Sulindac

Mechanism of Action

Sulindac is a nonselective COX (cyclooxygenase) inhibitor that reversibly inhibits COX-1 and COX-2 enzymes. The COX pathway is one of the 2 main pathways in arachidonic acid metabolism (the other involves leukotriene synthesis). The COX pathway results in the synthesis of both prostaglandins and thromboxanes. These are both critical mediators of inflammation and platelet aggregation.[4]

Prostaglandin E2 (PGE2) is a trigger of the cardinal signs of inflammation: rubor (erythema), calor (warmth), tumor (swelling), and dolor (pain); PGE2 increases blood flow and vascular permeability. PGE2 also triggers systemic fever through a hypothalamic-mediated reaction. Sulindac and other NSAIDs are responsible for inhibiting the synthesis of this prostaglandin and others. Sulindac exists as a pro-drug that activates upon initial metabolism. The metabolism forms sulfide and sulfone derivatives, which inhibit prostaglandin synthesis.[5][6]

Pharmacokinetics

Absorption: Sulindac tablets have a similar extent of absorption compared to sulindac solution. Antacids containing aluminum hydroxide 225 mg and magnesium hydroxide 200 mg per 5 mL do not change absorption extent.

Distribution: Sulindac, sulfone, and sulfide metabolites are highly protein-bound (more than 90%), mainly to albumin. Sulindac can penetrate both the blood-brain barrier and the placental barrier.[7][8]

Metabolism: Sulindac goes through 2 major biotransformations of the sulfoxide moiety: reduction to the pharmacologically active sulfide metabolite and oxidation to the inactive sulfone metabolite.

Elimination: Approximately half of the administered dose of sulindac is eliminated by urine with the conjugated sulfone metabolite. Approximately 25% of the administered dose of sulindac is excreted in the feces, the majority as the sulfone or sulfide metabolites. The mean plasma effective half-life for sulindac and its active sulfide metabolite is 7.8 hours and 16.4 hours, respectively.[9]

Administration

Available Dosage Forms and Strengths

Sulindac is available as 150 mg and 200 mg oral tablets. The maximum recommended daily dosage is 400 mg. Healthcare providers recommend administering the lowest effective dose tailored to each patient's needs for the initial treatment and for the shortest duration possible. Sulindac should be taken with food or milk to decrease gastrointestinal adverse effects. Clinicians should carefully consider the potential risks to the benefit of sulindac and other relevant treatment options before use. 

Adult Dosage

Osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis: The initial recommended dosage of sulindac is 150 mg twice a day. This dose can be increased or decreased based on the patient's response. The dosage can be increased up to 400 mg daily. Half of the patient population may expect a prompt response within 1 week of treatment; other patients may require prolonged treatment.[10][11]

Acute supraspinatus tendinitis/subacromial bursitis (acute painful shoulder): The initial recommended dosage of sulindac is 200 mg twice daily. This dose can be increased or decreased based on the therapeutic response. The dosage can be increased up to 400 mg daily. An adequate response may be achieved from 7 to 14 days of therapy.[12]

Acute gouty arthritis: The initial recommended dosage of sulindac is 200 mg twice a day. This dose can be increased or decreased based on the therapeutic response. The dosage can be increased up to 400 mg daily. An adequate response may be achieved within 7 days.[13]

Specific Patient Populations

Hepatic impairment: Use sulindac with caution and monitor treatment in patients with hepatic impairment. Reduction of dose may be needed due to extensive metabolism in the liver.[14]

Renal impairment: Patients with impaired renal function should be monitored. Dose reduction may be needed in patients with advanced renal disease. Dose reduction is recommended for patients with an eGFR of 30 to 60 mL/min/1.73m².[9] Discontinuing the treatment is advised if comorbid kidney diseases are present. However, use should be avoided for individuals with an eGFR less than 30 mL/min/1.73m².

Pregnancy considerations: The FDA warns that using NSAIDs, including sulindac, after around 20 weeks of pregnancy may cause fetal renal dysfunction, leading to oligohydramnios and neonatal renal impairment. These effects occur on average after days to weeks of treatment. Oligohydramnios can be reversed upon discontinuation, but it may cause complications such as delayed lung maturation and limb contractures. In cases where NSAIDs are necessary between 20 to 30 weeks of pregnancy, restrict the use to the lowest effective dosage and shortest duration. Avoid administration of NSAIDs at 30 weeks and later due to the additional risk of premature closure of the fetal ductus arteriosus. Consider ultrasound monitoring if treatment extends beyond 48 hours, and discontinue NSAIDs in oligohydramnios.[15]

Breastfeeding considerations: It is unknown if sulindac transfers to breast milk. Some NSAIDs with established safety data and short half-lives are considered compatible with lactating patients to treat rheumatic and musculoskeletal diseases. Due to some potential adverse effects of sulindac in the breastfeeding infant, the manufacturer recommends discontinuing treatment or breastfeeding based on risk-benefit assessments.[16][17]

Pediatric patients: The safety and effectiveness of sulindac in pediatric patients have not been established.

Older patients: As per the American Geriatric Society 2023 Beers Criteria for potentially inappropriate medication use in older adults, the use of NSAIDs, including sulindac, is associated with an elevated risk of upper gastrointestinal ulcers, bleeding, or perforation. Complications occur in 1% of individuals undergoing a 3-month to 6-month treatment and 2% to 4% of those subjected to a 1-year treatment duration, with the associated risks gradually increasing over extended periods of use. Additionally, NSAIDs, including sulindac, have the potential to raise blood pressure and induce kidney injury, and these risks are correlated with the dosage.[18]

Adverse Effects

Prostaglandins and thromboxanes have critical functions throughout the body. The wide range of functions results in adverse effects. Blood vessels, the gastrointestinal tract, and kidneys are critical organ systems impacted by sulindac.

• Sulindac is commonly associated with nausea and vomiting, stomach pain, indigestion, diarrhea, constipation, gas, anxiety, dizziness, tinnitus, and urticaria.

• The most common and severe adverse effect of NSAID use involves ulceration of the gastrointestinal tract, as gastrointestinal mucosa appears to be protected by prostaglandins. Sulindac is commonly thought to have associations with lower rates of gastrointestinal-related complications when compared to other nonselective NSAIDs; however, the gastrointestinal adverse effects related to NSAID use appear to be mediated through COX-1, as COX-2 selective NSAIDs are associated with lower risks of gastrointestinal complications. The simultaneous use of alcohol and or steroids exacerbates adverse effects.[19]

• Sulindac also correlates with renal adverse effects. Certain prostaglandins dilate the afferent arteriole and may result in a reduced GFR and increased risk of acute kidney injury. Sulindac and other NSAIDs may also be nephrotoxic and induce renal papillary necrosis and interstitial nephritis. This condition may be exacerbated with the simultaneous use of other nephrotoxic agents.[20][21]

• Sulindac is associated with various critical adverse effects, including changes in vision, hepatoxicity, pancreatitis, anemia, and Steven-Johnson syndrome.[22]

Drug-Drug Interactions

• Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists: NSAIDs may attenuate the antihypertensive effects of ACE inhibitors and angiotensin II antagonists. This interaction should be considered, particularly in patients concurrently using NSAIDs with ACE inhibitors or angiotensin II antagonists. In patients with compromised renal function, coadministration of NSAIDs with ACE inhibitors or angiotensin II antagonists may exacerbate renal deterioration, leading to reversible acute renal failure. Therefore, regular monitoring of renal function is advised for patients under combination therapy.[23]

• Aspirin: Combining aspirin with sulindac significantly decreases plasma levels of the active sulfide metabolite. In addition, the combination showed that aspirin with sulindac increases gastrointestinal adverse effects.

• Cyclosporine: Concomitant use of NSAIDs with cyclosporine may increase cyclosporine-induced toxicity due to reduced renal prostacyclin synthesis. Caution is advised, and renal function should be monitored.[24]

• Diuretics: Sulindac can diminish the natriuretic effect of furosemide and thiazides in some patients, leading to renal failure. Close observation is recommended during concomitant therapy with NSAIDs.[25]

• Lithium: NSAIDs may elevate plasma lithium levels and reduce renal lithium clearance, leading to toxicity. Monitoring for signs of lithium toxicity is advised when NSAIDs and lithium are administered concurrently.

• Methotrexate: Caution should be exercised when coadministering NSAIDs with methotrexate due to the risk of methotrexate toxicity resulting from methotrexate accumulation.[26]

• NSAIDs: Concomitant use of sulindac with other NSAIDs is not suggested due to an increased risk of gastrointestinal toxicity without a significant increase in efficacy.[27]

• Oral anticoagulants: Monitoring is recommended when combining sulindac with oral anticoagulants, particularly in patients receiving higher doses or those with renal impairment due to increased bleeding risk.[28]

Contraindications

Per the manufacturer, a few absolute contraindications to the use of sulindac are as follows:

• The first is a previous hypersensitivity reaction to sulindac or other NSAIDs. NSAID hypersensitivity can present in a variety of ways.[21] The hypersensitivity can result in chronic respiratory disease because of the formation of nasal polyps. Cutaneous signs include urticaria, angioedema, and generalized anaphylaxis.

• The other absolute contraindication is in patients in status post coronary artery bypass graft (CABG) operations.

Box Warnings

• NSAIDs increase the risk of serious and fatal cardiovascular thrombotic events, including stroke and myocardial infarction. This risk can occur in an early phase of treatment and may increase with the duration of administration.

• NSAIDs increase the risk of serious and fatal gastrointestinal bleeding, ulceration, and perforation of the stomach or intestines. These adverse events may occur anytime and without warning. Senior adults are at higher risk of serious gastrointestinal events.[18]

Warnings and Precautions

• Sulindac can increase the risk of hypertension or exacerbate existing hypertension.[29]

• The risk of hospitalizations for patients with heart failure is increased.[30]

• Cholestatic hepatitis cases are reported in some patients. Therefore, if abnormal liver tests persist or worsen, clinical signs and symptoms consistent with liver disease develop, or systemic manifestations occur (eg, eosinophilia and rash), and sulindac should be discontinued.[31]

• Chronic use of NSAIDs is linked with renal papillary necrosis and other renal injuries. Therefore, caution is recommended in patients with heart failure, impaired renal function, liver dysfunction, volume-depleted patients, those prescribed diuretics and ACE inhibitors, and older patients.[29][32]

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is observed in patients administered sulindac, so use is discontinued if any signs or symptoms of DRESS develop.[33]

Monitoring

Sulindac use, as is the case with other NSAIDs, does not involve routine monitoring. No regular blood work is necessary; however, sulindac is not free from toxic adverse drug reactions. Adhering to the dosing regimen is critical in preventing some of the abovementioned adverse effects.[34]

• Clinicians should check hemoglobin or hematocrit if a patient develops any signs or symptoms of anemia.[35]

• If pancreatitis develops, monitor closely with appropriate laboratory studies (lipase, serum, and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, and glucose)[36]

• Patients with hepatic impairment need close monitoring.

• Pregnant women who use sulindac for more than 48 hours between 2 and 30 weeks of gestation should be monitored for oligohydramnios.[37]

• Patients on long-term treatment should have CBC and chemistry profiles checked periodically since sulindac might cause unexpected severe gastrointestinal bleeding and ulcerations.[38]

Toxicity

Signs and Symptoms of Overdose

Sulindac toxicity is rare; few cases are reported in the literature. Though sulindac is an NSAID, the toxicity does not present similarly to salicylate (aspirin) toxicity with metabolic acidosis, respiratory alkalosis, and tinnitus. Cases in the literature have demonstrated hepatic and renal toxicity associated with sulindac overdose; a case of granulocytosis is secondary to sulindac toxicity. One of the cases with hepatorenal toxicity further resulted in ischemic skin changes and ulceration.[39][40]

Management of Overdose

Since exceedingly few cases of sulindac toxicity are reported, many implications of overdose have not been investigated. Other research has demonstrated the utility of activated charcoal in the acute treatment of sulindac toxicity. Charcoal can help minimize absorption and some of the later sequelae associated with the drug's toxicity. However, other studies have demonstrated that once the drug is in the system, proper treatment protocol involves supportive care, which includes aggressive hydration, fluid replacement, and hemodialysis in some instances.[39]

Enhancing Healthcare Team Outcomes

NSAIDs such as sulindac are frequently prescribed for patients with arthritis, spondylitis, and tendinitis. Nurses should have a comprehensive understanding of the signs and symptoms of potential toxicities and should provide thorough counseling to patients regarding the importance of adhering to scheduled dosing regimens. Pharmacists should meticulously check the dosage, confirm the suitability of sulindac treatment, and promptly communicate any concerns to the clinicians.

A study was conducted to assess the influence of medication reviews and pharmacist counseling on NSAID utilization among individuals aged 60 and older. The findings revealed that among the 83 participants, a significant proportion (47.6%) reported NSAID usage, with 71.8% exhibiting inappropriate use. Following counseling, post-intervention follow-up indicated a positive impact, with the proportion of appropriate users increasing to 51.3% and inappropriate users decreasing to 48.7%. Notably, participants reported enhanced comprehension of NSAID-related risks, and 55.6% of those in the study reported engaging in more meaningful discussions with clinicians.

The findings suggest that pharmacist counseling can be pivotal in mitigating potentially inappropriate NSAID use and enhancing risk awareness among older adults.[41] An interprofessional healthcare team, including clinicians, specialists, specialty-trained nurses, and pharmacists collaborating across disciplines, can work together to attain optimal patient outcomes concerning sulindac therapy.