Sulindac

Pronunciation

(sul IN dak)

U.S. Brand Names

Clinoril®

Generic Available

Yes

Canadian Brand Names

Apo-Sulin®; Novo-Sundac; Nu-Sundac

Use

Management of inflammatory disease, rheumatoid disorders, acute gouty arthritis, ankylosing spondylitis, bursitis, tendonitis

Pregnancy Risk Factor

B/D (3rd trimester)

Lactation

Excretion in breast milk unknown

Contraindications

Hypersensitivity to sulindac, any component of the formulation, aspirin or other NSAIDs; pregnancy (3rd trimester)

Warnings/Precautions

Fatal asthmatic and anaphylactoid reactions have occurred in patients with "aspirin triad." Use with caution in patients with CHF, hypertension, dehydration, decreased renal or hepatic function, history of GI disease (bleeding, ulcers, or previous GI symptoms with NSAID use), or those receiving anticoagulants and/or corticosteroids. Use lowest effective dose for shortest period possible; bleeding risk has been correlated to dose and duration of therapy. Gastrointestinal bleeding may occur without prior symptoms of gastrointestinal irritation. Elderly are at a high risk for adverse effects from NSAIDs. As many as 60% of elderly can develop peptic ulceration and/or hemorrhage asymptomatically.

Use of NSAIDs can compromise existing renal function especially when Clcr<30 mL/minute. CNS adverse effects such as confusion, agitation, and hallucination are generally seen in overdose or high-dose situations; however, elderly may demonstrate these adverse effects at lower doses than younger adults. Withhold for at least 4-6 half-lives prior to surgical or dental procedures.

Adverse Reactions

1% to 10%:

Cardiovascular: Edema

Central nervous system: Dizziness, headache, nervousness

Dermatologic: Pruritus, rash

Gastrointestinal: GI pain, heartburn, nausea, vomiting, diarrhea, constipation, flatulence, anorexia, abdominal cramps

Otic: Tinnitus

<1% (Limited to important or life-threatening): CHF, hypertension, palpitation, arrhythmia, convulsions, aseptic meningitis, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, anaphylaxis, angioneurotic edema, peptic ulcer, GI bleeding, GI perforation, agranulocytosis, aplastic anemia, hemolytic anemia, bone marrow depression, leukopenia, thrombocytopenia, neutropenia, increased prothrombin time, abnormal LFTs, pancreatitis, jaundice, hepatitis, hepatic failure, proteinuria, crystalluria, renal impairment, renal failure, nephrotic syndrome, interstitial nephritis, bronchial spasm, dyspnea, depression, psychosis, hypersensitivity reaction

Overdosage/Toxicology

Symptoms of overdose include dizziness, vomiting, nausea, abdominal pain, hypotension, coma, stupor, metabolic acidosis, leukocytosis, and renal failure. Management of NSAID intoxication is supportive and symptomatic. Seizures tend to be short-lived and often do not require drug treatment.

Drug Interactions

ACE inhibitors: Antihypertensive effects may be decreased by concurrent therapy with NSAIDs; monitor blood pressure.

Angiotensin II antagonists: Antihypertensive effects may be decreased by concurrent therapy with NSAIDs; monitor blood pressure.

Anticoagulants (warfarin, heparin, LMWHs) in combination with NSAIDs can cause increased risk of bleeding.

Other antiplatelet drugs (ticlopidine, clopidogrel, aspirin, abciximab, dipyridamole, eptifibatide, tirofiban) can cause an increased risk of bleeding.

Corticosteroids may increase the risk of GI ulceration; avoid concurrent use.

Cyclosporine: NSAIDs may increase serum creatinine, potassium, blood pressure, and cyclosporine levels; monitor cyclosporine levels and renal function carefully.

Hydralazine's antihypertensive effect is decreased; avoid concurrent use.

Lithium levels can be increased; avoid concurrent use if possible or monitor lithium levels and adjust dose. Sulindac may have the least effect. When NSAID is stopped, lithium will need adjustment again.

Loop diuretic efficacy (diuretic and antihypertensive effect) may be reduced.

Methotrexate: Severe bone marrow suppression, aplastic anemia, and GI toxicity have been reported with concomitant NSAID therapy. Avoid use during moderate or high-dose methotrexate (increased and prolonged methotrexate levels). NSAID use during low-dose treatment of rheumatoid arthritis has not been fully evaluated; extreme caution is warranted.

Thiazides antihypertensive effects are decreased; avoid concurrent use.

Warfarin's INRs may be increased by piroxicam. Other NSAIDs may have the same effect depending on dose and duration. Monitor INR closely. Use the lowest dose of NSAIDs possible and for the briefest duration.

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may enhance gastric mucosal irritation).

Food: Food may decrease the rate but not the extent of oral absorption. The therapeutic effect of sulindac may be decreased if taken with food.

Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, ginseng (all have additional antiplatelet activity).

Mechanism of Action

Inhibits prostaglandin synthesis by decreasing the activity of the enzyme, cyclooxygenase, which results in decreased formation of prostaglandin precursors

Pharmacodynamics/Kinetics

Onset of action: Analgesic: ~1 hour

Duration: 12-24 hours

Absorption: 90%

Metabolism: Hepatic; prodrug requiring metabolic activation to sulfide metabolite (active) for therapeutic effects and to sulfone metabolites (inactive)

Half-life elimination: Parent drug: 7 hours; Active metabolite: 18 hours

Excretion: Urine (50%); feces (25%)

Dosage

Maximum therapeutic response may not be realized for up to 3 weeks

Oral:

Children: Dose not established

Adults: 150-200 mg twice daily or 300-400 mg once daily; not to exceed 400 mg/day

Dosing adjustment in hepatic impairment: Dose reduction is necessary

Administration

Should be administered with food or milk.

Monitoring Parameters

Liver enzymes, BUN, serum creatinine, CBC, blood pressure; signs and symptoms of GI bleeding

Test Interactions

Increased chloride (S), increased sodium (S), increased bleeding time

Dietary Considerations

Drug may cause GI upset, bleeding, ulceration, perforation; take with food or milk to minimize GI upset.

Patient Education

Take this medication exactly as directed; do not increase dose without consulting prescriber. Take with food or milk to reduce GI distress. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. Do not use alcohol, aspirin or aspirin-containing medication, or any other anti-inflammatory medications without consulting prescriber. Regularly scheduled ophthalmic exams are advised with long-term use of NSAIDs. You may experience dizziness, nervousness, or headache (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or heartburn (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); or constipation (increased exercise, fluids, fruit, or fiber may help). GI bleeding, ulceration, or perforation can occur with or without pain; discontinue medication and contact prescriber if persistent abdominal pain, cramping, or blood in stool occurs. Report breathlessness or respiratory difficulty; unusual bruising or bleeding; blood in urine, stool, mouth, or vomitus; unusual fatigue; skin rash or itching; change in urinary pattern; or change in hearing or ringing in ears. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. This drug should not be used in the 3rd trimester of pregnancy. Consult prescriber if breast-feeding.

Anesthesia and Critical Care Concerns/Other Considerations

The 2002 ACCM/SCCM guidelines for analgesia (critically-ill adult) suggest that NSAIDs may be used in combination with opioids in select patients for pain management. Concern about adverse events (increased risk of renal dysfunction, altered platelet function and gastrointestinal irritation) limits its use in patients who have other underlying risks for these events.

In short-term use, NSAIDs vary considerably in their effect on blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short. The use of NSAIDs in the treatment of patients with congestive heart failure may be associated with an increased risk for fluid accumulation and edema; may precipitate renal failure in dehydrated patients.

Sulindac is associated with the highest incidence of upper GI bleeds among NSAIDs. It may be less likely to inhibit renal prostaglandin synthesis and adversely affect renal function than most other NSAIDs. Maximum therapeutic response may not be realized for up to 3 weeks.

Cardiovascular Considerations

In short-term use, NSAIDs vary considerably in their effect on blood pressure. A recent meta-analysis (see References) showed that indomethacin and naproxen had the largest effect on blood pressure. Other NSAIDs, including piroxicam, ibuprofen, and sulindac had less of an effect. Ibuprofen combined with captopril or losartan may attenuate the antihypertensive effects of ACE inhibition or receptor blockade on sitting or 24-hour ambulatory diastolic blood pressure. When NSAIDs are used in patients with hypertension, appropriate monitoring of blood pressure responses should be completed and the duration of therapy, when possible, kept short. The use of NSAIDs in the treatment of patients with congestive heart failure may be associated with an increased risk for fluid accumulation and edema. One study showed that NSAID use in elderly patients had an increased risk of hospitalization for heart failure. This study gives compelling reasons to avoid or limit the use of NSAIDs in patients with congestive heart failure, particularly in the elderly population.

Dental Health: Effects on Dental Treatment

NSAID formulations are known to reversibly decrease platelet aggregation via mechanisms different than observed with aspirin. The dentist should be aware of the potential of abnormal coagulation. Caution should also be exercised in the use of NSAIDs in patients already on anticoagulant therapy with drugs such as warfarin (Coumadin®).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Dizziness is common; may cause nervousness; may rarely cause drowsiness, confusion, insomnia, hallucinations, or depression

Mental Health: Effects on Psychiatric Treatment

May rarely cause agranulocytosis; use caution with clozapine and carbamazepine; may decrease lithium clearance (evidence suggest that this effect may be less than with other NSAIDs) resulting in an increase in serum lithium levels and potential lithium toxicity; monitor serum lithium levels

Dosage Forms

[DSC] = Discontinued product

Tablet: 150 mg, 200 mg

Clinoril®: 150 mg [DSC]; 200 mg

Extemporaneously Prepared

A suspension of sulindac can be prepared by triturating 1000 mg sulindac (5 x 200 mg tablets) with 50 mg of kelco and 400 mg of Veegum® until a powder mixture is formed; then add 30 mL of sorbitol 35% (prepared from 70% sorbitol) to form a slurry; finally add a sufficient quantity of 35% sorbitol to make a final volume of 100 mL; the final suspension is 10 mg/mL and is stable for 7 days

References

Brooks PM and Day RO, "Nonsteroidal Anti-inflammatory Drugs - Differences and Similarities," N Engl J Med , 1991, 324(24):1716-25.

Clinch D, Banerjee AK, and Ostick G, "Absence of Abdominal Pain in Elderly Patients With Peptic Ulcer," Age Ageing , 1984, 13(2):120-3.

Clive DM and Stoff JS, "Renal Syndromes Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1984, 310(9):563-72.

Conlin P, Moore T, Swartz S, et al, "Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients," Hypertension , 2000, 36(3):461-5.

Court H and Volans GN, "Poisoning After Overdose With Nonsteroidal Anti-inflammatory Drugs," Adverse Drug React Acute Poisoning Rev , 1984, 3(1):1-21.

Graham DY, "Prevention of Gastroduodenal Injury Induced by Chronic Nonsteroidal Anti-inflammatory Drug Therapy," Gastroenterology , 1989, 96(2 Pt 2 Suppl):675-81.

Gurwitz JH, Avorn J, Ross-Degnan D, et al, "Nonsteroidal Anti-Inflammatory Drug-Associated Azotemia in the Very Old," JAMA , 1990, 264(4):471-5.

Harima Y, Maekawa T, Miyauchi Y, et al, "Intoxication With Sulindac, Tiaramide Hydrochloride and Diclofenac Sodium," Intensive Care Med , 1987, 13(5):361-2.

Hawkey CJ, Karrasch JA, Szczepañski L, et al, "Omeprazole Compared With Misoprostrol for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1998, 338(11):727-34.

Heerdink ER, Leufkens HG, Herings RM, et al, "NSAIDs Associated With Increased Risk of Congestive Heart Failure in Elderly Patients Taking Diuretics," Arch Intern Med , 1998, 158(10):1108-12.

Hoppmann RA, Peden JG, and Ober SK, "Central Nervous System Side Effects of Nonsteroidal Anti-inflammatory Drugs. Aseptic Meningitis, Psychosis, and Cognitive Dysfunction," Arch Intern Med , 1991, 151(7):1309-13.

Jacobi J, Fraser GL, Coursin DB, et al, "Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult," Crit Care Med , 2002, 30(1):119-41. Available at: http://www.sccm.org/pdf/sedatives.pdf. Accessed August 2, 2003.

Knodel LC, "Preventing NSAID-Induced Ulcers: The Role of Misoprostol," Consult Pharm , 1989, 4:37-41.

Kulling EJ, Beckman EA, and Skagius AS, "Renal Impairment After Acute Diclofenac, Naproxen, and Sulindac Overdoses," J Toxicol Clin Toxicol , 1995, 33(2):173-7.

Morgan TO, Anderson A, and Bertram D, "Effect of Indomethacin on Blood Pressure in Elderly People With Essential Hypertension Well Controlled on Amlodipine or Enalapril," Am J Hypertens , 2000, 13(11):1161-7.

Page J and Henry D, "Consumption of NSAIDs and the Development of Congestive Heart Failure in Elderly Patients: An Underrecognized Public Health Problem," Arch Intern Med , 2000, 160(6):777-84.

Park GD, Spector R, Headstream T, et al, "Serious Adverse Reactions Associated With Sulindac," Arch Intern Med , 1982, 142(7):1292-4.

Pope JE, Anderson JJ, and Felson DT, "A Meta-analysis of the Effects of Nonsteroidal Anti-inflammatory Drugs on Blood Pressure," Arch Intern Med , 1993, 153(4):477-84.

Pounder R, "Silent Peptic Ulceration: Deadly Silence or Golden Silence?" Gastroenterology , 1989, 96(2 Pt 2 Suppl):626-31.

Smolinske SC, Hall AH, Vandenberg SA, et al, "Toxic Effects of Nonsteroid Anti-inflammatory Drugs in Overdose. An Overview of Recent Evidence on Clinical Effects and Dose-Response Relationships," Drug Saf , 1990, 5(4):252-74.

Vale JA and Meredith TJ, "Acute Poisoning Due to Nonsteroidal Anti-inflammatory Drugs," Med Toxicol , 1986, 1(1):12-31.

Verbeeck RK, "Pharmacokinetic Drug Interactions With Nonsteroidal Anti-inflammatory Drugs," Clin Pharmacokinet , 1990, 19(1):44-66.

Yeomans ND, Tulassay Z, Juhasz L, et al, "A Comparison of Omeprazole With Ranitidine for Ulcers Associated With Nonsteroidal Anti-inflammatory Drugs," N Engl J Med , 1998, 338(11):719-26.

International Brand Names

Aclin® (AU); Adco-Sulindac® (ZA); Algocetil® (IT); Apo-Sulin® (CA); Arthrocine® (FR); Artribid® (PT); Cenlidac® (TH); Clinoril® (AT, AU, BE, CH, CY, DK, EG, GB, HK, HU, IE, IT, JO, KW, LB, LU, MX, NL, NO, NZ, SE, SY, TH, ZA); Copal® (MX); Daclin® (NZ); Huma-Sundac® (HU); Kenalin® (MX); Mobilin® (IL); Novo-Sundac (CA); Nu-Sundac (CA); Saldac® (NZ); Sindac® (EG, JO, KW, LB, SY); Sudaclin® (PL); Sulen® (IT); Sulindac® (GB); Sulindaco Lisan® (CR); Sulindal® (ES)

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