 20% of the patients reported con-
`sumption of alcohol, and 15% smoked more than 10
`cigarettes per day. The mean reported duration of os-
`teoarthritis was 9.7 years and of NSAID use, 1.6 years.
`The proportion of patients using each of the three
`
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`A Cox proportional hazards model (stepwise-forward)
`was fit
`to the time to gastric ulceration using peptic
`ulcer disease history and the presence of gastric ero-
`sions at the time of initial screening endoscopy among
`the covariates. Treatment group entered the model at
`step | (improvement chi-square P < 0.001; global chi-
`square P < 0.001) and baseline erosion entered at step
`2 (improvement chi-square P = 0.02; global chi-square
`P < 0.001).
`term,
`The coefficient associated with the treatment
`comparing sucralfate to misoprostol,
`is 2.4 (CI, 0.9 to
`3.8), The adjusted hazard (risk) ratio is then 10.9 (CI,
`2.6 to 44.7). The graph of the log negative-log survival
`function stratified by treatment group is roughly paral-
`lel. Therefore,
`the proportional hazards assumption is
`satisfied. A history of peptic ulcer disease was not as-
`sociated with an increased risk of gastric ulcer forma-
`tion among the evaluable cohort (P > 0,2). Twenty-six
`of the 122 (21%) evaluable misoprostol-treated patients
`and 35 of the 131 (27%) sucralfate-treated patients re-
`ported one previous episode of ulcer disease. One of the
`two patients who developed a gastric ulcer while taking
`misoprostol had a history of a previous ulcer, and 3 of the
`21 patients who developed a gastric ulcer while taking
`sucralfate had a history of a previous ulcer.
`Baseline gastric erosions in the evaluable cohort were
`present in 47 of 122 (39%) patients randomized to mi-
`soprostol and in 50 of 131 (38%) patients randomized to
`sucralfate. The frequency of erosions decreased over
`the 3-month period in the misoprostol group and re-
`mained unchanged in the sucralfate-treated patients.
`Erosions at baseline were found to be significantly re-
`lated to ulcer development, regardless of the treatment
`
`
`
`
`18
`
`16
`
`16.0%
`
`
`
`WH Sucralfate
`Misoprostol
`*P<0.001
`** P = 0.003
`
`14
`
`12
`
`
`
`PercentwithGastricUlcers
`
`
`
`NSAIDs was comparable: 38% ibuprofen, 26% piroxi-
`cam, and 36% naproxen. The proportions within each
`treatment group were also comparable. In the misopros-
`tol group, 35% were using ibuprofen; 40%, naproxen;
`and 25%, piroxicam. In the sucralfate group, 41% were
`using ibuprofen; 31%, naproxen; and 28%, piroxicam. A
`history of ulcer disease was reported by 25%ofpatients
`randomized,
`Of the 356 patients, 253 could be evaluated using
`life-table analysis. One hundred and three patients were
`not evaluable for efficacy: 57 in the misoprostol group
`and 46 in sucralfate group (P = 0.2). In the misoprostol
`group, 43 of these 57 patients (75%) were noncompliant,
`7 were lost to follow-up, and 7 had a protocol violation.
`In the sucralfate group, 41 of the 46 patients (89%) were
`noncompliant, 4 were lost
`to follow-up, and | had a
`protocol violation, There were no clinically significant
`differences in clinical or demographic characteristics be-
`tween the groups in the evaluable cohort or in the
`patients who dropped out of the study.
`
`Prevention of Nonsteroidal Anti-inflammatory
`Drug-induced Ulcers
`
`Analyzing the 253 evaluable patients who completed
`the study, 2 of 122 (1.6%; Cl, 0.3% to 6.4%) patients
`randomized to receive misoprostol developed a gastric
`ulcer compared with 21 of 131
`(16%; CI, 10.4% to
`23.7%) patients randomized to receive sucralfate over
`the 3-month study period (P < 0.001; Figure 1). The
`difference between groups in the frequency of gastric
`ulcer development
`(14.4%; Cl, 10.4% to 19.5%)
`re-
`mained significant when the analysis was restricted to
`ulcers equal
`to or greater than 0.5 cm in diameter
`(8.4%; 95% Cl, 5.4% to 12.7%). The frequency of gas-
`tric ulcers of 0.5 cm or greater in patients randomized
`to receive misoprostol was 0.8% (CI, 0.04%to 5.1%)
`compared with 9.2% (Cl, 5.1% to 15.8%) in patients
`randomized to receive sucralfate (P = 0.003; Figure 1).
`Figure 2 shows the probability of being free of a gastric
`ulcer as a function of the treatment interval using life-
`table analysis of the 253 evaluable patients.
`When results were analyzed based on the principle of
`intention-to-treat, 5 of 179 (3%) patients randomized to
`misoprostol and 25 of 177 (14%) of patients randomized
`to sucralfate developed a gastric ulcer (P < 0.005).
`Of the 356 patients who were randomized, 292 (82%)
`used some aluminum hydroxide tablets during thefirst
`week for treatment of ongoing upper gastrointestinal
`pain. There was nostatistical difference between treat-
`ment groups in the proportion of patients taking alumi-
`num hydroxide (P > 0.2). Further, the use of aluminum
`hydroxide was not predictive of the subsequent devel-
`opment of a gastric ulcer (P > 0.2). In patients random-
`ized to receive misoprostol, 5 of 151 (3%) patients who
`took aluminum hydroxide developed a gastric ulcer,
`whereas none of the 28 patients who did not take alu-
`minum hydroxide developed a gastric ulcer. In the su-
`cralfate group, 19 of the 141 (14%) patients who took
`aluminum hydroxide during the first week developed a
`gastric ulcer, compared to 6 of the 36 patients (17%)
`who did not take aluminum hydroxide during the first
`week.
`
`203 cm
`
`20.5 cm
`
`Ulcer Diameter
`
`Figure 1. Percentage of patients with gastric ulcers as a function
`of ulcer diameter. Among sucralfate-treated patients, 16.0%
`(98% Cl, 10.4% to 23.7%) had an ulcer 20.3 cm in diameter
`compared with 1.6% (Cl, 0.3% to 6.4%) in the misoprostol
`group (P < 0.001). Ulcers = 0.5 cm in diameter developed in
`9.2% (Cl, 5.1% to 15.8%) of the sucralfate group compared
`with 0.8% (CI, 0.04% to 5.1%) of the misoprostol group (P =
`0.003. P values are derived from the methods of Fleiss).
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`

`group. The overall relative odds ratio, which includes
`all evaluable patients in both the misoprostol and the
`sucralfate groups, was 2.75 (odds of ulcer with erosions
`divided by odds of ulcer without erosions; CI, 1.14 to
`6.63). The presence of gastric erosions at the time of
`initial endoscopy was associated with an increased risk
`of gastric ulcer development (P = 0.02). Thirteen of 50
`(26%) patients in the sucralfate group, who had erosions
`at baseline endoscopy, developed a gastric ulcer com-
`pared with 8 of 81 (10%) patients without
`initial ero-
`sions. A gastric ulcer developed in | of the 47 miso-
`prostol-treated patients who had gastric erosions at
`baseline endoscopy compared with | of 75 misoprostol-
`treated patients who had no baseline gastric erosions.
`The assessment of duodenal ulcer development was
`not a primary objective of this prospective study. How-
`ever, a review of the endoscopy results from the 253
`evaluable patients revealed only three duodenal ulcers:
`two in the misoprostol-treated group and one in the
`sucralfate-treated group.
`
`Frequency of Adverse Experiences
`
`frequent adverse effect was dyspepsia,
`The most
`which was reported by 55 (31%) patients in the miso-
`prostol group and 42 (24%) in the sucralfate group (P =
`0.1). Overall, diarrhea developed in 45 (26%) patients
`randomized to receive misoprostol and in 9 (5%) pa-
`tients randomized to receive sucralfate (P < 0.01). Six-
`ty-eight percent of the diarrheal episodes occurred in
`the first 2 weeks of misoprostol therapy. The episodes
`of diarrhea in the misoprostol group were mild or mod-
`erate in 79% of patients. Twenty-one percent of the
`
`
`
`Probability(%)
`
`100
`
`
`
`Figure 2. Percentage of patients without a nonsteroidal anti-
`inflammatory drug-induced gastric ulcer as determined by life-
`table analysis. At 3 months,
`the probability of being free of
`gastric ulcer was 97.2% (95% Cl, 93.3% to 100%) in the mis-
`oprostol-treated group and 80.8% (CI, 73.0 to 88.5%) in the
`sucralfate-treated group. * = significantly shorter time to ulcer
`development compared with misoprostol (log rank P < 0.001).
`
`episodes were classified as severe, but the drop-out rate
`attributed to diarrhea was only 3% (Table 2).
`Thirty-one of the 176 (18%) patients randomized to
`receive misoprostol and 16 of the 176 (9%) patients
`randomized to receive sucralfate, who took at least one
`dose of study medication, terminated the study because
`of an adverse event (P = 0.02). Among patients ran-
`domized to receive misoprostol,
`15
`(9%) patients
`stopped the study because of dyspepsia and 5 (3%)
`patients terminated the study because of diarrhea.
`In
`patients randomized to sucralfate, 10 (6%) patients ter-
`minated the study because of ongoing dyspepsia and
`one patient terminated the study because of diarrhea.
`A total of 14 patients (seven in each treatment group)
`reported adverse experiences that were regarded as po-
`tentially serious. However, none of these events re-
`sulted in death. Chest pain was the most frequently
`occurring s¢rious event (two patients in the misoprostol
`group and one in the sucralfate group). There were no
`clinically significant differences between treatment
`groups in changesin any of the laboratory values during
`the study (P > 0.2 for all comparisons).
`
`Discussion
`
`Two anti-ulcer drugs were compared for their ability
`to prevent gastric ulcers in patients with osteoarthritis
`who were receiving chronic NSAID therapy. Misopros-
`tol is a synthetic prostaglandin E, analog that has been
`proved to prevent NSAID-induced gastric ulcer in ar-
`thritic patients (9). Although the mechanism is still un-
`clear, evidence is mounting that one major effect
`is
`through the replacement of mucosal prostaglandins (17-
`20). Misoprostol decreases gastric acid secretion, stim-
`ulates the production and release of bicarbonate and
`mucus, and maintains mucosal blood flow. It had been
`suggested that sucralfate might be useful for this indi-
`cation because ofits ability to reduce mucosal damage
`from various
`irritants,
`including ethanol
`(21) and
`NSAIDs(15, 22, 23).
`The current study indicates that in patients with os-
`teoarthritis and abdominal pain who are receiving
`NSAIDs, use of misoprostol for 3 months is associated
`with a significantly lower frequency of gastric ulcer
`compared with use of sucralfate. Larger studies are
`needed to determine whether the lower frequency of
`gastric ulcer development associated with the use of
`misoprostol
`leads to a lower frequency of complica-
`tions, such as upper gastrointestinal hemorrhage or per-
`foration, This study did not address the issue of which
`NSAID users are at
`risk for ulcer development and
`should receive prophylaxis. However, Fries and co-
`workers have examined patients at risk of NSAID-in-
`duced gastric ulcer and the patients within that group
`whoare at particularly high risk (4). They reported that
`patients at high risk for hospitalization and death from
`gastrointestinal
`complications
`are
` characteristically
`older, have had previous upper abdominal pain, have
`previously stopped taking NSAIDs because of adverse
`gastrointestinal side effects, have previously used ant-
`acids or H,-receptor antagonists for gastrointestinal side
`effects, and are often taking corticosteroids. Fries and
`associates (4) noted thal a patient with any two major
`
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`Table 2. Frequency of the Most Commonly Reported Adverse Experiences and the Frequency with Which They Led to
`Withdrawal from the Trial
`
`Event
`
`Misoprostal
`ta = 176)
`
`Frequency of Event*
`Sucralfate
`(a = 176)
`
`P Value
`
`Frequency of Termination
`Misoprostol
`Sucralfate
`(a = 176)
`(ea = 176)
`
`P Value
`
`n (36)
`
`n(%6)
`
`> 0.2
`10 (5.7)
`15 (8.5)
`0.1
`42 (23.9)
`$5 (31.3)
`Dyspepsia
`0.2
`1 (0.6)
`$ (2.8)
`<= 0.01
`9 (5.1)
`45 (25.6)
`Diarrhea
`> 0.2
`1 (0.6)
`3 (1.7)
`0.07
`18 (10.2)
`9 (5,1)
`Nausea
`
`Constipation >o2 5 (2.8) & (4.5) > 0.2 1 (0.6) 1 (0.6)
`
`
`
`
`
`
`* Includes all patients who took at least one dose of study medication. Three patients randomized to misoprostol and one patient randomized to
`sucralfate never took study medication. Patients who experienced more than one episode of an event were counted only ance.
`
`
`
`risk factors may reasonably be expected to have at least
`two to three times the risk for serious complications
`
`compared with a patient with no risk factors, whereas a
`patient with four or more risk factors may be at ex-
`tremely high risk.
`In short-term studies done in animals, sucralfate has
`been shown to increase mucosal prostaglandin synthesis
`(24, 25). This effect
`is believed to be nonspecific and
`due to minor epithelial damage caused by the aluminum
`present
`in sucralfate. Although this mechanism may
`prevent damage in animals pretreated with sucralfate, it
`would be unlikely to occur during chronic NSAID ad-
`ministration, because the enhanced mucosal prostaglan-
`din synthesis induced by sucralfate is effectively abol-
`ished by NSAID pretreatment (15,
`16).
`In a clinical
`study involving arthritic patients, sucralfate was found
`to be no better
`than placebo in the treatment of
`NSAID-induced gastrointestinal
`injury (26).
`In another
`short-term (2-week) study, sucralfate provided no gas-
`tric protection against aspirin-induced mucosal damage
`in healthy human volunteers (27). A clinical pharmaco-
`logic study performed in healthy subjects receiving as-
`pirin (1 g four times daily for 6 days) found misoprostol
`to be significantly more effective than sucralfate or pla-
`cebo in protecting the gastroduodenal mucosa (28).
`The influence of certain risk factors on gastrointesti-
`nal
`toxicity associated with the use of NSAIDs has
`been well established. A history of peptic ulcer disease
`has been shown in some studies to be associated with
`an increased incidence of NSAID-induced gastrointesti-
`nal mucosal injury (4, 29). Because our study excluded
`patients with a recurrent history of peptic ulcer,
`the
`effect of this risk factor on the frequency of ulcer for-
`mation could not be determined, However, 24.5% of the
`evaluable patients did report one previous episode of
`ulcer disease. One of the two patients on misoprostol
`
`and 3 of the 21 patients on sucralfate who developed a
`gastric ulcer had a history of a previous ulcer. There
`was no Statistically significant association between ulcer
`history and the development of gastric ulcer during the
`study in the evaluable cohort (P > 0.2).
`The presence of gastric erosions has never been an-
`alyzed as a potential risk factor for the development of
`a gastric ulcer in chronic NSAID users.
`In our study,
`the presence of endoscopically documented gastric mu-
`cosal erosions at the time of baseline endoscopic eval-
`uation was associated with an increased risk of the
`subsequent development of a gastric ulcer.
`
`
`
`Neither form of treatment ameliorated the problem of
`dyspepsia. Dyspepsia occurred in 31% and 24% of the
`patients randomized to receive misoprostol and sucral-
`fate, respectively, Ongoing dyspepsia was the most im-
`portant reason for patient withdrawal in both treatment
`groups. Dyspepsia, however, may not have represented
`a true adverse effect because it was also an entry cri-
`terion.
`It
`is thus impossible to distinguish dyspepsia
`related to NSAID use from that possibly related to use
`of the study medication. Further, our study was not
`designed to evaluate the effects of the study medica-
`tions on the relief of symptoms because it was single-
`blind. In NSAID-induced ulcer prevention studies, mi-
`soprostol was found to be associated with diarrhea and
`abdominal cramping early in the course of therapy (9).
`In our study, diarrhea occurred with greater frequency
`in patients receiving misoprostol compared with sucral-
`fate (26% and 5%,
`respectively).
`In most
`instances,
`however,
`the diarrhea was transient and disappeared
`
`despite continued drug administration. Diarrhea is a
`relatively common side effect associated with initiation
`of misoprostol
`therapy. Nausea and constipation oc-
`curred at a slightly higher frequency with sucralfate
`than with misoprostol. There was no statistically signif-
`icant difference (P = 0.2) between the treatment groups
`in the proportion of patients withdrawing due to dys-
`pepsia, diarrhea, nausea, or constipation (Table 2).
`In conclusion, the administration of misoprostol, 200
`we four limes a day for 3 months is more effective than
`sucralfate,
`|
`g@ four times a day,
`in the prevention of
`gastric ulceration in patients with osteoarthritis receiv-
`ing chronic NSAID therapy.
`This study represents the work of a nationwide study group, which, in
`addition to the authors,
`includes the following investigators: Richard
`Aaronson, MD, Chicago Heights, Illinois: Alphonse Belsito, MD, Brad-
`enton, Florida: Jacques R. Caldwell, MD, Gainesville, Florida; Don E.
`Cheatum, MD, Dallas, Texas, Robert E. Ettlinger, MD, Tacoma, Wash-
`ington; Edward Fudman, MD, Austin, Texas; Oren B. Gum, MD, New
`Orleans, Louisiana; Richard Jaszewski, MD, Allen Park, Michigan;
`Abraham Kolodny, MD. Baltimore, Maryland; Pamela Prete, MD, Long
`Beach, California; Martin Lidsky, MD, Houston, Texas; Jeffrey Lisse,
`MD, Galveston, Texas; Maren Mahowald, MD, Minneapolis, Minne-
`sota; R. K. Marwah, MD, El Paso, Texas; Ronald Messner, MD,
`Minneapolis, Minnesota; Jehangir Rao, MD, Wayne, Michigan; William
`Tatum, MD, Oklahoma City, Oklahoma; Elizabeth Tindall, MD, Port-
`land, Oregon; Robert Trapp, MD, Springfield,
`Illinois; J, P. Waring,
`MD, Phoenix, Arizona.
`
`
`
`from G. D. Searle & Company, which
`Grant Support; By a grant
`provided the study design and data analyses.
`Current Author Addresses: Dr. Agrawal: Tulane University School of
`Medicine, Section of Gastroenterology, 1430 Tulane Avenue, New Or-
`leans. LA TOLI2.
`
`1 August 199]
`
`* Annals of Internal Medicine + Volume 115 * Number3
`
`199
`
`MYLAN PHARMS.INC. EXHIBIT 1062 PAGE 5
`
`MYLAN PHARMS. INC. EXHIBIT 1062 PAGE 5
`
`MYLAN PHARMS. INC. EXHIBIT 1062 PAGE 5
`
`

`

`Dr Brown: University of Illinois Medical Center, 1740 W Taylor,
`Chicago, IL 60612
`Dr Germain: University of South Florida Medical Center, Division of
`Rheumatology, 12901 Bruce B Downs Boulevard, Box 19, Tampa, FL
`33612
`Dr Graham: Baylor Health Science Center/Veterans Affairs Medical
`Center, 2002 Holcombe Boulevard (HID), Houston, TX 77211
`Dr Roth: Arizona Arthritis Research & Education, Ltd , 3330 North
`2nd Street, Phoenix, AZ 85012
`Dr Stromatt: Chicago Medical School, 3333 Green Bay Road, North
`Chicago, IL 60064
`Dr White: University of California, Davis, Department of Internal
`Medicine, 2221 Stockton Boulevard, Sacramento, CA 95817
`
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