Sulindac

(BAN, USAN, rINN)
Synonyms: MK-231; Sulindaakki; Sulindaco; Sulindacum; Sulindak; Szulindak. (Z)-[5-Fluoro-2-methyl-1-(4-methylsulphinylbenzylidene)inden3-yl]acetic acid.
Cyrillic synonym: Сулиндак.

💊 Chemical information

Chemical formula: C20H17FO3S = 356.4.
CAS — 38194-50-2.
ATC — M01AB02.
ATC Vet — QM01AB02.

Pharmacopoeias.

In Chin., Eur., and US.

Ph. Eur. 6.2

(Sulindac). A yellow, polymorphic, crystalline powder. Very slightly soluble in water and in ether; sparingly soluble in alcohol; soluble in dichloromethane; dissolves in dilute solutions of alkali hydroxides. Protect from light.

USP 31

(Sulindac). A yellow, odourless or practically odourless, crystalline powder. Practically insoluble in water and in hexane; slightly soluble in alcohol, in acetone, in chloroform, and in methyl alcohol; very slightly soluble in ethyl acetate and in isopropyl alcohol.

💊 Adverse Effects, Treatment, and Precautions

Urine discoloration has occasionally been reported with sulindac. Sulindac metabolites have been reported as major or minor components in renal stones. It should therefore be used with caution in patients with a history of renal stones and such patients should be kept well hydrated while receiving sulindac. UK licensed product information recommends that patients with hepatic impairment should not be given sulindac; in the USA, however, licensed information states that patients with poor hepatic function may be given a reduced dose of sulindac with close monitoring. The dose of sulindac may also need to be reduced in those with renal impairment. Licensed information recommends that sulindac is not used in patients with advanced renal disease, but this appears to be based on a lack of data in such patients.

Effects on the blood.

Agranulocytosis,1 thrombocytopenia,2haemolytic anaemia,3 and aplastic anaemia4 have been reported in patients taking sulindac.
1. Romeril KR, et al. Sulindac induced agranulocytosis and bone marrow culture. Lancet 1981; ii: 523
2. Karachalios GN, Parigorakis JG. Thrombocytopenia and sulindac. Ann Intern Med 1986; 104: 128
3. Johnson FP, et al. Immune hemolytic anemia associated with sulindac. Arch Intern Med 1985; 145: 1515–16
4. Andrews R, Russell N. Aplastic anaemia associated with a nonsteroidal anti-inflammatory drug: relapse after exposure to another such drug. BMJ 1990; 301: 38.

Effects on the CNS.

Acute deterioration of parkinsonism occurred in a patient after starting sulindac.1 See also Hypersensitivity, below.
1. Sandyk R, Gillman MA. Acute exacerbation of Parkinson’s disease with sulindac. Ann Neurol 1985; 17: 104–5.

Effects on the endocrine system.

A case of reversible gynaecomastia associated with sulindac therapy has been reported.1There has also been a report2 of reversible hypothyroidism in an elderly patient taking sulindac.
1. Kapoor A. Reversible gynecomastia associated with sulindac therapy. JAMA 1983; 250: 2284–5
2. Iyer RP, Duckett GK. Reversible secondary hypothyroidism induced by sulindac. BMJ 1985; 290: 1788.

Effects on the gallbladder.

A "sludge" composed of crystalline metabolites of sulindac has been found in the common bile duct during surgery for biliary obstruction in patients who had been taking sulindac.1
1. Anonymous. Rare complication with sulindac. FDA Drug Bull 1989; 19: 4.

Effects on the kidneys.

Sulindac-induced renal impairment, interstitial nephritis, and nephrotic syndrome have been reported.1 It has been suggested that sulindac, as a prodrug, may not inhibit renal prostaglandin synthesis in therapeutic doses. However, this potentially important therapeutic advantage has not been uniformly seen in short-term studies in patients with renal dysfunction.2-4 There have been reports of renal stones consisting of between 10 and 90% of sulindac metabolites developing in patients given sulindac.5
1. Whelton A, et al. Sulindac and renal impairment. JAMA 1983; 249: 2892
2. Klassen DK, et al. Sulindac kinetics and effects on renal function and prostaglandin excretion in renal insufficiency. J Clin Pharmacol 1989; 29: 1037–42
3. Eriksson L-O, et al. Effects of sulindac and naproxen on prostaglandin excretion in patients with impaired renal function and rheumatoid arthritis. Am J Med 1990; 89: 313–21
4. Whelton A, et al. Renal effects of ibuprofen, piroxicam, and sulindac in patients with asymptomatic renal failure. Ann Intern Med 1990; 112: 568–76
5. Anonymous. Rare complication with sulindac. FDA Drug Bull 1989; 19: 4.

Effects on the liver.

Hepatotoxicity reported in patients receiving sulindac includes hepatocellular injury and cholestatic jaundice.1,2 Symptoms of hypersensitivity including rash, fever, or eosinophilia have been reported in 35 to 55% of patients with sulindac-induced liver damage;2 in these patients the liver damage occurred usually within 4 to 8 weeks of beginning sulindac therapy. For reference to a report citing the strongest evidence for an association of sulindac with liver disease compared with other NSAIDs, see under NSAIDs. See also Effects on the Skin, below.
1. Gallanosa AG, Spyker DA. Sulindac hepatotoxicity: a case report and review. Clin Toxicol 1985; 23: 205–38
2. Tarazi EM, et al. Sulindac-associated hepatic injury: analysis of 91 cases reported to the Food and Drug Administration. Gastroenterology 1993; 104: 569–74.

Effects on the lungs.

For reference to pneumonitis associated with sulindac therapy, see Hypersensitivity, below.

Effects on the skin.

Toxic epidermal necrolysis has occurred in patients taking sulindac.1 In a patient toxic hepatitis and the Stevens-Johnson/toxic epidermal necrolysis syndrome resulted in death.2 An unusual pernio-like reaction affecting the toes, which was also confirmed by rechallenge, has been reported.3 Sulindac has also been reported to cause photosensitivity reactions.4
1. Small RE, Garnett WR. Sulindac-induced toxic epidermal necrolysis. Clin Pharm 1988; 7: 766–71
2. Klein SM, Khan MA. Hepatitis, toxic epidermal necrolysis and pancreatitis in association with sulindac therapy. J Rheumatol 1983; 10: 512–13
3. Reinertsen JL. Unusual pernio-like reaction to sulindac. Arthritis Rheum 1981; 24: 1215
4. Anonymous. Drugs that cause photosensitivity. Med Lett Drugs Ther 1986; 28: 51–2.

Hypersensitivity.

Hypersensitivity reactions to sulindac include pneumonitis,1,2 generalised lymphadenopathy,3 aseptic meningitis,4 and anaphylactoid reaction.5 See also Effects on the Liver and Effects on the Skin, above.
1. Smith FE, Lindberg PJ. Life-threatening hypersensitivity to sulindac. JAMA 1980; 244: 269–70
2. Fein M. Sulindac and pneumonitis. Ann Intern Med 1981; 95: 245
3. Sprung DJ. Sulindac causing a hypersensitivity reaction with peripheral and mediastinal lymphadenopathy. Ann Intern Med 1982; 97: 564
4. Fordham von Reyn C. Recurrent aseptic meningitis due to sulindac. Ann Intern Med 1983; 99: 343–4
5. Hyson CP, Kazakoff MA. A severe multisystem reaction to sulindac. Arch Intern Med 1991; 151: 387–8.

Pancreatitis.

Reports1-4 of pancreatitis associated with sulindac therapy.
1. Goldstein J, et al. Sulindac associated with pancreatitis. Ann Intern Med 1980; 93: 151
2. Siefkin AD. Sulindac and pancreatitis. Ann Intern Med 1980; 93: 932–3
3. Lilly EL. Pancreatitis after administration of sulindac. JAMA 1981; 246: 2680
4. Memon AN. Pancreatitis and sulindac. Ann Intern Med 1982; 97: 139.

💊 Interactions

For interactions associated with NSAIDs. Dimethyl sulfoxide reduces plasma concentrations of the active metabolite of sulindac and use of the two drugs together has also resulted in peripheral neuropathy. Diflunisal and aspirin are reported to reduce the plasma concentration of the active metabolite of sulindac. Unlike other NSAIDs, sulindac is reported not to reduce the antihypertensive effects of drugs such as thiazide diuretics, but nevertheless licensed product information recommends that blood pressure be closely monitored in patients taking antihypertensives with sulindac.

💊 Pharmacokinetics

Sulindac is absorbed from the gastrointestinal tract. It is metabolised by reversible reduction to the sulfide metabolite, which appears to be the active form, and by irreversible oxidation to the sulfone metabolite. Peak plasma concentrations of the sulfide metabolite are achieved in about 2 hours. The mean elimination halflife of sulindac is about 7.8 hours and of the sulfide metabolite about 16.4 hours. Sulindac and its metabolites are over 90% bound to plasma proteins. About 50% is excreted in the urine mainly as the sulfone metabolite and its glucuronide conjugate, with smaller amounts of sulindac and its glucuronide conjugate; about 25% appears in the faeces, primarily as sulfone and sulfide metabolites. Sulindac and its metabolites are also excreted in bile and undergo extensive enterohepatic circulation.
1. Davies NM, Watson MS. Clinical pharmacokinetics of sulindac: a dynamic old drug. Clin Pharmacokinet 1997; 32: 437–59.

💊 Uses and Administration

Sulindac is an NSAID structurally related to indometacin; its activity appears to be due to its sulfide metabolite. Sulindac is used in musculoskeletal and joint disorders such as ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis, and also in the short-term management of acute gout and peri-articular conditions such as bursitis and tendinitis. It has also been used to reduce fever. A usual initial oral dose of sulindac is 150 or 200 mg twice daily, reduced according to response; the maximum recommended daily dose is 400 mg. Licensed product information recommends that the treatment of peri-articular disorders should be limited to 7 to 14 days; for acute gout, 7 days of therapy is usually adequate. Sulindac sodium has been given by rectal suppository.

Administration in hepatic or renal impairment.

The dose of sulindac may need to be reduced in patients with hepatic or renal impairment but see Adverse Effects and Precautions, above..

Gastrointestinal disorders.

In placebo-controlled studies1,2sulindac 150 to 200 mg twice daily for 6 to 9 months has reduced the number and size of polyps in patients with familial adenomatous polyposis but the effect may be incomplete and in a study2only polyps less than 2 mm in size regressed. In addition, the size and number of polyps has been reported1 to increase on stopping treatment. The benefit of long-term therapy has therefore been studied. Reduced effectiveness has been seen3 with long-term use but others4 have reported management of recurrences by adjustment of maintenance dosage; there seemed to be individual variations in sensitivity to sulindac with respect to prevention of polyp recurrence although an average maintenance dose of 200 mg daily appeared to be needed.4 There is evidence5 that sulindac alters the ratio of apoptosis of surface cells relative to those lying deeper in the crypt of rectal mucosa, thus altering epithelial homoeostasis. Whether sulindac prevents malignant degeneration is unknown but there have been reports6-8 of patients who developed rectal cancer during or after long-term therapy for adenomatous polyposis. A more recent, placebo-controlled trial9 has also reported that sulindac did not reduce the development of adenomas in patients with familial adenomatous polyposis. Some1,9 consider that sulindac is unlikely to replace surgery as primary therapy for familial adenomatous polyposis. A sulfone metabolite of sulindac, exisulind has also been investigated for the treatment of familial adenomatous polyposis. Sulindac has also been reported to have produced beneficial effects in a patient with duodenal polyps associated with Gardner’s syndrome10 but a placebo-controlled study has suggested that it may not be effective against sporadic type colonic polyps.11 For a discussion of evidence suggesting that regular use of NSAIDs may protect against various types of malignant neoplasms of the gastrointestinal tract, see Malignant Neoplasms in NSAIDs.
1. Giardiello FM, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 1993; 328: 1313–16
2. Debinski HS, et al. Effect of sulindac on small polyps in familial adenomatous polyposis. Lancet 1995; 345: 855–6
3. Tonelli F, Valanzano R. Sulindac in familial adenomatous polyposis. Lancet 1993; 342: 1120
4. Labayle D, et al. Sulindac in familial adenomatous polyposis. Lancet 1994; 343: 417–18
5. Keller JJ, et al. Rectal epithelial apoptosis in familial adenomatous polyposis patients treated with sulindac. Gut 1999; 45: 822–8
6. Thorson AG, et al. Rectal cancer in FAP patient after sulindac. Lancet 1994; 343: 180
7. Matsuhashi N, et al. Rectal cancer after sulindac therapy for a sporadic adenomatous colonic polyp. Am J Gastroenterol 1998; 93: 2261–6
8. Cruz-Correa M, et al. Long-term treatment with sulindac in familial adenomatous polyposis: a prospective cohort study. Gastroenterology 2002; 122: 641–5
9. Giardiello FM, et al. Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med 2002; 346: 1054–9
10. Parker AL, et al. Disappearance of duodenal polyps in Gardner’s syndrome with sulindac therapy. Am J Gastroenterol 1993; 88: 93–4
11. Ladenheim J, et al. Effect of sulindac on sporadic colonic polyps. Gastroenterology 1995; 108: 1083–7.

Premature labour.

The most common approach to postponing premature labour with drugs has historically been with a selective beta2 agonist. However, as prostaglandins have a role in uterine contraction and cervical ripening and dilatation, prostaglandin synthetase inhibitors such as indometacin have also been used. Sulindac has also been tried1,2 as an alternative to indometacin as it appears to have little placental transfer and may therefore have fewer fetal adverse effects.1 However, the authors of a subsequent study suggested that sulindac had many of the same adverse fetal effects as indometacin and its use could only be described as investigational.3 A study4 using relatively low doses of sulindac (100 mg twice daily) did not note any significant fetal or maternal adverse effects but also found the drug to be ineffective in extending gestation or improving outcome.
1. Carlan SJ, et al. Randomized comparative trial of indomethacin and sulindac for the treatment of refractory preterm labor. Obstet Gynecol 1992; 79: 223–8
2. Carlan SJ, et al. Outpatient oral sulindac to prevent recurrence of preterm labor. Obstet Gynecol 1995; 85: 769–74
3. Kramer WB, et al. A randomized double-blind study comparing the fetal effects of sulindac to terbutaline during the management of preterm labor. Am J Obstet Gynecol 1999; 180: 396–401
4. Humphrey RG, et al. Sulindac to prevent recurrent preterm labor: a randomized controlled trial. Obstet Gynecol 2001; 98: 555–62.

💊 Preparations

BP 2008: Sulindac Tablets; USP 31: Sulindac Tablets.

Proprietary Preparations

Austral.: Aclin; Clinoril†; Austria: Clinoril; Belg.: Clinoril; Canad.: ApoSulin; Novo-Sundac; Cz.: Clinoril†; Denm.: Clinoril†; Fr.: Arthrocine; Hong Kong: Aclin; Clinoril; Irl.: Clinoril; Ital.: Algocetil; Clinoril; Sulen†; Malaysia: Aclin†; Apo-Sulin†; Clinoril†; Mex.: Atriser; Bio-Dac; Clinoril; Clison; Copal; Kenalin; Renidac; Sulifur; Vindacin; Norw.: Clinoril; NZ: Clinoril; Daclin; Port.: Artribid; Singapore: Apo-Sulin; Spain: Sulindal; Swed.: Clinoril; Switz.: Clinoril†; Thai.: Cenlidac; Clinoril; UK: Clinoril; USA: Clinoril; Venez.: Clinoril†.
Published April 13, 2019.