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Sulindac

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

Medically reviewed by Drugs.com on Nov 9, 2020. Written by ASHP.

Warning

Special Alerts:

[Posted 10/15/2020]

AUDIENCE: Consumer, Patient, Health Professional, Pharmacy

ISSUE: FDA is warning that use of NSAIDs around 20 weeks or later in pregnancy may cause rare but serious kidney problems in an unborn baby. This can lead to low levels of amniotic fluid surrounding the baby and possible complications.

For prescription NSAIDs, FDA is requiring changes to the prescribing information to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.

For over-the-counter (OTC) NSAIDs intended for use in adults, FDA will also update the Drug Facts labels, available at: [Web]. These labels already warn to avoid using NSAIDs during the last 3 months of pregnancy because the medicines may cause problems in the unborn child or complications during delivery. The Drug Facts labels already advise pregnant and breastfeeding women to ask a health care professional before using these medicines.

BACKGROUND:

NSAIDs

  • are a class of medicines available by prescription and OTC. They are some of the most commonly used medicines for pain and fever.

  • are used to treat medical conditions such as arthritis, menstrual cramps, headaches, colds, and the flu.

  • work by blocking the production of certain chemicals in the body that cause inflammation.

  • are available alone and combined with other medicines. Examples of NSAIDs include aspirin, ibuprofen, naproxen, diclofenac, and celecoxib.

Common side effects of NSAIDs include: stomach pain, constipation, diarrhea, gas, heartburn, nausea, vomiting, and dizziness.

RECOMMENDATION:

Consumers/Patients

  • If you are pregnant, do not use NSAIDs at 20 weeks or later in pregnancy unless specifically advised to do so by your health care professional because these medicines may cause problems in your unborn baby.

  • Many OTC medicines contain NSAIDs, including those used for pain, colds, flu, and insomnia, so it is important to read the Drug Facts labels, available at: [Web], to find out if the medicines contain NSAIDs.

  • Talk to your health care professional or pharmacist if you have questions or concerns about NSAIDs or which medicines contain them.

  • Other medicines, such as acetaminophen, are available to treat pain and fever during pregnancy. Talk to your pharmacist or health care professional for help deciding which might be best.

Health Care Professionals

  • FDA recommends that health care professionals should limit prescribing NSAIDs between 20 to 30 weeks of pregnancy and avoid prescribing them after 30 weeks of pregnancy. If NSAID treatment is determined necessary, limit use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours and discontinue the NSAID if oligohydramnios is found. FDA is warning that use of NSAIDs around 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment.

  • These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation.

  • Oligohydramnios is often, but not always, reversible with treatment discontinuation.

  • Complications of prolonged oligohydramnios may include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required.

  • If NSAID treatment is deemed necessary between 20 to 30 weeks of pregnancy, limit use to the lowest effective dose and shortest duration possible. As currently described in the NSAID labels, avoid prescribing NSAIDs at 30 weeks and later in pregnancy because of the additional risk of premature closure of the fetal ductus arteriosus.

  • The above recommendations do not apply to low-dose 81 mg aspirin prescribed for certain conditions in pregnancy.

  • Consider ultrasound monitoring of amniotic fluid if NSAID treatment extends beyond 48 hours. Discontinue the NSAID if oligohydramnios occurs and follow up according to clinical practice.

For more information visit the FDA website at: [Web] and [Web].

Warning

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

  • Contraindicated in the setting of CABG surgery.

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

Introduction

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

Uses 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.

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).

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

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.

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†
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

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.

  • 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.

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

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

Lactation

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

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.

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. 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

Drug

Interaction

Comments

ACE inhibitors

Reduced BP response to ACE inhibitor

Possible deterioration of renal function in individuals with renal impairment

Monitor BP

Acetaminophen

Pharmacokinetic interaction unlikely

Angiotensin II receptor antagonists

Reduced BP response to angiotensin II receptor antagonist

Possible deterioration of renal function in individuals with renal impairment

Monitor BP

Antacids (magnesium- or aluminum-containing)

Change in sulindac bioavailability unlikely

Anticoagulants, oral

Possibility of bleeding complications

Protein binding interaction unlikely

Caution advised; monitor PT; adjust anticoagulant dosage as needed

Cyclosporine

Possible increase in cyclosporine-induced toxicity

Use with caution; monitor renal function

Dimethylsulfoxide

Decreased plasma concentrations of sulfide metabolite of sulindac

Peripheral neuropathy reported

Avoid concomitant use

Diuretics (furosemide, thiazides)

Reduced natriuretic effects possible

Monitor for diuretic efficacy and renal failure

Hypoglycemic agents, oral

Protein binding interaction unlikely

Lithium

Pharmacokinetic interaction unlikely

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

Methotrexate

Possible increased plasma methotrexate concentrations

Use with caution

NSAIAs

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

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

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

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

Concomitant use not recommended

Probenecid

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

Reduced uricosuric action of probenecid

Change in uricosuric action unlikely to be clinically important

Propoxyphene

Pharmacokinetic interaction unlikely

Thrombolytic agents

Possible bleeding complications

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

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.

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

  • Risk of GI bleeding and ulceration.

  • Risk of serious skin reactions. Risk of 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.

  • Importance of discontinuing sulindac and contacting clinician if rash or other signs of hypersensitivity (blisters, fever, pruritus) develop. 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 sulindac in late pregnancy (third trimester).

  • 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.

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

Sulindac

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

150 mg*

Sulindac Tablets

200 mg*

Sulindac Tablets

AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 9, 2020. 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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