‘IECEMBER 1995
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`Diseases of the
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`«assuzexa-2tmasasasmusmauaiusimtauamas
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`ANNUAL MEETING OF THE AMERICAN SOCIETY
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`OF COLON AND RECTAL SURGEONS
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`Seattle Convention Center, Seattle, Washington, June 9-14, 1996
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`OFFICIALIJOURNAL OF
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`THE AMERICAN SOCIETY OF
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`COLON AND RECTAL SURGEONS
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`Williams & Wilkins
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`Cosmo Ex. 2164, Page 1
`CFAD v. Cosmo; IPRZO15-00988
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`CURRENT STATUS Lee E. Smith, M.D., Editor
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`Toxicity of Nonsteroidal
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`Anti-Inflammatory Drugs in the
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`Large Intestine
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`Neal M. Davies, Ph.D. Can.
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`From £199 Faculty of Pharmacy and Pbczrmczceztficczl Sciences, Um‘versz'zy of/llbemz,
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`Edmonton, Alberta, Canada
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`PURPOSE: Adverse effects of nonsteroiclal anti-inflammatory
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`drugs (NSAIDS) on the upper gastrointestinal (GI) tract and
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`small intestine are well described. Evidence is also accumu-
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`lating that implicate NSAIDS in inducing and exacerbating
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`damage in the distal GI tract. The purpose of this review is
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`to identify possible adverse effects of NSAIDS on the large
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`intestine and increase the clinical awareness of these toxi-
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`cologic effects. METHODS: A literature review identified
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`the diversity of toxicologic effects induced by NSAIDS in
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`the large intestine. The epidemiology, pathogenesis, and
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`clinical implications of these adverse effects are described.
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`RESULTS: NSAID use has been associated with colonic
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`bleeding,
`iron deficiency anemia, strictures, ulcerations,
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`perforations, diarrhea, and death. In addition, NSAIDS can
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`exacerbate inflammatory bowel disease and ulcerative coli-
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`tis. The prevalence of NSAID—induced large intestinal dam-
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`age is unknown. Diagnosis can be made by colonoscopy
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`and barium scans. Although the clinical presentation of
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`NSAID-induced gastropathy and enteropathy, bleeding or
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`perforation, may be more dramatic than colonopathy, the
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`overall clinical significance of these adverse effects of
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`NSAIDS on the large intestine has not been fully character-
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`ized. CONCLUSIONS: This review illustrates that NSAID-
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`induced large bowel toxicity can cause significant morbid-
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`ity in some patients, ranging from profuse diarrhea, chronic
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`blood loss, and iron deficiency anemia to fatality. The patho-
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`genesis is likely multifactorial and is thought to be related to
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`inhibition of prostaglandin synthesis. Because NSAIDS are
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`widely prescribed and some are available without a pre-
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`scription, heightened awareness of these toxicologic man-
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`ifestations throughout the GI tract may reduce morbidity.
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`[Key Words: NSAIDS, Large intestine, Toxicity]
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`Davies NM. Toxicity of nonsteroidal anti-inflammatory
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`drugs in the large intestine. Dis Colon Rectum 199538:
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`1311-1321.
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`onsteroidal anti-inflammatory drugs (NSAIDS)
`N are used extensively in treatment of chronic
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`arthropathies,
`in patients with trauma, surgery, or
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`other painful states, and are among the most com-
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`Address reprint requests to Dr. Davies: Faculty of Pharmacy and
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`Pharmaceutical Sciences, University of Alberta, 5118 Dentistry/
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`Pharmacy Centre, Edmonton, Alberta, T6G 2N8, Canada.
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`monly prescribed medications in the world, which
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`attests to their efficacy as both anti—inflammatory and
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`analgesic agents. During the past 50 years, there has
`been a substantial increase in the number of NSAIDS
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`available, and the indications for NSAIDS use has
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`been broadened to include postoperative analgesia,
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`dysmenorrhea, prevention of thrombosis, and cancer
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`pain.
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`Although NSAIDS were previously thought to be
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`relatively safe, in view of their frequent use, numer-
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`ous spontaneously reported adverse drug reactions,
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`case control, cohort, and postmarketing surveillance
`studies reveal that NSAIDS are associated with exten—
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`sive side effects, the most frequent being gastrointes-
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`tinal (GI) disturbancesl NSAlD—induced GI damage
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`appears to be dose-dependent, and statistically signif-
`icant differences between individual NSAIDS have
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`been reportecl.2‘5 As awareness of GI side effects
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`associated with NSAIDS increases, safety has become
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`a primary requisite in treatment.
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`Numerous articles examining the gastric and duo-
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`denal damage caused by NSAIDS l1ave been pub-
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`lished; however, only recently have the more distal
`intestinal disturbances induced by these drugs re-
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`ceived closer attention.6’7 The concept of selective
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`and site—specific damage to the upper GI tract follow-
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`ing NSAIDS has been ‘questioned, particular by the
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`works of Bjarnason er a1.8 who showed that patients
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`on long—term NSAID therapy develop small intestinal
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`inflammation that may contribute to significant mor-
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`bidity by manifesting itself in blood and protein loss,
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`ulceration, “diaphragm”—like strictures, perforation,
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`and hemorrhage.
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`An inherent problem in examining adverse effects
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`in the GI tract is that diagnosis is difficult, usually
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`1311
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`Cosmo Ex. 2164, Page 2
`CFAD V. Cosmo; IPRZO15-00988
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`Cosmo Ex. 2164, Page 2
`CFAD v. Cosmo; IPR2015-00988
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`1312
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`DAVIES
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`Dis Colon Rectum, December 1995
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`requires invasive techniques, and is usually only dem-
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`onstrated after one of the complications (obstruction,
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`perforation, or hemorrhage) becomes clinically ap-
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`parent. In addition, there is a poor correlation be-
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`tween p2tti€1'1[~1'€pO1'[€d
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`tress and endoscopically proven gastropathy.9 This
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`may suggest affliction of more distal parts of the
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`A present trend in NSAID development is to im-
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`prove therapeutic efficacy and reduce the severity of
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`upper GI side effects through modification of dosage
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`forms of NSAIDS by enteric—coating or through sus-
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`tained release (SR) formulations. Indeed, enteric coat-
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`ing and SR formulations of several NSAIDS have re-
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`sulted in a reduction in endoscopic findings in the
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`intended to release NSAIDS in the intestine.1°’“
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`However, the more distal intestinal toxicologic man-
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`largely ignored; although the likelihood of its in-
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`creased occurrence with more frequent use of NSAID
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`medication has been previously predicted.” Cost
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`containment of pharmaceuticals is topical, and the
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`therapeutic rationale behind enteric—coated and sus-
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`is not clear cut.
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`Recent work has highlighted the association of
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`NSAIDS and adverse effects on the ileum and jeju-
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`num, but it is not widely appreciated that NSAIDS
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`induce significant damage in the colon.8’ 13 However, “
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`an increasing number of reports describe deleterious
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`effects on the large intestine, with findings ranging
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`from asymptomatic mucosal inflammation, iron defi-
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`ciency anemia, bloody diarrhea, strictures, perfora-
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`tions, major hemorrhages, and induction and exacer-
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`bation of
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`disease.14‘1°5
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`A systematic search was made through MEDLI./\/E
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`Index Meoiiczis, and .E.£Y.‘C€7])f0l Medical to identify pos-
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`sible adverse effects of NSAIDS on the large intestine.
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`The results of a review of the diversity of adverse
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`effects induced by NSAIDS on the large intestine,
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`epidemiology, pathogenesis, and clinical implications
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`REVIEW OF NSAID-INDUCED LARGE
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`INTESTINAL DAl\/[AGE
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`A large body of literature including case reports and
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`epidemiologic evidence implicates NSAIDS as induc-
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`ing large intestine toxicologic manifestations.
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`Case Reports
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`These toxicologic manifestations can be grouped
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`into four major categories: ale 110220 toxicity; hypersen-
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`sitivity reactions; suppository-induced; reactivation of
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`De N000 Toxicologic Colonic Manifestations. One
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`hundred ninety—eight patients with de novo drug~in—
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`duced damage of the large intestine, which was at-
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`tributable to NSAID use, have been described in the
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`literature from 1966 to present (Table 1). These pa—
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`tients, whose ages ranged from 32 to 90 (mean, 64.4)
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`years, were taking many types of NSAIDS for inflam-
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`matory conditions such as rheumatoid arthritis and
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`osteoarthritis. The general clinical manifestations‘
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`were GI bleeding, abdominal pain,
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`anemia, obstruction, ulceration, stricture, and cliar-
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`rhea. Of the 73 in whom gender was reported, 49
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`were female and 24 were male. Of the 87 patients in
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`whom duration of NSAID use was reported, 67 had
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`been taking NSAIDS for less than one year. Fifteen
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`patients were
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`colonopathy after use of medication for less than four
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`weeks. Of the 70 patients for whom drug and formu-
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`lation were reported, 17 had been taking sustained
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`release NSAIDS, 14 had been taking a fenemate
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`NSAID, and 18 had been taking diclofenac prepara-
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`Five different types of colitis induced by NSAIDS
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`are presented, which shows the diversity of toxico-
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`logic manifestations in the colon: pseudomembra-
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`nous colitis with diclofenac ingestion“; eosinophilic
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`colitis associated with naproxen therapy”; collage-
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`nous colitis with a variety of NSAIDSZO’ 42’ 83-, de novo
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`colitis25' 47; reactivation of ulcerative colitis (Table 2).
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`It has been suggested that NSAIDS can induce in-
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`creases in colonic permeability that may precede the
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`gross pathologic findings in the colon.” In addition,
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`an association between NSAID ingestion and stercoral
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`perforation of the colon in patients on codeine prep-
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`arations and antidepressant medications has been
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`suggested;54 Three patients were described in the
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`biomedical literature ashaving presented with fecal
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`loading of the colon, increased white cell counts, and
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`peritonitis. Ulcers of the colon are associated with many
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`other re o1’ts.30’59’95 More recentl
`strictures of the
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`P
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`colon have been increasingly reported.5S' 51’ 56’ 67‘
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`Furthermore, enteral administration of indomethacin
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`to infants for closure of persistent patent ductus arte-
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`riosus has been associated with necrotizing enteroco-
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`litis and colitis.” 68
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`Cosmo Ex. 2164, Page 3
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`Cosmo Ex. 2164, Page 3
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`V01. 38, No. 12
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`NSAIDS AND THE LARGE INTESTINE
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`1313
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`Table 1.
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`Case Reports of NSAlD—lnduced De Novo Toxicity in the Large intestine
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`Drug
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`Histopathologic Clinical Findings
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`References
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`23, 43, 67, 82, 93
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`49
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`23, 38, 41, 43, 47,
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`51, 56, 59, 63,
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`72, 86, 99
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`20, 88
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`84
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`25, 26, 42, 84
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`30, 42, 54, 75, 91
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`54
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`30, 36, 63, 66, 73,
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`78, 84, 93, 102
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`13, 18, 43, 54, 88,
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`95
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`Aspirin
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`Azapropazone
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`Diclofenac
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`Fenbufen
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`Flufenamic acid
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`ibuprofen
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`lndomethacin
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`Ketoprofen
`Meclofenamate
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`Mefenamic acid
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`Naproxen
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`Oxyphenbutazone
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`Piroxicam
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`Phenylbutazone
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`Sulindac
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`Various
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`Ulcerations, bloody stools, steatorrhea, fibrosis multiple
`recurrent colonic strictures, anemia, abdominal pain,
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`weight loss, diarrhea, fibrosis
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`Colonic ulceration, rectal bleeding
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`Ulceration, anemia, diarrhea, diaphragms, intestinal
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`obstruction, melena, perforation, hemorrhage,
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`stenoses, weight loss, colicky pain, fibrosis of
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`submucosa, peritonitis, stercoral ulcers
`pseudomembraneous
`
`
`
`
`
`
`
`Watery diarrhea, collagenous colitis, weight loss,
`
`
`
`
`abdominal cramps, bleeding, ulceration, elevated
`
`
`
`
`lymphocytes, inflammatory lesions, perforated
`diverticulitis, anemia
`
`
`
`
`
`
`
`Anemia, bleeding, inflamed rectal mucosa,
`
`
`
`
`proctocolitis, diarrhea, weight loss, malaise,
`abdominal tenderness
`
`
`
`
`
`
`
`Diarrhea, rectal bleeding, inflammation collagenous
`
`
`
`
`
`colitis, pseudomembranes of large bowel mucosa
`
`
`
`
`
`cecal ulcer, abdominal pain, peritonitis
`
`
`
`
`
`
`Diarrhea, ulceration of ascending colon, perforation,
`
`
`
`
`
`
`death, abdominal pain, peritonitis, multiple sigmoid
`
`
`
`
`diverticula, collagenous colitis, pseudomembranes,
`
`
`
`
`
`
`stercoral perforation of the sigmoid colon
`
`
`
`
`
`
`Stercoral perforation of the sigmoid colon
`
`
`
`
`
`Abdominal pain, bloody diarrhea, colitis
`
`
`
`
`
`
`
`Bloody stools, abdominal colic, weight loss, diarrhea,
`
`
`
`
`
`
`aphthous ulceration and a cobble stone appearance,
`
`
`
`
`
`
`
`pus, proctitis, mucus in stools, death, cecal
`ulceration, anemia, dilated transverse and
`
`
`
`
`
`
`
`
`
`
`descending colon, steatorrhea, stricture of sigmoid
`colon, inflammatory cell infiltrate
`
`
`
`
`
`
`
`Proctitis, hemorrhage granulomas, inflammatory
`infiltrate, eosinophilic colitis, hypersensitivity,
`
`
`
`
`proctitis, steatorrhea, fibrosis, stercoral perforation,
`
`
`
`
`
`
`
`
`
`
`
`bloody diarrhea, abdominal cramping, weight loss,
`
`
`
`
`
`ulcerations, eosinophilia, bleeding, elevated white
`
`
`
`
`
`blood count, perforated diverticulitis, anemia
`
`
`
`
`
`Perforated cecal ulcer, abdominal pain, intraperitoneal
`
`
`
`
`
`gas, nectrotic tissue, lymphocyte infiltration
`
`
`
`
`
`
`Rectal bleeding, mucosal ulcers of cecum, ascending
`
`
`
`
`
`colon, anemia, proctitis, weight loss
`
`
`
`
`Diarrhea, hematochezia, rectal proctocolitis, bleeding,
`
`
`
`
`
`
`stenosis of sigmoid colon and ulceration,
`
`
`inflammatory infiltrate
`
`
`
`
`
`Multiple recurrent colonic strictures, anemia, abdominal
`
`
`
`
`
`pain, weight loss, diarrhea, fibrosis
`,
`
`
`
`
`
`Cecal diaphragm, iron deficiency anemia, inflammatory
`
`
`
`
`infiltrate, submucosal fibrosis, lymphocyte infiltration,
`
`
`
`
`
`collagenous colitis, diarrhea, circumferential scars
`
`
`
`
`
`and stricturing, inflammation, perforation and
`
`
`
`
`bleeding, proctocolitis, peritonitis, benign gastrocolic
`fistula
`
`
`
`
`
`NSAIDS = nosteroidal anti—inflammatory drugs.
`
`
`
`
`
`
`
`31
`
`
`87. 93
`
`
`
`17, 69, 85
`
`
`
`
`
`
`67
`
`
`
`
`
`
`
`52, 61, 62, 90, 92
`
`
`
`
`
`
`Cosmo Ex. 2164, Page 4
`CFAD v. Cosmo; lPR2015-00988
`
`
`
`Cosmo Ex. 2164, Page 4
`CFAD v. Cosmo; IPR2015-00988
`
`

`
`
`
`DAVIES
`
`
`Dis Colon Rectum, December 1995
`
`
`
`
`
`
`
`Table 2.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Case Reports of NSAID-Induced Reactivation of Bowel Disease in the Large Intestine
`
`
`
`NSAIDS
`
`
`
`Duration of Use
`
`
`
`
`
`
`Age and
`Sex
`
`
`No.
`
`
`
`Toxicologic Effect
`
`
`
`
`Reference
`
`
`
`
`4—1 8 days
`
`
`
`NR
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`82F
`
`74F
`
`NR
`
`
`49M
`34M
`
`
`
`
`36F
`
`33F
`
`54F
`
`79F
`
`
`74F
`
`
`
`
`NR
`
`2
`
`
`
`3
`
`
`
`1
`
`
`
`
`
`
`Rerforation, diverticula, stenosis, peritonitis,
`
`
`
`
`
`ulcerations, pus
`Colitis
`
`
`
`
`Diffuse mucosal colonic ulceration
`
`
`
`
`
`
`
`Sigmoid edema, bleeding, friability,
`diarrhea
`
`
`
`
`*
`
`
`
`
`Sigmoid coion perforation, abdominal
`
`
`tenderness, peritonitis
`
`
`
`Perforated divertioulum, colitis
`
`
`
`
`
`29
`
`
`
`22
`
`
`86
`
`
`77'
`
`
`
`
`
`
`
`Indomethacin
`
`Indomethacin
`Enemas
`
`
`
`Ibuprofen
`Indomethacin
`
`
`
`
`
`
`
`
`Ibuprofen
`Flurbiprofen
`Benorilate
`
`Osmotic slow release
`
`
`
`
`
`
`
`
`
`
`Indomethacin
`Indomethacin and
`naproxen
`
`
`Acetylsalicylic acid
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`F:M 1:1
`
`
`
`(20-93)
`F:M 1.6:1
`
`
`
`(35-89)
`75F
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Loose stools, rectal bleeding, mucous,
`
`
`
`
`abdominal pain, malaise, inflammation
`
`
`
`
`
`Bloody diarrhea, relapse ulcerative colitis
`lleocolitis, diarrhea
`
`
`Internal pelvic fistulas, colovesical,
`
`
`
`
`
`
`colovaginal, coloenterlc, vesicovaginal,
`colocutaneous, enterovesical
`
`
`
`
`
`
`
`
`Ulcerations of rectum and sigmoid colon
`
`
`
`
`Fecal and purulent peritonitis, extracolonic
`abscess, fistula
`
`
`
`
`
`
`Cramping, abdominal pain, bloody diarrhea
`
`
`
`
`Sigmoid ulcer, inflammation, pancolitis,
`
`
`
`stricture, bioody diarrhea
`
`
`
`
`
`
`
`
`
`
`
`
`Watery diarrhea, lower abdominal pain,
`
`
`
`
`weight loss, sigmoid diverticular disease,
`
`
`neutrophil infiltrates
`
`
`
`Pericoiic abscess, peritonitis, bleeding,
`fistula
`
`
`
`
`Diverticular disease, perforation, bleeding
`
`
`
`
`
`
`
`
`
`
`
`Cecal ulcer, sigmoid diverticulosis with
`spasm
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ibuprofen
`
`Diclofenac
`
`Various NSAIDS
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Diclofenac, naproxen
`
`Various NSAIDS
`
`
`
`
`
`
`
`Days
`NR
`
`
`
`
`24-48 hours
`
`Hours to 1
`
`
`
`week
`
`
`6 months
`
`
`
`
`
`
`NR
`
`
`
`Various NSAIDS
`
`
`
`
`Diflunisal
`
`
`
`
`
`4 weeks to 5
`
`
`
`years
`
`8 weeks
`
`
`
`
`Piroxicam
`
`Naproxen
`
`
`
`
`Azodisallcylate
`Phenylbutazone
`
`
`
`
`
`Indomethacin
`Piroxicam
`
`
`Naproxen
`Piroxicam
`
`Indomethacin
`SR
`
`Various NSAI DS
`
`
`
`
`
`
`
`
`
`
`
`
`NSAIDS = nonsteroidal anti—inflammatory drugs; NR = not reported.
`
`
`
`
`
`
`
`
`
`
`
`The majority of literature case reports describe a
`
`
`
`
`
`
`temporal relationship between NSAID use and occur-
`
`
`
`
`
`
`
`
`
`rence of large intestinal side effects. In 12 cases re-
`
`
`
`
`
`
`
`challenge with NSAID gives a more convincing rela-
`
`
`
`
`
`tionship.55' 50’ 67* 84’ 88 However, ethics of rechallenge
`
`
`
`
`
`
`
`
`
`
`because of severity of the presumed cause prohibited
`
`
`
`
`
`
`
`
`this in many patients. The cessation of NSAID therapy
`
`
`
`
`
`
`
`resulted in rapid improvement, in most cases without
`
`
`
`
`
`
`additional therapy. The use of sulfasalazine, pred-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`nisolone,3'6 or 5—acetylsalicylic acid“ is often sufficient
`
`
`
`
`
`
`to induce remission, although immediate surgeiy with
`
`
`
`
`
`
`
`resection of affected bowel segments may be re
`
`quired.
`
`
`
`
`
`
`
`
`The first suggestion of a presystemic or local effect
`
`
`
`
`
`
`
`of NSAIDS in inducing large intestinal
`toxicologic
`
`
`
`
`
`
`manifestations because of incomplete absorption of
`
`
`
`
`
`
`
`
`the NSAID resulting in high local concentrations in
`
`
`
`
`
`
`
`
`
`the colon was originally put forward in 1966.51 A
`
`Cosmo Ex. 2164, Page 5
`CFAD v. Cosmo; |PR2015-00988
`
`Cosmo Ex. 2164, Page 5
`CFAD v. Cosmo; IPR2015-00988
`
`

`
`Vol. 38, No. 12
`
`
`
`
`
`NSAIDS AND THE LARGE INTESTINE
`
`
`
`
`
`
`
`1515
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`physical association between the drug and side effect
`
`
`
`
`
`
`
`
`has since been reported. Evidence for this has come
`
`
`
`
`
`from the osinotically activated, slow—release formula-
`
`
`
`
`
`
`tion of indomethacin (Osmosin®, Mercl<:—Sharpe and
`
`
`
`
`
`
`
`Dohine, London, United Kingdom), which is no
`
`
`
`
`
`longer commercially available. Osmosin® capsules
`
`
`
`
`
`
`
`
`
`
`were located at the site of perforating colonic and ileal
`
`
`
`
`
`
`
`
`ulcers and free in the peritoneal cavity.50 The potas-
`
`
`
`
`
`
`
`
`sium added to this preparation may have precipitated
`
`
`
`
`
`
`the vasospasm with subsequent ischemia. However, a
`use LA
`;_
`a
`
`
`
`
`
`
`
`
`
`more recent report has lso suggested the location of
`
`
`
`
`
`
`
`
`possible diclofenac pill fragments at the site of ulcer"-
`
`ation and strictures.”
`
`
`
`
`
`
`
`Hypersensitivity Reactions. Several cases of acute
`
`
`
`
`
`proctocolitis associated with salicylate sensitivity have
`
`
`
`
`
`
`
`been reported (Table 5). These patients were aspirin—
`
`
`
`
`
`
`
`
`sensitive and had a history of asthma, rhinitis, and
`
`
`
`
`
`
`nasal polyps. Proctocolitis was reversible on avoid-
`
`
`
`
`
`
`
`ance of salicyl,ates.75’S6 In addition, a naproxen hy-
`
`
`
`
`
`
`
`
`persensitivity reaction with colitis has also been de-
`scribed.”
`
`
`
`
`The
`Siippositoiylnduced.
`
`
`
`
`
`
`
`NSAIDS in suppository form imposes the problem of
`
`
`
`
`
`
`
`high rectal concentrations of the drug, which may
`
`
`
`
`
`
`
`induce rectal bleeding and proctitis (Table 4). Occa-
`
`
`
`
`
`
`
`sional reports suggest that NSAID suppositories can
`
`
`
`
`
`
`
`induce rectal inflammation, pain, and bleeding, the
`
`
`
`
`
`
`
`severity of which may be dose~dependent.47’65 It is
`
`
`
`
`
`
`
`
`
`
`
`estimated that between 10 and 30 percent of patients
`
`
`
`
`
`
`using NSAJD suppositories have distressing side ef-
`
`
`
`
`
`
`
`
`fects.16'1°4"1°5 In addition to proctitis there are also
`
`
`
`
`
`
`cases of ulceration and strictures following supposi—
`
`
`tory administration.44
`
`
`
`
`
`
`I€eacl'iz/ation ofBowel Disease. One hundred twen-
`
`
`
`
`
`
`ty~two patients with reactivation of bowel disease
`attributable to NSAID use have been described in the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`literature from 1978 to present (Table 2). These pa-
`
`administration
`
`of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`tients, whose ages ranged from 21 to 93 (mean, 54.17)
`
`
`
`
`
`
`
`
`years, were taking many types of NSAIDS from vari-
`ous structural classes. Clinical manifestations were GI
`
`
`
`
`
`
`
`
`
`
`
`
`
`bleeding, abdominal pain,
`iron deficiency anemia,
`
`
`
`
`
`
`
`
`
`obstruction, or diarrhea. Of the 62 in whom gender
`
`
`
`
`
`
`
`
`
`was reported, 34 were female and 28 were male.
`
`
`
`
`
`
`
`Several case reports have suggested a relapse in
`ulcerative colitis or Crohn’s disease in association
`
`
`
`
`
`
`
`
`
`
`
`with NSAID ingestion.” 76 The relationship be-
`
`
`
`
`
`
`
`
`tween rechallenge and relapse has also been de-
`
`
`
`
`
`
`
`scribed.58' 76’ 78 In patients with a history of lower
`
`
`
`
`
`
`
`
`
`bowel disease, particularly ulcerative colitis,
`it ap-
`
`
`
`
`
`
`
`
`pears that virtually any of the nonsteroidals may re-
`
`
`
`
`
`
`activate the disease.” 78’ 83’ 97 Moreover, case reports
`
`
`
`
`
`
`
`
`
`
`also describe patients taking NSAIDS for extremely
`
`
`
`
`
`
`
`
`short periods who appeared to experience relapse of
`
`
`
`
`
`
`
`their quiescent colitis. Ibuprofen has been associated
`
`
`
`
`
`
`
`
`
`with acute relapse of ulcerative colitis after only six
`tablets.97
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`An association between NSAID usage and internal
`
`
`
`
`
`
`
`
`
`pelvic fistulas has also been reported to develop from
`
`
`
`
`
`
`
`
`
`the colon to other pelvic viscera, spontaneously or in
`
`association with colonic diverticula.” Other case.re—
`
`
`
`
`
`
`
`
`
`
`
`ports also describe this temporal association between
`
`
`
`
`
`acute perforation of colonic diveiticula associated
`
`
`
`
`with short-term NSAJD the1‘apy.29‘5O’45'91
`
`
`
`
`
`
`
`
`Epidemiologic Evidence
`
`
`
`
`
`
`
`
`
`
`There are a number of epidemiologic studies relat-
`
`
`
`
`
`
`
`
`ing NSAIDS to large intestinal toxicity. The most con-
`
`
`
`
`
`
`
`
`vincing evidence linking NSAIDS as a cause of signif-
`
`
`
`
`
`
`icant colonic problems comes from a retrospective
`
`
`
`
`
`
`
`
`epidemiologic study of 268 cases of colonic or small
`
`
`
`
`
`
`bowel perforations or hemorrhage. The expected in-
`
`
`
`
`
`
`
`cidences of lower bowel perforations and bleedings
`
`
`
`
`
`
`
`
`
`are reported to be 10 and 7 per 100,000, respectively.61
`
`
`
`
`
`Table 3.
`
`
`
`
`
`
`
`
`
`
`
`Case Reports of NSAID-induced Hypersensitivity Reactions in the Large intestine
`
`
`
`
`Drug
`
`
`
`Duration of Use
`
`
`
`
`
`Age and Sex
`
`
`
`
`Toxicologic Effect
`
`
`
`Reference
`
`
`
`
`71
`
`
`
`86
`
`18
`
`
`
`
`
`
`
`Bloody diarrhea, proctitis,
`uticaria, asthma, nasal
`
`
`
`. polyps
`
`
`Severe proctocolitis,
`
`
`rectal bleeding
`
`
`Eosinophilic colitis,
`
`hypersensitivity, bloody
`diarrhea, abdominal
`
`
`cramping, weight loss,
`
`
`ulcerations
`
`
`
`
`
`
`Cosmo Ex. 2164, Page 6
`CFAD v. Cosmo; |PR2015-00988
`
`
`Aceiylsalicylic acid
`
`
`
`Hours
`
`
`
`
`Aceiylsaiicylic acid
`
`
`
`Naproxen
`
`
`
`
`1 week
`
`
`
`
`3 weeks
`
`
`
`55l\/l
`
`
`
`35M
`
`
`
`57F
`
`
`
`
`
`
`NSAID = nonsteroidal anti-inflammatory drug.
`
`
`
`
`Cosmo Ex. 2164, Page 6
`CFAD v. Cosmo; IPR2015-00988
`
`

`
`1316
`
`
`
`DAVIES
`
`
`Dis Colon Rectum, December 1995
`
`
`
`
`
`
`
`Tablel4.
`
`
`
`
`
`
`
`
`
`
`
`Case Reports of NSA|D—lnduced Suppository Toxicity in the Large intestine
`
`
`
`Drug
`
`
`
`
`
`Duration of Use
`
`
`
`
`
`Age and Sex
`
`
`
`
`Toxioologic Effect
`
`
`
`
`
`Reference No.
`
`No.
`
`
`
`14
`
`
`
`1
`
`1
`
`20
`
`
`
`10
`
`4
`"I
`8
`
`
`
`
`
`
`1
`1
`3
`
`
`
`
`
`Discomfort, loose stools, local
`
`
`
`irritation, flatulence, colic
`
`
`
`
`
`
`Rectal ulcer and hemorrhage,
`inflammation
`
`
`
`Rectal bleeding, inflammation,
`necrosis of the mucosa
`
`
`
`
`Ulceration, -erosion, edema,
`
`
`
`
`bleeding, flatus
`Rectal irritation
`
`
`
`
`Rectal irritation, hemorrhage
`
`
`Rectal irritation
`Loose stools, trace of rectal
`
`
`
`
`
`
`
`bleeding, edema, excess
`
`
`mucus, irritation
`
`
`Nonspecific proctolitis
`
`Proctocolitis, hemorrhage
`
`
`Anorectal lesions
`
`
`
`
`
`Ulcer, stenosis of anal verge,
`
`
`proctitis, bleeding
`
`
`
`104
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`96
`
`
`65
`
`16
`
`
`
`~
`105
`
`
`37
`
`33
`82
`
`
`47
`15
`44
`
`
`
`
`
`lndomethacin
`
`lndomethacin
`
`lndomethacin
`
`
`
`
`
`
`
`
`
`
`Naproxen
`lndomethacin
`lndomethacin
`
`
`Diclofenac
`
`Diclofenac
`lndomethacin
`
`
`
`NR
`
`
`
`<3 weeks
`
`
`
`
`5 months
`
`
`
`9 weeks
`
`
`
`
`NR
`
`
`64F
`
`
`
`15M
`
`
`
`NR
`
`
`
`
`1-21 months
`
`
`
`3-90 days
`
`
`
`At least 14 days
`4 weeks
`
`
`
`
`
`1
`
`
`
`
`Mefenamic acid
`
`Pirprofen
`
`Diclofenac
`lndomethacin
`
`
`
`
`
`1 week
`
`
`5 days
`
`
`
`
`3 weeks to 1 year
`
`
`10 years
`
`
`
`‘
`
`
`
`NR
`
`
`NR
`
`NR
`3M
`
`
`5F
`(35-72)
`
`59M
`
`42F
`
`36F
`
`41F
`
`53F
`
`
`
`
`
`
`
`NSAID = nonsteroidal anti-inflammatory drug; NR = not reported.
`
`
`
`
`
`
`
`
`
`
`
`
`There was a threefold higher rate of large intestine per~
`
`
`
`
`
`
`
`foration compared with small intestine perforation in
`
`patients on NSAIDS61 In a recent retrospective study
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`there was a threefold increase in risk of death from large
`
`
`
`
`
`
`
`bowel peiforation in patients taking NSAIDS compared
`
`
`
`
`
`
`
`
`
`with controls.12 NSAID use was also investigated in 30
`
`
`
`
`
`
`
`
`patients with collagenous colitis who had diarrhea and
`
`
`
`
`
`
`
`
`
`large bowel biopsies and in 30 matched patients with
`irritable bowel disease and diverticulosis as controls.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Use of NSAIDS was five times higher in the collagenous
`
`
`colitis group.”
`
`
`
`
`
`
`
`A prospective study suggests that 10 percent of
`
`
`
`
`
`
`newly diagnosed colonic inflammation may be re-
`
`
`
`
`
`
`
`lated to NSAID medication and that patients taking
`
`
`
`
`
`
`
`
`
`NSAIDS appear to be five times more likely to de-
`
`
`
`
`
`
`velop colonic inflamrnation than the general popula-
`
`
`
`
`
`tion.95 Furthermore, supporting the association of
`
`
`
`
`
`
`
`NSAIDS and large bowel toxicity is recent retrospecw
`
`
`
`
`
`
`
`tive case—control study data, which indicates that pa-
`
`
`
`
`
`
`tients admitted with lower gastrointestinal tract bleed—
`
`
`
`
`
`
`
`
`ing made on the basis of colonoscopic examination
`
`
`
`
`
`
`
`
`
`are twice as likely to have ingested NSAIDS than
`
`
`
`
`
`
`
`
`patients without GI disease admitted to the hospitalsj
`
`
`
`
`
`
`
`The reported low incidence of NSAID large intesti—
`
`
`
`
`
`
`
`nal toxicity may genuinely reflect the relative abun~
`
`
`
`
`
`
`
`
`
`
`dance, the lack of recognition of the problem, or lack
`
`
`
`
`
`
`
`
`of publication. A report suggests the existence of
`
`
`
`
`
`
`
`
`four other possible cases of lower bowel toxicity
`
`
`
`
`
`
`
`
`with rnefenarnic acid, which was made known to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`\X/'arner—Lambert Co, Ltd., London, United Kingdom?” _
`
`
`
`
`
`
`
`
`Another report suggests the existence of nine other
`
`
`
`
`
`
`
`possible cases of lower bowel toxicity with meclofe~
`
`
`
`
`
`
`
`namate, which was made known to Parke-Davis (Ann
`
`
`
`
`
`
`
`
`Arbor, MI).35 In addition, six other cases of colonic
`mucosal lesions with NSAIDS in France have been
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`reported.” The existence of four other cases of lower
`
`
`
`
`
`
`
`GI bleeding, which was reported to Upjohn (Kalama~
`
`
`
`
`
`
`
`zoo, MI), has been suggested.89 Moreover the exis-
`
`
`
`
`
`
`
`
`tence of 19 other cases of NSAID—induced large intes~
`
`
`
`
`
`
`
`tinal damage with eight fatalities have been reported
`
`
`
`
`
`
`
`
`to the United Kingdom Committee on Safety of Med-
`
`
`
`
`
`
`
`
`
`icines.” Finally, the existence of three cases of di-
`
`
`
`
`
`
`
`clofenac—induced colitis has also been stiggestedml It
`
`
`
`
`
`
`
`
`
`would, therefore, appear that only a fraction of the
`
`
`
`
`
`
`
`
`cases of toxicologic manifestations of NSAIDS on the
`
`
`
`
`
`
`
`large intestine have been published.45 Additionally, as
`
`
`
`
`
`
`
`some NSAIDS are available without a prescription, its
`
`
`
`
`
`
`
`
`use may not be volunteered, and the association
`
`
`
`
`
`
`
`could, therefore, pass unrecognized by the clinician.
`
`
`
`
`
`
`Whether the manifestation reflects provocation of
`
`
`
`
`
`
`
`
`underlying colitis or de novo disease remains unclear.
`
`
`
`
`
`
`
`
`
`
`It is suggested that there is a roughly fivefold increase
`
`
`
`
`
`
`
`
`in the risk of developing inflammatory bowel disease
`
`
`
`
`
`
`
`
`with NSAID ingestion.93 In a retrospective study 4
`
`
`
`
`
`
`
`
`percent of patients with ulcerative colitis appeared to
`
`
`
`
`
`
`
`
`
`
`have colitis induced by the use of NSAIDS52 In a
`
`
`
`
`
`
`questionnaire to 82 consecutive ulcerative colitis pa~
`
`Cosmo Ex. 2164, Page 7
`CFAD v. Cosmo; lPR2015-00988
`
`Cosmo Ex. 2164, Page 7
`CFAD v. Cosmo; IPR2015-00988
`
`

`
`Vol. 58, No. 12
`
`
`
`
`
`
`NSAIDS AND THE LARGE INTESTINE
`
`
`
`
`
`
`
`1317
`
`
`
`
`
`
`
`
`
`
`
`
`
`tients, 25 of whom had relapse confirmed and 53 of
`
`
`
`
`
`
`
`
`
`whom were in remission, it was learned that patients
`
`
`
`
`
`
`
`
`
`
`in relapse were more than 1.7 times more likely to
`
`
`
`
`
`
`
`have consumed an NSAID preparation during the
`
`
`
`
`
`
`
`previous month than a patient in remission. Although
`
`
`
`
`
`
`
`
`
`this study did not achieve statistical significance, it is
`
`
`
`
`
`
`
`
`probable that NSAID consumption can act as a trigger
`
`
`
`
`
`
`in precipitating attacks in some patients.“
`
`
`
`
`
`
`
`
`In a retrospective study 59 percent of patients with
`
`
`
`
`
`
`
`diverticulitis requiring a laparotomy were users of
`
`
`
`
`
`NSAIDS, with an NSAID—related laparotomy relative
`
`
`
`
`
`
`
`
`
`
`
`
`risk to controls of 4.5.32 In parallel to these findings, a
`
`
`
`
`
`
`
`
`case control study revealed that more patients with
`
`
`
`
`
`
`complicated diverticular disease were taking NSAIDS
`
`
`
`
`
`than randomly selected emergency hospital admis-
`
`
`
`
`
`
`sions or patients with uncomplicated diverticular dis-
`
`
`
`
`
`
`
`
`
`
`
`ease matched for age and sex with a relative risk of
`
`
`
`
`
`
`
`fourfold.21 In another prospective study associating
`
`
`
`
`
`
`
`complications of diverticular disease and NSAIDS, a
`
`
`
`
`
`
`temporal relationship among induction of fistulas