Sulindac

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke.

• Incidence of serious cardiovascular thrombotic events greater in patients with known cardiovascular disease or risk factors.
• Increased risk has been observed as early as the first weeks of treatment (based on observational studies).
• Higher doses have been linked to increased cardiovascular thrombotic risk.
• To minimize risk, use the lowest effective dose for the shortest time possible.
• Evidence regarding use of aspirin to mitigate risk has not been consistent; aspirin coadministered with sulindac may increase the risk of serious GI adverse events.

NSAIDs are contraindicated in the setting of coronary artery bypass graft (CABG) surgery. Based on findings from 2 large studies evaluating a COX-2 selective NSAID, use in the first 10-14 days after CABG resulted in an increased incidence of MI and stroke. 

Among patients treated with NSAIDs in the post-MI period, there was an increase in the risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment, according to observational studies. 

• Incidence of death in the first year in the NSAID cohort: 20 per 100 person years
• Incidence of death in the first year in the non-NSAID cohort: 12 per 100 person years
• The relative risk of death in NSAID users persisted over at least the next 4 years of follow up.

Avoid the use of sulindac in patients with recent MI unless the benefits are expected to outweigh the risk of recurrent cardiovascular thrombotic events. Monitor for signs of cardiac ischemia if used in patients with recent MI.

Hypertension

• NSAIDs can lead to new onset hypertension or worsening of pre-existing hypertension.
• Impaired responses to thiazides and loop diuretics possible when taken with NSAIDs.
• Use with caution in patients with hypertension; monitor BP.

Heart Failure and Edema

• Meta-analysis of randomized controlled trials showed ~2-fold increase in hospitalizations for heart failure in patients treated with COX-2 selective and nonselective NSAIDs compared with placebo.
• NSAID use was also associated with increased risk of MI, hospitalization for heart failure and death in a Danish National Registry study of patients with heart failure.
• Fluid retention and edema have been observed in some patients treated with NSAIDs.
• Sulindac may blunt the cardiovascular effects of diuretics, ACE inhibitors, ARBs.
• Avoid use in patients with severe heart failure unless benefits outweigh risk of worsening heart failure.
• Monitor for signs of worsening heart failure if sulindac is used in patients with severe heart failure.

Gastrointestinal (GI) Effects

• NSAIDs can cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine.
• These can occur at any time, with or without warning symptoms (only 1 in 5 patients who develop a serious upper GI adverse event on NSAIDs is symptomatic),
• Incidence of upper GI ulcers, gross bleeding, or perforation with NSAIDs: ~1% of patients treated for 3-6 months and 2-4% of patients treated for 1 year.
• Prior history of ulcer disease or GI bleeding: Prescribe with caution; these patients have a >10-fold increased risk for developing GI bleed vs those without these risk factors.
• Other factors that increase risk of GI bleed in patients treated with NSAIDs: concomitant oral corticosteroids, anticoagulants; longer duration of NSAID use; smoking; alcohol; older age; and poor general health status.
• Use the lowest effective dose for the shortest possible duration to minimize the potential for GI adverse events.
• If a serious GI adverse event occurs, discontinue NSAID therapy.
• Alternative therapies should be explored for patients considered at high risk for GI effects.

Hepatic Effects

• Borderline elevations of 1 or more liver tests without any other signs and symptoms may occur in up to 15% of patients taking NSAIDs.
• For patients with symptoms/signs suggesting liver dysfunction, or in whom abnormal liver test has occurred: evaluate for more severe hepatic reaction.
• Discontinue sulindac if abnormal liver tests persist or worsen, if clinical signs/symptoms of liver disease develop, or if systemic manifestations (eg, eosinophilia, rash) occur.
• The use of sulindac 600mg/day has been associated with increased incidence of mild liver test abnormalities.

Renal Effects

• Long-term NSAID use has been associated with renal papillary necrosis and other renal injury.
• Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion; in these patients administration of NSAIDs may cause a dose-dependent reduction in prostaglandin formation and, secondarily in renal blood flow, which may result in overt renal decompensation.
• Patients with impaired renal function, heart failure, liver dysfunction, on diuretics or ACE inhibitors, those who are volume-depleted and the elderly are at greatest risk of this reaction.
• Discontinuing NSAID therapy usually leads to recovery.
• Use with caution in patients with a history of renal lithiasis; patients should be kept well hydrated while on treatment.

Anaphylactic/Anaphylactoid Reactions

• Sulindac should not be given to patients with the aspirin triad.
• This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs.
• Use with caution in patients with preexisting asthma.

Skin Reactions

• NSAIDs can cause serious skin adverse events including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
• Discontinue treatment at the first appearance of skin rash or any other sign of hypersensitivity.
• DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) has been reported in patients taking NSAIDs.
• Symptoms of DRESS: Fever, rash, lymphadenopathy, and/or facial swelling; may resemble acute viral infection.
• Other clinical manifestations of DRESS: Hepatitis, nephritis, hematological abnormalities, myocarditis, myositis.
• Discontinue treatment if signs/symptoms of DRESS develop.

Hypersensitivity

• If unexplained fever or other evidence of hypersensitivity occurs (eg, abnormalities in 1 or more liver function tests, severe skin reactions), discontinue sulindac.
• Elevated temperature and liver test abnormalities generally revert to normal after discontinuation.
• Do not restart sulindac in patients who experience hypersensitivity.

Hematological Effects

• Anemia is sometimes seen in patients receiving NSAIDs.
• Check hemoglobin/hematocrit if patients exhibit signs/symptoms of anemia.

Pancreatitis

• Pancreatitis has been reported in patients receiving sulindac.
• Discontinue sulindac and do not restart should pancreatitis be suspected.

Ocular Effects

• Adverse eye reactions have been reported with NSAIDs.
• For patients who develop eye complaints, ophthalmologic studies are recommended.

Systemic Lupus Erythematosus (SLE) and Mixed Connective Tissue Disease

• In these patients, there may be an increased risk of aseptic meningitis.