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


Special Alerts:

[Posted 07/09/2015]

AUDIENCE: Health Professional, Consumer

ISSUE: FDA is strengthening an existing label warning that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) increase the chance of a heart attack or stroke. Based on FDAs comprehensive review of new safety information, FDA is requiring updates to the drug labels of all prescription NSAIDs. As is the case with current prescription NSAID labels, the Drug Facts labels of over-the-counter (OTC) non-aspirin NSAIDs already contain information on heart attack and stroke risk. FDA will also request updates to the OTC non-aspirin NSAID Drug Facts labels. See the FDA Drug Safety Communication (Table 1) at: for a list of non-aspirin nonsteroidal anti-inflammatory drug products.

Prescription NSAID labels will be revised to reflect the following information:

  • The risk of heart attack or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with longer use of the NSAID.

  • The risk appears greater at higher doses.

  • It was previously thought that all NSAIDs may have a similar risk. Newer information makes it less clear that the risk for heart attack or stroke is similar for all NSAIDs; however, this newer information is not sufficient for us to determine that the risk of any particular NSAID is definitely higher or lower than that of any other particular NSAID.

  • NSAIDs can increase the risk of heart attack or stroke in patients with or without heart disease or risk factors for heart disease. A large number of studies support this finding, with varying estimates of how much the risk is increased, depending on the drugs and the doses studied.

  • In general, patients with heart disease or risk factors for it have a greater likelihood of heart attack or stroke following NSAID use than patients without these risk factors because they have a higher risk at baseline.

  • Patients treated with NSAIDs following a first heart attack were more likely to die in the first year after the heart attack compared to patients who were not treated with NSAIDs after their first heart attack.

  • There is an increased risk of heart failure with NSAID use.

BACKGROUND: The risk of heart attack and stroke with NSAIDs, either of which can lead to death, was first described in 2005 in the Boxed Warning and Warnings and Precautions sections of the prescription drug labels. Since then, FDA reviewed a variety of new safety information on prescription and OTC NSAIDs, including observational studies, a large combined analysis of clinical trials, and other scientific publications. These studies were also discussed at a joint meeting of the Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committee held on February 10-11, 2014.

RECOMMENDATION: Patients and health care professionals should remain alert for heart-related side effects the entire time that NSAIDs are being taken. Patients taking NSAIDs should seek medical attention immediately if they experience symptoms such as chest pain, shortness of breath or trouble breathing, weakness in one part or side of their body, or slurred speech.

For more information visit the FDA website at: and .


  • Cardiovascular Risk
  • Possible increased risk of serious (sometimes fatal) cardiovascular thrombotic events (e.g., MI, stroke).100 Risk may increase with duration of use.100 Individuals with cardiovascular disease or risk factors for cardiovascular disease may be at increased risk.100 (See Cardiovascular Effects under Cautions.)

  • Contraindicated for the treatment of pain in the setting of CABG surgery.100

  • 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


Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • 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

  • Treatment of perioperative pain in the setting of CABG surgery.100



Cardiovascular Effects

Selective COX-2 inhibitors have been associated with an increased risk of cardiovascular events in certain situations.170 Several prototypical NSAIAs also have been associated with an increased risk of cardiovascular events.173 174 175 Current data insufficient to assess risk associated with sulindac.173 174 175

Use NSAIAs with caution and careful monitoring (e.g., monitor for development of cardiovascular events), and at the lowest effective dosage for the shortest duration necessary.100

Short-term use to relieve acute pain, especially at low dosages, does not appear to be associated with increased risk of serious cardiovascular events (except immediately following CABG surgery).170

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

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 certain diuretics may occur.100 (See Specific Drugs under Interactions.)

Fluid retention and edema reported.100 Caution in patients with fluid retention or heart failure.100

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

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

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

  • Risk of serious cardiovascular events with long-term use.100

  • 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 notifying clinician if signs and symptoms of a cardiovascular event (chest pain, dyspnea, weakness, slurred speech) occur.100

  • 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

  • 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*

Clinoril (scored)


Sulindac Tablets

AHFS DI Essentials. © Copyright 2017, Selected Revisions August 27, 2015. 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.


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