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Class: Other Nonsteroidal Anti-inflammatory Agents
CAS Number: 38194-50-2

Medically reviewed by Last updated on Apr 3, 2020.


    Cardiovascular Risk
  • Increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).100 500 502 508 Risk may occur early in treatment and may increase with duration of use.500 502 505 506 508 (See Cardiovascular Thrombotic Effects under Cautions.)

  • Contraindicated in the setting of CABG surgery.508

    GI Risk
  • Increased risk of serious (sometimes fatal) GI events (e.g., bleeding, ulceration, perforation of the stomach or intestine).100 Serious GI events can occur at any time and may not be preceded by warning signs and symptoms.100 Geriatric individuals are at greater risk for serious GI events.100 (See GI Effects under Cautions.)


Prototypical NSAIA; indeneacetic acid derivative; structurally related to indomethacin.100 a

Uses for Sulindac

Consider potential benefits and risks of sulindac therapy as well as alternative therapies before initiating therapy with the drug.100 Use lowest effective dosage and shortest duration of therapy consistent with the patient's treatment goals.100

Inflammatory Diseases

Symptomatic treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), and acute gouty arthritis.100

Colorectal Polyps

Has been associated with a reduction of the number of adenomatous colorectal polyps in adults with familial adenomatous polyposis (FAP).157 158 159 160

Sulindac Dosage and Administration


  • Consider potential benefits and risks of sulindac therapy as well as alternative therapies before initiating therapy with the drug.100


Oral Administration

Administer orally twice daily with food.100


To minimize the potential risk of adverse cardiovascular and/or GI events, use lowest effective dosage and shortest duration of therapy consistent with the patient's treatment goals.100 Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.100


Inflammatory Diseases
Osteoarthritis, Rheumatoid Arthritis, or Ankylosing Spondylitis

Initially, 150 mg twice daily.100 Adjust dosage based on response.100

Acute Painful Shoulder

200 mg twice daily; reduce dosage based on response.100 7–14 days of therapy usually adequate.100


200 mg twice daily; reduce dosage based on response.100 7 days of therapy usually adequate.100

Colorectal Polyps

150 mg twice daily.158

Prescribing Limits


Inflammatory Diseases

Maximum 400 mg daily.100

Special Populations

Hepatic Impairment

Dosage reduction may be required.100

Renal Impairment

Dosage reduction may be required.100

Cautions for Sulindac


  • Known hypersensitivity to sulindac or any ingredient in the formulation.100

  • History of asthma, urticaria, or other sensitivity reaction precipitated by aspirin or other NSAIAs.100

  • In the setting of CABG surgery.508



Cardiovascular Thrombotic Effects

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) increase the risk of serious adverse cardiovascular thrombotic events (e.g., MI, stroke) in patients with or without cardiovascular disease or risk factors for cardiovascular disease.500 502 508

Findings of FDA review of observational studies, meta-analysis of randomized controlled trials, and other published information500 501 502 indicate that NSAIAs may increase the risk of such events by 10–50% or more, depending on the drugs and dosages studied.500

Relative increase in risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, but the absolute incidence of serious NSAIA-associated cardiovascular thrombotic events is higher in those with cardiovascular disease or risk factors for cardiovascular disease because of their elevated baseline risk.500 502 506 508

Increased risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use.500 502 505 506 508

In controlled studies, increased risk of MI and stroke observed in patients receiving a selective COX-2 inhibitor for analgesia in first 10–14 days following CABG surgery.508

In patients receiving NSAIAs following MI, increased risk of reinfarction and death observed beginning in the first week of treatment.505 508

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI;500 508 511 absolute mortality rate declined somewhat after the first post-MI year, but the increased relative risk of death persisted over at least the next 4 years.508

Some systematic reviews of controlled observational studies and meta-analyses of randomized studies suggest naproxen may be associated with lower risk of cardiovascular thrombotic events compared with other NSAIAs.173 174 175 176 500 501 502 503 506 FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.500

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events throughout therapy, even in those without prior cardiovascular symptoms) and at the lowest effective dosage for the shortest duration necessary.100 500 508

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease.505 511 512 516 Avoid use in patients with recent MI unless benefits of therapy are expected to outweigh risk of recurrent cardiovascular thrombotic events; if used, monitor for cardiac ischemia.508 Contraindicated in the setting of CABG surgery.508

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs.100 502 508 (See Specific Drugs under Interactions.)

GI Effects

Serious GI toxicity (e.g., bleeding, ulceration, perforation) can occur with or without warning symptoms; increased risk in those with a history of GI bleeding or ulceration, geriatric patients, smokers, those with alcohol dependence, and those in poor general health.100 154 156

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), consider concomitant use of misoprostol;112 125 154 155 alternatively, consider concomitant use of a proton-pump inhibitor (e.g., omeprazole)112 125 154 or use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib).112


Hypertension and worsening of preexisting hypertension reported; either event may contribute to the increased incidence of cardiovascular events.100 Use with caution in patients with hypertension; monitor BP.100

Impaired response to ACE inhibitors, angiotensin II receptor antagonists, β-blockers, and certain diuretics may occur.100 508 509 (See Specific Drugs under Interactions.)

Heart Failure and Edema

Fluid retention and edema reported.100 508

NSAIAs (selective COX-2 inhibitors, prototypical NSAIAs) may increase morbidity and mortality in patients with heart failure.500 501 504 507 508

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema.508 (See Specific Drugs under Interactions.)

Manufacturer recommends avoiding use in patients with severe heart failure unless benefits of therapy are expected to outweigh risk of worsening heart failure; if used, monitor for worsening heart failure.508

Some experts recommend avoiding use, whenever possible, in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure.507

Renal Effects

Direct renal injury, including renal papillary necrosis, reported in patients receiving long-term NSAIA therapy.100 167

Potential for overt renal decompensation.100 109 110 111 Increased risk of renal toxicity in patients with renal or hepatic impairment or heart failure, in geriatric patients, in patients with volume depletion, and in those receiving a diuretic, ACE inhibitor, or angiotensin II receptor antagonist.100 109 110 111 172 (See Actions.)

Symptomatic renal calculi containing sulindac metabolites reported rarely.100 121 Factors predisposing to urinary crystal formation include increased urinary excretion of sulindac metabolites (related to size of single doses as well as total daily dosage), decreased urine flow, and relatively low urinary pH.121 Formation of crystals, and presumably renal calculi, appears unlikely when urine output >240 mL/hour or pH >5.8.121 (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported.100 Hypersensitivity (e.g., severe dermatologic manifestations, hepatic abnormalities) reactions associated with fever reported.100

Immediate medical intervention and discontinuance for anaphylaxis.100 Discontinue if unexplained fever or other evidence of hypersensitivity occurs.100

Avoid in patients with aspirin triad (aspirin sensitivity, asthma, nasal polyps); caution in patients with asthma.100

Dermatologic Reactions

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; can occur without warning.100 Discontinue at first appearance of rash or any other sign of hypersensitivity (e.g., blisters, fever, pruritus).100

Major Toxicities


Pancreatitis reported.100

If pancreatitis is suspected, discontinue the drug and appropriately evaluate, monitor, and treat the patient; do not reinstitute sulindac therapy.100 Rule out other possible causes of pancreatitis or conditions that may mimic pancreatitis.100

General Precautions

Hepatic Effects

Severe reactions including jaundice, fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal) reported rarely with NSAIAs.100 a

Elevations of serum ALT or AST reported.100

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results.100 Discontinue if signs or symptoms of liver disease or systemic manifestations (e.g., eosinophilia, rash) occur or if liver function test abnormalities persist or worsen.100

Hematologic Effects

Anemia reported rarely.100 Determine hemoglobin concentration or hematocrit in patients receiving long-term therapy if signs or symptoms of anemia occur.100

May inhibit platelet aggregation and prolong bleeding time.100

Ocular Effects

Visual disturbances reported; if such effects occur, perform ophthalmic evaluation.100

Aseptic Meningitis

Increased risk of aseptic meningitis in patients with systemic lupus erythematosus or mixed connective tissue disease.b

Other Precautions

Not a substitute for corticosteroid therapy; not effective in the management of adrenal insufficiency.100

May mask certain signs of infection.100

Obtain CBC and chemistry profile periodically during long-term use.100

Specific Populations


Category C.100 Avoid use in third trimester because of possible premature closure of the ductus arteriosus.100


Distributed into milk in rats; not known whether distributed into milk in humans.100 Discontinue nursing or the drug.100

Pediatric Use

Safety and efficacy not established.100

Geriatric Use

Caution advised.100 Geriatric adults appear to tolerate NSAIA-induced adverse effects less well than younger individuals.100 Fatal adverse GI effects reported more frequently in geriatric patients than younger adults.100

Select dosage with caution because of age-related decreases in renal function.100 May be useful to monitor renal function.100

Hepatic Impairment

Monitor closely.100 (See Hepatic Impairment under Dosage and Administration and see Special Populations under Pharmacokinetics.)

Renal Impairment

Use not recommended in patients with advanced renal disease; close monitoring of renal function advised if used.100 (See Renal Impairment under Dosage and Administration.)

Sulindac and the sulfone metabolite eliminated principally via the kidney.100 (See Special Populations under Pharmacokinetics.)

Use with caution in patients with a history of renal lithiasis; ensure proper hydration.100 (See Renal Effects under Cautions.)

Common Adverse Effects

Dyspepsia, nausea, diarrhea, constipation, rash, dizziness, headache.100

Interactions for Sulindac

Protein-bound Drugs

Potential for sulindac and its sulfide metabolite to be displaced from binding sites by, or to displace from binding sites, other protein-bound drugs.a Observe for adverse effects (especially in patients receiving higher than recommended dosages of sulindac and those with renal impairment or other metabolic dysfunction that might increase plasma concentrations of sulindac or its sulfide metabolite).a

Specific Drugs




ACE inhibitors

Reduced BP response to ACE inhibitor100

Possible deterioration of renal function in individuals with renal impairment100

Monitor BP100


Pharmacokinetic interaction unlikely100

Angiotensin II receptor antagonists

Reduced BP response to angiotensin II receptor antagonist100

Possible deterioration of renal function in individuals with renal impairment100

Monitor BP100

Antacids (magnesium- or aluminum-containing)

Change in sulindac bioavailability unlikely100

Anticoagulants, oral

Possibility of bleeding complications100

Protein binding interaction unlikely100

Caution advised; monitor PT; adjust anticoagulant dosage as needed100


Possible increase in cyclosporine-induced toxicity100

Use with caution; monitor renal function100


Decreased plasma concentrations of sulfide metabolite of sulindac100

Peripheral neuropathy reported100

Avoid concomitant use100

Diuretics (furosemide, thiazides)

Reduced natriuretic effects possible100

Monitor for diuretic efficacy and renal failure100

Hypoglycemic agents, oral

Protein binding interaction unlikely100


Pharmacokinetic interaction unlikely135 136 137 138 139

Nevertheless, monitor for altered response to lithium when initiating or discontinuing sulindac136


Possible increased plasma methotrexate concentrations100 126 127 128 129 130 131 132

Use with caution100


NSAIAs including aspirin: Increased risk of GI ulceration and other complications100

Aspirin: Decreased plasma concentrations of sulfide metabolite of sulindac with aspirin 2.4 g daily100

Aspirin: No consistent evidence that low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs100 502 508

Diflunisal: Decreased plasma concentrations of the sulfide metabolite of sulindac with diflunisal100

Concomitant use not recommended100


Increased plasma concentrations of sulindac and its sulfone metabolite; minimal changes in plasma concentrations of the sulfide metabolite100

Reduced uricosuric action of probenecid100

Change in uricosuric action unlikely to be clinically important100


Pharmacokinetic interaction unlikely100

Thrombolytic agents

Possible bleeding complicationsa

Sulindac Pharmacokinetics



Prodrug with little pharmacologic activity until reduced to active sulfide metabolite;100 peak plasma concentrations of sulfide metabolite attained within about 5 hours.100

Special Populations

Concentrations of the sulfide metabolite are higher in patients with alcoholic liver disease than in healthy individuals.b

In patients with end-state renal disease requiring dialysis, concentrations of sulindac and the sulfone metabolite are similar to those in healthy individuals and concentrations of the sulfide metabolite are lower than those in healthy individuals.b



Widely distributed in animals.a

Plasma Protein Binding

Sulindac: 93%.b

Sulfide metabolite: 98%.b



Reduced to an active sulfide metabolite (reversible reaction) and oxidized to an inactive sulfone metabolite (irreversible reaction).100 Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation.100

Elimination Route

Excreted in urine (50%) principally as sulindac and its conjugated sulfone metabolite and in feces (25%) as the sulfone and sulfide metabolites.100

Sulindac and its metabolites not removed by hemodialysis.b


Sulindac: 7.8 hours.100

Sulfide metabolite: 16.4 hours.100







  • Inhibits cyclooxygenase-1 (COX-1) and COX-2.148 149 150 151 152 153

  • Pharmacologic actions similar to those of other prototypical NSAIAs; exhibits anti-inflammatory, analgesic, and antipyretic activity.100 a

  • Conflicting data regarding effects on renal prostaglandin synthesis and renal function.101 102 103 104 105 106 107 108 Some studies suggest no effect;101 102 105 others suggest that sulindac inhibits renal prostaglandin synthesis and impairs renal function, but possibly to lesser degree than other NSAIAs (i.e., ibuprofen, indomethacin).101 103 104 106 107

Advice to Patients

  • Importance of reading the medication guide for NSAIAs that is provided each time the drug is dispensed.100

  • Risk of serious cardiovascular events (e.g., MI, stroke).100 500 508

  • Risk of GI bleeding and ulceration.100

  • Risk of serious skin reactions.100 Risk of anaphylactoid and other sensitivity reactions.100

  • Risk of hepatotoxicity.100

  • Importance of seeking immediate medical attention if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.100 500 508

  • Importance of notifying clinician if signs and symptoms of GI ulceration or bleeding, unexplained weight gain, or edema develops.100

  • Importance of discontinuing sulindac and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop.100 Importance of seeking immediate medical attention if an anaphylactic reaction occurs.100

  • Importance of discontinuing therapy and contacting clinician immediately if signs and symptoms of hepatotoxicity (nausea, fatigue, lethargy, pruritus, jaundice, upper right quadrant tenderness, flu-like symptoms) occur.100

  • Risk of heart failure or edema; importance of reporting dyspnea, unexplained weight gain, or edema.508

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.100 Importance of avoiding sulindac in late pregnancy (third trimester).100

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.100

  • Importance of informing patients of other important precautionary information.100 See Cautions.


Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name



Dosage Forms


Brand Names




150 mg*

Sulindac Tablets

200 mg*

Sulindac Tablets

AHFS DI Essentials™. © Copyright 2020, Selected Revisions April 13, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.


100. Merck & Co. Clinoril (sulindac) tablets prescribing information. Whitehouse Station, NJ; 2006 Feb.

101. Swainson CP, Griffiths P. Acute and chronic effects of sulindac on renal function in chronic renal disease. Clin Pharmacol Ther. 1985; 37:298-300.

102. Ciabattoni G, Cinotti GA, Pierucci A et al. Effects of sulindac and ibuprofen in patients with chronic glomerular disease: evidence for the dependence of renal function on prostacyclin. N Engl J Med. 1984; 310:279-83.

103. Roberts DG, Gerber JG, Barnes JS et al. Sulindac is not renal sparing in man. Clin Pharmacol Ther. 1985; 38:258-65.

104. Berg KJ, Talseth T. Acute renal effects of sulindac and indomethacin in chronic renal failure. Clin Pharmacol Ther. 1985; 37:447-52.

105. Sedor JR, Williams SL, Chremos AN et al. Effects of sulindac and indomethacin on renal prostaglandin synthesis. Clin Pharmacol Ther. 1984; 36:85-91.

106. Brater DC, Anderson S, Baird B et al. Effects of ibuprofen, naproxen, and sulindac on prostaglandins in men. Kidney Int. 1985; 27:66-73.

107. Daskalopoulos G, Kronborg I, Katkov WM et al. Sulindac and indomethacin suppress the diuretic action of furosemide in patients with cirrhosis and ascites: evidence that sulindac affects renal prostaglandins. Am J Kidney Dis. 1985; 6:217-21.

108. Bunning RD, Barth WF. Sulindac: a potentially renal-sparing nonsteroidal anti-inflammatory drug. JAMA. 1982; 248:2864-7.

109. The Upjohn Company. Motrin prescribing information. Kalamazoo, MI; 1985 Jul.

110. McNeil Pharmaceutical. Tolectin and Tolectin DS prescribing information. Spring House, PA; 1985 Aug.

111. Clive DM, Stoff JS. Renal syndromes associated with nonsteroidal anti-inflammatory agents. N Engl J Med. 1984; 310:563-72.

112. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum. 2002; 46:328-46.

113. Settipane GA. Adverse reactions to aspirin and other drugs. Arch Intern Med. 1981; 141:328-32.

114. Weinberger M. Analgesic sensitivity in children with asthma. Pediatrics. 1978; 62(Suppl):910-5.

115. Settipane GA. Aspirin and allergic diseases: a review. Am J Med. 1983; 74(Suppl):102-9.

116. VanArsdel PP Jr. Aspirin idiosyncracy and tolerance. J Allergy Clin Immunol. 1984; 73:431-3.

117. Stevenson DD. Diagnosis, prevention, and treatment of adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol. 1984; 74(4 Part 2):617-22.

118. Stevenson DD, Mathison DA. Aspirin sensitivity in asthmatics: when may this drug be safe? Postgrad Med. 1985; 78:111-3,116-9. (IDIS 205854)

119. Syntex Puerto Rico, Inc. Naprosyn prescribing information. Humacao, PR; 1985 Jun.

120. Pleskow WW, Stevenson DD, Mathison DA et al. Aspirin desensitization in aspirin-sensitive asthmatic patients: clinical manifestations and characterization of the refractory period. J Allergy Clin Immunol. 1982; 69(1 Part 1):11-9.

121. Food and Drug Administration. Rare complication of sulindac. FDA Drug Bull. 1989; 19:4.

122. Palmer JF. Letter sent to Berger ET, of Merck Sharp & Dohme regarding labeling revisions about gastrointestinal adverse reactions to Clinoril (sulindac) Rockville, MD: Food and Drug Administration, Division of Oncology and Radiopharmaceutical Drug Products; 1988 Sep.

123. Anon. Labeling revisions for NSAIDs. FDA Drug Bull. 1989; 19:3-4.

124. Searle. Cytotec (misoprostol) prescribing information. Skokie, IL; 1989 Jan.

125. Anon. Drugs for rheumatoid arthritis. Med Lett Drugs Ther. 2000; 42:57-64.

126. Thyss A, Milano G, Kubar J et al. Clinical and pharmacokinetic evidence of a life-threatening interaction between methotrexate and ketoprofen. Lancet. 1986; 1:256-8.

127. Ellison NM, Servi RJ. Acute renal failure and death following sequential intermediate-dose methotrexate and 5-FU: a possible adverse effect due to concomitant indomethacin administration. Cancer Treat Rep. 1985; 69:342-3.

128. Singh RR, Malaviya AN, Pandey JN et al. Fatal interaction between methotrexate and naproxen. Lancet. 1986; 1:1390.

129. Day RO, Graham GG, Champion GD et al. Anti-rheumatic drug interactions. Clin Rheum Dis. 1984; 10:251-75.

130. Daly HM, Scott GL, Boyle J et al. Methotrexate toxicity precipitated by azapropazone. Br J Dermatol. 1986; 114:733-5.

131. Hansten PD, Horn JR. Methotrexate interactions: ketoprofen (Orudis). Drug Interact Newsl. 1986; 6(Updates):U5-6.

132. Maiche AG. Acute renal failure due to concomitant action of methotrexate and indomethacin. Lancet. 1986; 1:1390.

133. Soll AH, Weinstein WM, Kurata J et al. Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. Ann Intern Med. 1991; 114:307-19.

134. Hyson CP, Kazakoff MA. A severe multisystem reaction to sulindac. Arch Intern Med. 1991; 151:387-8.

135. Lithium/NSAIAs. In: Tatro DS, Olin BR, Hebel SK, eds. Drug interaction facts. St. Louis: JB Lippincott Co; 1993(April):463.

136. Nonsteroidal anti-inflammatory drug interactions: Lithium. In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc; 1993:610.

137. Ragheb M, Powell AL. Lithium interaction with sulindac and naproxen. J Clin Psychopharmacol. 1986; 6:150-4.

138. Furnell MM, Davies J. The effect of sulindac on lithium therapy. Drug Intell Clin Pharm. 1985; 19:374-6.

139. Miller LG, Bowman RC, Bakht F. Sparing effect of sulindac on lithium levels. J Fam Prac. 1989; 28:592-3.

140. Ciba Geigy, Ardsley, NY: Personal communication on diclofenac 28:08:04.

141. Reviewers’ comments (personal observations) on diclofenac 28:08:04.

142. Corticosteroid interactions: nonsteroidal anti-inflammatory drugs (NSAIDs). In: Hansten PD, Horn JR. Drug interactions and updates. Vancouver, WA: Applied Therapeutics, Inc., 1993:562.

143. Garcia Rodriguez LA, Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs. Lancet. 1994; 343:769-72.

144. Hollander D. Gastrointestinal complications of nonsteroidal anti-inflammatory drugs: prophylactic and therapeutic strategies. Am J Med. 1994; 96:274-81.

145. Schubert TT, Bologna SD, Yawer N et al. Ulcer risk factors: interaction between Helicobacter pylori infection, nonsteroidal use, and age. Am J Med. 1993; 94:413-7.

146. Piper JM, Ray WA, Daugherty JR et al. Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs. Ann Intern Med. 1991; 114:735-40.

147. Bateman DN, Kennedy JG. Non-steroidal anti-inflammatory drugs and elderly patients: the medicine may be worse than the disease. BMJ. 1995; 310:817-8.

148. Hawkey CJ. COX-2 inhibitors. Lancet. 1999; 353:307-14.

149. Kurumbail RG, Stevens AM, Gierse JK et al. Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996; 384:644-8.

150. Riendeau D, Charleson S, Cromlish W et al. Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol. 1997; 75:1088-95.

151. DeWitt DL, Bhattacharyya D, Lecomte et al. The differential susceptibility of prostaglandin endoperoxide H synthases-1 and -2 to nonsteroidal anti-inflammatory drugs: aspirin derivatives as selective inhibitors. Med Chem Res. 1995; 5:325-43.

152. Cryer B, Dubois A. The advent of highly selective inhibitors of cyclooxygenase—a review. Prostaglandins Other Lipid Mediators. 1998; 56:341-61.

153. Simon LS. Role and regulation of cyclooxygenase-2 during inflammation. Am J Med. 1999; 106(Suppl 5B):37-42S.

154. Wolfe MM, Lichtenstein DR, Singh G. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med. 1999; 340:1888-99.

155. Lanza FL, and the members of the Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology. A guideline for the treatment and prevention of NSAID-induced ulcers. Am J Gastroenterol. 1998; 93:2037-46.

156. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol. 1999; 26(suppl 56):18-24.

157. Giardiello FM, Yang VW, Hylind LM et al. Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med. 2002; 346:1054-9.

158. Giardiello FM, Hamilton SR, Krush AJ et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993; 328:1313-6.

159. Labayle D, Fischer D, Vielh P et al. Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology. 1991; 101:635-9.

160. Nugent KP, Farmer KC, Spigelman AD et al. Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg. 1993; 80:1618-9.

161. in’t Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med. 2001; 345:1515-21.

162. Breitner JCS, Zandi PP. Do nonsteroidal antiinflammatory drugs reduce the risk of Alzheimer’s disease? N Engl J Med. 2001; 345:1567-8. Editorial.

163. McGeer PL, Schulzer M, McGeer EG. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer’s disease: a review of 17 epidemiologic studies. Neurology. 1996; 47:425-32.

164. Beard CM, Waring SC, O’sBrien PC et al. Nonsteroidal anti-inflammatory drug use and Alzheimer’s disease : a case-control study in Rochester, Minnesota, 1980 through 1984. Mayo Clin Proc. 1998; 73:951-5.

165. in’t Veld BA, Launer LJ, Hoes AW et al. NSAIDs and incident Alzheimer’s disease: the Rotterdam Study. Neurobiol Aging. 1998; 19:607-11.

166. Stewart WF, Kawas C, Corrada M et al. Risk of Alzheimer’s disease and duration of NSAID use. Neurology. 1997; 48:626-32.

167. Pharmacia. Daypro (oxaprozin) caplets prescribing information. Chicago, IL; 2002 May.

168. Chan FKL, Hung LCT, Suen BY et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 2002; 347:2104-10.

169. Graham DY. NSAIDs, Helicobacter pylori, and Pandora’s box. N Engl J Med. 2002; 347:2162-4.

170. Food and Drug Administration. Analysis and recommendations for agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. 2005 Apr 6.

171. Cush JJ. The safety of COX-2 inhibitors: deliberations from the February 16-18, 2005, FDA meeting. From the American College of Rheumatology website ( Accessed 2005 Oct 12.

172. Novartis Pharmaceuticals. Diovan (valsartan) capsules prescribing information (dated 1997 Apr). In: Physicians’ desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:2013-5.

173. McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA. 2006; 296: 1633-44.

174. Kearney PM, Baigent C, Godwin J et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ. 2006; 332: 1302-5.

175. Graham DJ. COX-2 inhibitors, other NSAIDs, and cardiovascular risk; the seduction of common sense. JAMA. 2006; 296:1653-6.

176. Chou R, Helfand M, Peterson K et al. Comparative effectiveness and safety of analgesics for osteoarthritis. Comparative effectiveness review no. 4. (Prepared by the Oregon evidence-based practice center under contract no. 290-02-0024.) . Rockville, MD: Agency for Healthcare Research and Quality. 2006 Sep. Available at:

500. Food and Drug Administration. Drug safety communication: FDA strengthens warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes. Silver Spring, MD; 2015 Jul 9. From the FDA web site. Accessed 2016 Mar 22.

501. Coxib and traditional NSAID Trialists' (CNT) Collaboration, Bhala N, Emberson J et al. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet. 2013; 382:769-79.

502. Food and Drug Administration. FDA briefing document: Joint meeting of the arthritis advisory committee and the drug safety and risk management advisory committee, February 10-11, 2014. From FDA web site

503. Trelle S, Reichenbach S, Wandel S et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011; 342:c7086.

504. Gislason GH, Rasmussen JN, Abildstrom SZ et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med. 2009; 169:141-9.

505. Schjerning Olsen AM, Fosbøl EL, Lindhardsen J et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study. Circulation. 2011; 123:2226-35.

506. McGettigan P, Henry D. Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies. PLoS Med. 2011; 8:e1001098.

507. Yancy CW, Jessup M, Bozkurt B et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013; 62:e147-239.

508. Epic Pharma, LLC. Sulindac tablets prescribing information. Laurelton, NY; 2015 Aug.

509. Cumberland Pharmaceuticals Inc. Caldolor (ibuprofen) injection prescribing information. Nashville, TN; 2016 Apr.

511. Olsen AM, Fosbøl EL, Lindhardsen J et al. Long-term cardiovascular risk of nonsteroidal anti-inflammatory drug use according to time passed after first-time myocardial infarction: a nationwide cohort study. Circulation. 2012; 126:1955-63.

512. Olsen AM, Fosbøl EL, Lindhardsen J et al. Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among myocardial infarction patients--a nationwide study. PLoS One. 2013; 8:e54309.

516. Bavry AA, Khaliq A, Gong Y et al. Harmful effects of NSAIDs among patients with hypertension and coronary artery disease. Am J Med. 2011; 124:614-20.

a. AHFS Drug Information 2003. McEvoy GK, ed. Sulindac. Bethesda, MD: American Society of Health-System Pharmacists; 2003:1997-2001.

b. Merck & Co. Clinoril (sulindac) tablets prescribing information. Whitehouse Station, NJ; 2007 Feb.