Drug class: Reversible COX-1/COX-2 Inhibitors

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

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

Uses for Sulindac

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

Inflammatory Diseases

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

Colorectal Polyps

Has been associated with a reduction of the number of adenomatous colorectal polyps in adults with familial adenomatous polyposis (FAP)^{† [off-label]}.

Sulindac Dosage and Administration

General

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

Administration

Oral Administration

Administer orally twice daily with food.

Dosage

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. Adjust dosage based on individual requirements and response; attempt to titrate to the lowest effective dosage.

Adults

Inflammatory Diseases

Osteoarthritis, Rheumatoid Arthritis, or Ankylosing Spondylitis

Oral

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

Acute Painful Shoulder

Oral

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

Gout

Oral

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

Colorectal Polyps† [off-label]

Oral

150 mg twice daily.

Prescribing Limits

Adults

Inflammatory Diseases

Oral

Maximum 400 mg daily.

Special Populations

Hepatic Impairment

Dosage reduction may be required.

Renal Impairment

Dosage reduction may be required.

Cautions for Sulindac

Contraindications

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

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

• In the setting of CABG surgery.

Warnings/Precautions

Warnings

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.

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

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.

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

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.

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

Increased 1-year mortality rate observed in patients receiving NSAIAs following MI; 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.

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. FDA states that limitations of these studies and indirect comparisons preclude definitive conclusions regarding relative risks of NSAIAs.

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.

Some clinicians suggest that it may be prudent to avoid NSAIA use, whenever possible, in patients with cardiovascular disease. 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. Contraindicated in the setting of CABG surgery.

No consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious adverse cardiovascular events associated with NSAIAs. (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.

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

Hypertension

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

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

Heart Failure and Edema

Fluid retention and edema reported.

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

NSAIAs may diminish cardiovascular effects of diuretics, ACE inhibitors, or angiotensin II receptor antagonists used to treat heart failure or edema. (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.

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

Renal Effects

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

Potential for overt renal decompensation. 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. (See Actions.)

Symptomatic renal calculi containing sulindac metabolites reported rarely. 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. Formation of crystals, and presumably renal calculi, appears unlikely when urine output >240 mL/hour or pH >5.8. (See Renal Impairment under Cautions.)

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylactoid reactions reported. Hypersensitivity (e.g., severe dermatologic manifestations, hepatic abnormalities) reactions associated with fever reported. Immediate medical intervention and discontinuance for anaphylaxis. Discontinue if unexplained fever or other evidence of hypersensitivity occurs.

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

Potentially fatal or life-threatening syndrome of multi-organ hypersensitivity (i.e., drug reaction with eosinophilia and systemic symptoms [DRESS]) reported in patients receiving NSAIAs. Clinical presentation is variable, but typically includes eosinophilia, fever, rash, lymphadenopathy, and/or facial swelling, possibly associated with other organ system involvement (e.g., hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis). Symptoms may resemble those of acute viral infection. Early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present in the absence of rash. If signs or symptoms of DRESS develop, discontinue sulindac and immediately evaluate the patient.

Dermatologic Reactions

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

Major Toxicities

Pancreatitis

Pancreatitis reported.

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

General Precautions

Hepatic Effects

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

Elevations of serum ALT or AST reported.

Monitor for symptoms and/or signs suggesting liver dysfunction; monitor abnormal liver function test results. 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.

Hematologic Effects

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

May inhibit platelet aggregation and prolong bleeding time.

Ocular Effects

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

Aseptic Meningitis

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

Other Precautions

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

May mask certain signs of infection.

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

Specific Populations

Pregnancy

Use of NSAIAs during pregnancy at about ≥30 weeks’ gestation can cause premature closure of the fetal ductus arteriosus; use at about ≥20 weeks’ gestation associated with fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment.

Effects of NSAIAs on the human fetus during third trimester of pregnancy include prenatal constriction of the ductus arteriosus, tricuspid incompetence, and pulmonary hypertension; nonclosure of the ductus arteriosus during the postnatal period (which may be resistant to medical management); and myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or renal failure, renal injury or dysgenesis potentially resulting in prolonged or permanent renal failure, oligohydramnios, GI bleeding or perforation, and increased risk of necrotizing enterocolitis.

Avoid use of NSAIAs in pregnant women at about ≥30 weeks’ gestation; if use required between about 20 and 30 weeks’ gestation, use lowest effective dosage and shortest possible duration of treatment, and consider monitoring amniotic fluid volume via ultrasound examination if treatment duration >48 hours; if oligohydramnios occurs, discontinue drug and follow up according to clinical practice. (See Advice to Patients.)

Fetal renal dysfunction resulting in oligohydramnios and, in some cases, neonatal renal impairment observed, on average, following days to weeks of maternal NSAIA use; infrequently, oligohydramnios observed as early as 48 hours after initiation of NSAIAs. Oligohydramnios is often, but not always, reversible (generally within 3–6 days) following NSAIA discontinuance. Complications of prolonged oligohydramnios may include limb contracture and delayed lung maturation. In limited number of cases, neonatal renal dysfunction (sometimes irreversible) occurred without oligohydramnios. Some neonates have required invasive procedures (e.g., exchange transfusion, dialysis). Deaths associated with neonatal renal failure also reported. Limitations of available data (lack of control group; limited information regarding dosage, duration, and timing of drug exposure; concomitant use of other drugs) preclude a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAIA use. Available data on neonatal outcomes generally involved preterm infants; extent to which risks can be generalized to full-term infants is uncertain.

Animal data indicate important roles for prostaglandins in kidney development and endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, inhibitors of prostaglandin synthesis increased pre- and post-implantation losses; also impaired kidney development at clinically relevant doses.

In animal studies, sulindac decreased fetal weight and increased pup mortality on first postpartum day; visceral and skeletal malformations observed at low incidence in some studies but not in other studies.

Effects of sulindac on labor and delivery not known. In animal studies, NSAIAs increased incidence of dystocia, delayed parturition, and decreased pup survival.

Lactation

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

Fertility

NSAIAs may be associated with reversible infertility in some women. Reversible delays in ovulation observed in limited studies in women receiving NSAIAs; animal studies indicate that inhibitors of prostaglandin synthesis can disrupt prostaglandin-mediated follicular rupture required for ovulation.

Consider withdrawal of NSAIAs in women experiencing difficulty conceiving or undergoing evaluation of infertility.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

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

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

Hepatic Impairment

Monitor closely. (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. (See Renal Impairment under Dosage and Administration.)

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

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

Common Adverse Effects

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

Drug Interactions

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. 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).

Specific Drugs

Sulindac Pharmacokinetics

Absorption

Bioavailability

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

Special Populations

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

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.

Distribution

Extent

Widely distributed in animals.

Plasma Protein Binding

Sulindac: 93%.

Sulfide metabolite: 98%.

Elimination

Metabolism

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

Elimination Route

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

Sulindac and its metabolites not removed by hemodialysis.

Half-life

Sulindac: 7.8 hours.

Sulfide metabolite: 16.4 hours.

Stability

Storage

Oral

Tablets

15–30°C.

Actions

• Inhibits cyclooxygenase-1 (COX-1) and COX-2.

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

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

Advice to Patients

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

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

• Risk of GI bleeding and ulceration.

• Risk of serious skin reactions, DRESS, and anaphylactoid and other sensitivity reactions.

• Risk of hepatotoxicity.

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

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

• Advise patients to stop taking sulindac immediately if they develop any type of rash or fever and to promptly contact their clinician. Importance of seeking immediate medical attention if an anaphylactic reaction occurs.

• 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.

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

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of avoiding NSAIA use beginning at 20 weeks’ gestation unless otherwise advised by a clinician; importance of avoiding NSAIAs beginning at 30 weeks’ gestation because of risk of premature closure of the fetal ductus arteriosus; monitoring for oligohydramnios may be necessary if NSAIA therapy required for >48 hours’ duration between about 20 and 30 weeks’ gestation.

• Advise women who are trying to conceive that NSAIAs may be associated with a reversible delay in ovulation.

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

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

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

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

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