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
`
`I Obieefives: To compare the efficacy and frequency
`of adverse experiences of misoprostol and sucraitate in
`the prevention of gastric ulcers in patients receiving
`nonsteroidal anti-inflammatory drug (NSAID) therapy.
`I Design: A prospective. randomized. single-blind.
`multicenter trial.
`
`I Patients: Patients with osteoarthritis receiving treat-
`ment with ibuprofen. piroxicam. or naproxen and expe-
`riencing abdominal pain were eligible.
`I Interventions: Patients who were expected to re-
`oeiveatleastamonthsofNSAIDtherapyandwhodid
`nothaveagastriculceratthetimeoftheinitial
`screening endoscopy were randomized to receive ml-
`aoprostoi.200pgiourtimesaday.oreucraiiate.1 g
`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-
`pieswereperformedafter4.8.and12weeks.
`I Main Measurement: The development of a gastric
`ulcer. which was regarded as a prophylaxis failure.
`I Results: Two hundred fifty-three patients were eval-
`uable for efficacy analysis. A gastric ulcer developed in
`2 of the 122 (1 .6%, 95% CI. 0.3% to 6.4%) patients on
`misoproflol. compared with 21 of 131 patients on
`eucraltate (16%. C). 10.4% to 23.7%). The difference in
`ulcer rates was 14.4% (CI. 10.4% to 19.5%; P < 0.001).
`I Conchrslan: in patients receiving chronic NSAID
`therapy for osteoarthritis. treatment with misoprostol
`for 3 months was associated with a significantly lower
`hermency of gastric ulcer formation. compared with
`treatment with sucraltate (P < 0.001).
`
`AnnaIJ of Internal Medicine. l99l:ll$:l95—200.
`
`From Tulane University School of Medicine. New Orleans.
`Louisiana; Arizona Arthritis Research & Education. Ltd..
`Phoenix. Arizona: Baylor College of MedicinelVeterans Affairs
`Medical Center. Houston. Texas: University of California. Da-
`vrs and Sacramento. California; University of South Honda.
`Tampa. Florida; University of Illinois. Chicago. Illinois; and
`University of Health Sciences/Chicago Medical School. Chi-
`cago.
`lllinois. 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 (l-4). The inhibitory efi'ect 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-
`tisecretory and mucosal protective properties. and
`NSAlD-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 shown to be effective in the prevention of NSAlD—
`induced gastric ulcers in patients with arthritis (9). This
`agent has also been shown to prevent the development
`of NSAlD-induccd duodenal lesions both in normal sub.
`
`jects (l0. ii) and in arthritic patients ()2). The bench-
`cial effects of misoprostol on the gastrointestinal tract
`are not accompanied by a compromise of the antirheu-
`matic efl‘ects of the NSAID (l3.
`l4).
`Sucralfate is an effective anti-ulcer drug that has been
`shown to increase the release of endogenous prostaglan-
`dins from the gastric mucosa (l5.
`)6). suggesting that
`stimulation of prostaglandin synthesis may be a mech-
`anism for its action. Despite the fact that sucralfate is
`widely used to prevent NSAlD-induced gastrointestinal
`mucosa! damage. no study has evaluated the efficacy of
`sucralfate in the prevention of NSAlD-induced mucosal
`damage in chronic NSAlD users.
`We compared misoprostol and sucralfate in the pre-
`vention of NSAlDinduced 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 academic institutions. 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 NSAle: ibuprofen. piroxicam. or naproxen. in addition.
`
`I August I99]
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`I95
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`it was required that all patients be expected to receive
`NSAle 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
`test was positive. the patient was excluded. Exclusion criteria
`included a history of recurrent peptic ulcer disease. active
`bleeding ulcer. upper gastrointestinal malignancy or metastasis
`to the upper gastrointestinal tract. pyloric or duodenal obstruc-
`tion. acute hepatitis. pancreatitis. inflammatory bowel disease.
`bleeding diathesis. upper gastrointestinal surgery within 30
`days. or severe renal impairment. Patients taking antineoplas-
`tic drugs. anticoagulants. or anti-ulcer dmgs. other than the
`study drugs. were excluded.
`
`Study Design
`
`The study was a prospective. randomized. single-blind. mul-
`ticenter comparison of misoprostol. 200 pg given four times a
`day (with meals and at bedtime) and sucralfate. l g four times
`a day (30 minutes before meals and at bedtirrtc). 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 underwent an 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 NSAle 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 frberoptic endoscopy
`after 4 weelrs (z 3 days). 8 weeks (2 5 days). and l2 weeks
`(2 5 days) after randomization. Patients were allowed to take
`up to four aluminum hydroxide antacid tablets per day. during
`the first weelt only. for relief of upper gastrointestinal pain.
`Patients were instnrcted to take the study medication the night
`before the endoscopy and not to talte the next dose until after
`the procedure was completed. Noncompliance was defined as
`failure to talte at least 75% of prescribed medication and was
`determined at 4. 8. and I2 weelts by counting pills not taken.
`The protocol was approved by an institutional review board.
`and each patient gave written. informed consent.
`
`End Point
`
`11te 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 baseline 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 deveioped 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 ranlt test was used to compare treatments. Addi-
`tionally. ulcer rates were analyzed by size at
`the Iz-week
`
`Table I. Der-opaphicandClinlcalCharaeterlatieaefthe
`lntenMo-Treat Cohort (All Randomized Patients)
`
`Characteristic
`
`Misoprostol
`Group
`
`Sucralfate
`Group
`
`I79
`60 (30 to 82)
`56:44
`
`I71
`60 (29 to 82)
`59:4I
`
`89
`l I
`
`84
`I6
`
`Patients. n
`Median age. (range) y
`Womenzmen. %
`Race. 9%
`White
`Nonwhite
`NSAID‘ used. %
`4|
`35
`Ibuprofen
`3|
`40
`Naproxen
`28
`25
`Piroxicam
`l5
`l4
`Smokers t) It) cigarettes/d). '1»
`23
`Ill
`Alcohol use. %
`80
`84
`Previous antacid use. %
`l0.l
`9.4
`Duration of osteoarthritis. y
`[.4
`L7
`Duration of NSAID use. y
`
`
`22.4History of ulcer disease. 96 26.6
`
`‘ NSAlD - nonsteroidal anti-inflammatory drug.
`
`period using the Fisher exact test. The time until gastric ulcer
`occurrence was analyzed by lilting 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 astritis.
`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 (I l.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. I79 (50%) were randomized to
`receive misoprostol and I77 (50%) were randomized to
`receive sucralfate. A total of 352 patients took at least
`one dose of the study medication (I76 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 alter randomization. One hundred
`twenty-two of the I79 patients randomized to receive
`misoprostol and I3! of the l7? 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 l). 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 l0
`cigarettes per day. The mean reported duration of os-
`teoarthritis was 9.7 years and of NSAID use. [.6 years.
`The proportion of patients using each of the three
`
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`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% of patients
`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. 4| of the 46 patients (89%) were
`noncompliant. 4 were lost
`to follow-up. and I 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%: CI. 0.3% to 6.4%) patients
`randomized to receive misoprostol developed a gastric
`ulcer compared with 2| of
`|3l ”6%: CI. 10.4% to
`23.7%) patients randomized to receive sucralfate over
`the 3-month study period (P < 0.001: Figure I). The
`difference between groups in the frequency of gastric
`ulcer development
`(14.4%: C1.
`l0.4"/r= to I959?)
`re-
`mained significant when the analysis was restricted to
`ulcers equal
`to or greater than 0.5 cm in diameter
`(8.4%: 95% CI. 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 S.l‘7()
`compared with 9.2% (CI. 5.1% to l5.8’/r) in patients
`randomized to receive sucralfate (P = 0.003; Figure I).
`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 I79 (3%) patients randomized to
`misoprostol and 25 of I77 ”4%) of patients randomized
`to sucralfate developed a gastric ulcer (P < 0.005).
`or the 356 patients who were randomized. 292 (82%)
`used some aluminum hydroxide tablets during the first
`week for treatment of ongoing upper gastrointestinal
`pain. There was no statistical 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 dcvel~
`opmcnt of a gastric ulcer W > 0.2). In patients random
`ized to receive misoprostol. 5 of ISI (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.
`I9 of the MI
`(I492) patients who took
`aluminum hydroxide during the first week developed a
`gastric ulcer. compared to 6 of the 36 patients “7%)
`who did not take aluminum hydroxide during the first
`week.
`
`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 covariatcs. Treatment group entered the model at
`step I (improvement chi-square P < 0.00l: 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).
`The coefficient associated with the treatment
`
`term,
`
`is 2.4 (CI. 0.9 to
`comparing sucralfate to misoprostol.
`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 IR (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
`2| 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 I22 (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
`
`I8
`
`16
`
`1‘
`
`
`
`
`“.090
`
`
`
`- Soersll’ate
`Misoprostol
`‘ P < EN]
`
`-- r = 0.003
`
`
`
`PercentwithGastricUlcers
`
`l2
`
`
`
`20.3 cm
`
`z 0.5 can
`
`Ulcer Diameter
`
`Figure I. Percentage of patients with gmtrle ulcers as a function
`of ulcer diameter. Among sucralfatevtreated patients. 16.0%
`(959? CI. was; to 23.7%) had an ulcer 20.3 cm in diameter
`compared with L6")?
`(Cl. 0.39? to 6.4%) in the misoprostol
`group (P < 0.001). Ulcers a 0.5 cm in diameter developed in
`9.295 (Cl. 5.I‘>} to 15.8%) of the sucralfate group compared
`with 0.89? (CI. 0.04% to SW?) of the misoprostol group (P =
`0.003. P values are derived from the methods of Fleiss).
`
`I August
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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; Cl. l.l4 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 8| “0%) patients without
`initial ero-
`sions. A gastric ulcer developed in l of the 47 miso-
`prostol-treated patients who had gastric erosions at
`baseline endoscopy compared with I 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 efl'ect was dyspepsia.
`The most
`which was reported by SS (31%) patients in the miso-
`prostol group and 42 (24%) in the sucralfate group (P =
`0.”. Overall. diarrhea developed in 45 (26%) patients
`randomized to receive misoprostol and in 9 (5%) pa-
`tients randomized to receive sucralfate (P < 0.0”. 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. Twentyone percent of the
`
`1“
`
`
`
`Probability(5)
`
`
`
`Figure 2. Percentage of patients without a noneteroldal anti-
`lalammatorydrug-Inducedgastrkuleerasdeternhedhyllfe—
`table analysis. At 3 months.
`the probability of being free of
`gastric ulcer was 97.2% (95% CI. 93.3% to ltl)%) in the mis-
`oprostol-treated group and 80.8% (CI. 73.0 to 88.5%) in the
`sucralfate-treated group. 0 e significantly shoner time to ulcer
`development compared with misoprostol (log rank P < 0.00I).
`
`episodes were classified as severe. but the drop-out rate
`attributed to diarrhea was only 3% (Table 2).
`Thiny-one of the I76 (18%) patients randomized to
`receive misoprostol and I6 of the I76 (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.
`I5 (9%) patients
`stopped the study because of dyspepsia and 5 (3%)
`patients terminated the study because of diarrhea.
`In
`patients randomized to sucralfate. I0 (6%) patients ter-
`minated the study because of ongoing dyspepsia and
`one patient terminated the study because of diarrhea.
`A total of I4 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
`occun-ing serious event (two patients in the misoprostol
`group and one in the sucralfate group). There were no
`clinically significant difi'erences between treatment
`groups in changes in 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 NSAlDinduced gastric ulcer in ar-
`thritic patients (9). Although the mechanism is still uno
`clear. evidence is mounting that one major efl'ect
`is
`through the replacement of mucosal prostaglandins (I7-
`20). Misoprostol decreases gastric acid secretion. stim-
`ulates the production and release of bicarbonate and
`mucus. and maintains mucosal blood flow. lt had been
`suggested that sucralfate might be useful for this indi-
`cation because of its ability to reduce mucosal damage
`from various
`irritants.
`including ethanol
`(2|) and
`NSAIDs (IS. 22. 23).
`The current study indicates that in patients with 05-
`teoarthritis and abdominal pain who are receiving
`NSAle. 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
`NSAlD users are at
`risk for ulcer development and
`should receive prophylaxis. However. Fries and co-
`workers have examined patients at risk of NSAlD-in-
`duced gastric ulcer and the patients within that group
`who are 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 NSAle because of adverse
`gastrointestinal side effects. have previously used ant-
`acids or Hz-receptor antagonists for gastrointestinal side
`effects. and are often taking corticosteroids. Fries and
`associates (4) noted that a patient with any two major
`
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`Table 1. Frequency of the Most lCommonly Reported Adverse Experiences and the Frequency with 1Which They Led to
`Withdrawal from the Trial
`
`Event
`
`Misoprostol
`in = ITij
`
`Freguency of Event‘
`Sucralfatc
`in = [To]
`
`P "v'alue
`
`Misoproslol
`in = I'Hit]
`
`Pregnancy of Termination
`Soot-alfate
`In = I'l'bi
`
`P Value
`
`rt {til-.1
`
`n iii-lit}
`
`an:
`miss:
`l5t$.5l
`t].l
`42i23.9l
`55:31.31:
`Dvswrsia
`0-2
`I that
`512.3]
`e li.l2tl
`it {so
`45 reset
`Diarrhea
`31 Ill
`I
`[Until
`3{I.'il
`Ill}?
`I3 ill}.2l
`9i5.ll
`Nausea
`
`Constipation is (Ll 5 [2.3: it {4.5} :4- tl.2 I idol I [fluid
`
`
`
`
`
`
`‘ Includes all patients who took at least one dose of study medication. Three patients randomized to misoprcstol and one patient rarvdotrlizod lo
`sucnll'at: never took study medication. Patients who esperiervced more than mu.- episode ot'an event Mr: counted only once.
`
`
`
`risk factors may reasonably be expected to have at least
`two to three times the risk for serious complications
`
`compared 1With a patient with no risk factors. whereas a
`patient with four or more risk factors may be at eat—
`tremely high risk.
`In shortvterm studies done in animals. suctalfate has
`been shown to increase mucosai 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 sueralfatc. it
`would be unlikely to occur during chronic NSMD ad—
`ministration. because the enhanced mucosal prostaglan—
`din synthesis induced by sucralfate is efl'eetively abolr
`ished by NSMD pretreatment {15.
`lol.
`In a clinical
`study involving arthritic patients. sueralfate tvas found
`to be no better
`than placebo in the treatment of
`NSAID-induced gastrointestinal
`injury :26].
`In another
`shun-term l2vwcek} study. sucralfate provided no gas—
`tric protection against aspirin-induced mucosal damage
`in healthy human volunteers (lit. a clinical pharmaco-
`logic study performed in healthy subjects receiving as-
`pirin {I g four times daily for a days} found misoprostol
`to be significantly more elfeetive than sucralt'ate or pla-
`cebo in protecting the gastroduodcnal mucosa tltii.
`The influence of certain risk factors on gastrointestii
`nal
`toxicity associated with the use of NSAle has
`been well established. a. history of peptic ulcer disease
`has been shown in some studies to be associated with
`
`an increased incidence of NSMD-induced gastrointesti-
`nal mucosal injury id. 29}. Because our study ettcluded
`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. Due ol‘ the two patients on misoprostol
`
`and 3 of the it patients on sueralfate who developed a
`gastric ulcer had a history of a previous ulcer. There
`was no statistically significant association betwecn ulcer
`history and the development of gastric ulcer during the
`study in the evaluable cohort it“ := ill}.
`The presence of gastric erosions has never been an-
`alyzed as a potential risk factor for the development of
`a gastric ulcer in chronic HSAID users.
`In our study.
`the presence of endoscopically documented gastric mu-
`cosal erosions at the time of baseline endoscopic eval-
`uation was assoctated with an inercascd 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 sacral—
`i‘atc. respectively. Ongoing dyspepsia was the most im-
`portant reason for patient withdrawal in both treatment
`groups. Dyspepsia. however. may not have rcpresented
`a true adverse effect because it was also an entry cri—
`terion.
`It
`is thus impossible to distinguish dyspepsia
`related to NSMD 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 NSnlD-induced ulcer prevention studies.
`tni-
`soprostol was found to be associated with diarrhea and
`abdominal cramping early in the course of therapy till.
`[a our study, diarrhea occurred with greater frequency
`in patients receiving misoprostol compared with sacral.
`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 difl'erertcc tP 2 till 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. lull
`pg four times a day for 3 months is more elfective than
`sucralfate.
`l g four times a day.
`in the prevention of
`gastric ulceration in patients with osteoarthritis receiv—
`ing chronic NSMD therapy.
`This study represents the wrath of a nationwide study group. which. in
`addition to the authors.
`includes the following inveslimttors: Richard
`Aaronson. MD. Chicago Heights. Illinois; Alphonso Helsito. MD. Bredr
`enton. Florida; Jacques R. Caldwell. MD. Gainesville. Florida; Don E.
`Cheatum. no. Dallas. Texas; Robert E. Etllittger. MD. Tacoma. Wash-
`ington.- Edward Fudman. MD. Austin. Tenant; fired 3. Gum. MD. New
`Orleans. Louisiana; Richard laszewslti. MD. Allen Park. Kathleen:
`Abraham Kolrt-dny. MD. Baltimore. Maryland; Pamela Prete. HD. Long
`Beach. California; Hat-tin Lidslty. MD. Houston. Texas: Iefl‘rey lit-tie.
`lle. Galveston. Teans; Maren Mathew-aid. MD. Minneapolis. Minn:-
`sota:
`It.
`It. Mara-alt. MD. El Paso. Tcaas'. Ronald Messner. h'lD.
`Minneapolis. Minnesota: .Teltangt'r Rad. MD. Wayne. Michigan: 1t't'il-littt'tt
`Tatum. MD. {litiahoma lIf.‘ily. Oklahoma: Elizabeth T'tndall. MD. P‘t‘n‘t-
`land. Dregon: Robert Trapp. MD. Springfield.
`Illinois; J. F. Waring.
`MD. Phoenix. Arizona.
`
`
`
`from G. D. Settle di. Company. which
`Grant Support: By a grant
`provided the study destgo and data analyses.
`Emmi-t Author Addresses: Dr. Aaron-3|: Tulane University School of
`Medicine. Section of Gastroenterology. Hill Tulane Avenue. New Do
`leans. Lr't TI'IIIE.
`
`I August
`
`l99l
`
`- Annals ufint‘ernoi Medicine -
`
`IIv'olumc ll5 . Numberi
`
`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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