Sulindac toxicity

Nonsteroidal antiinflammatory drugs (NSAIDs) are the mainstay of therapy because of their excellent efficacy and minimal toxicity with shortterm use. There is little evidence to support one NSAID as more efficacious than another, and three drugs (indomethacin, naproxen, and sulindac) have FDA approval for this indication (Table 1-1). 

Apart from the salicylates NSAIDs include several classes of weak acids like propionic acid derivatives such as ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen. Phenylbutazone is the most important representative of the pyrazolon derivatives which have a bad reputation for their risk of potentially fatal bone-marrow toxicity. To the acetic acid derivatives belong in-domethacin, diclofenac and sulindac. Sulindac is a pro-drug with less toxicity than indomethacin. The enolic acids include piroxicam, droxicam and tenoxicam. Meloxicam is an analog of piroxicam and has a high selectivity for COX-2. 

The interaction of NSAIDs with lithium has been reviewed briefly (663). Most NSAIDs, although perhaps not all (for example aspirin, sulindac), if given in sufficient dosages for sufficient time, can increase the serum lithium concentration, sometimes to the point of toxicity (664,665). 

Unlike other NSAIDs, sulindac supposedly does not interact with lithium (SEDA-10, 82). However, there has been a report of a toxic increase in serum lithium concentration in a 23-year-old man and a 27-year-old woman (to 2.0 and 1.7 mmol/1 respectively) (690). 

The types of skin adverse effect also vary with different compounds. The most serious life-threatening reactions, such as erythema multiforme and its variants (Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative erythroderma) are uncommon and occur mainly with the butazone derivatives and to a lesser extent with piroxicam, sulindac, and possibly fenbufen. In large series reported in France, Germany, and the USA, NSAIDs are most often implicated 12 (44%) of the most commonly implicated 29 drugs (168). 

Lithium Probably all NSAIDs ( except sulindac, aspirin) Inhibition of renal excretion of lithium, increasing lithium serum concentrations and increasing risk of toxicity Use sulindac or aspirin if an NSAID is unavoidable careful monitoring of serum lithium concentration and appropriate dosage reduction... 

Agranulocytosis (probably due to toxicity rather than hypersusceptibility) can be caused by sulindac (13), as can bone marrow aplasia (14) and severe thrombocytopenia (15,16), which may be the consequence of autoimmune platelet destruction in the presence of sulindac or its metabolite (SEDA-7, 109). Immune-mediated hemolytic anemia with a positive direct antiglobulin test has been reported (SEDA-18,103). 

Sulindac can cause toxic hepatitis, and several cases, some with positive rechallenge, have been described (27,28). A retrospective cohort study with secondary case-control analysis suggested that sulindac has a higher incidence of acute liver damage than all other NSAIDs, although the calculated risk is very low (27 per 100000 prescriptions) (29). Liver function impairment is generally mild and reversible. Analysis of spontaneous reports to the FDA and the Danish Committee on ADRs (SEDA-18, 103) has confirmed these data. 

Sulindac may be less hkely to cause renal toxicity than other NSAIDs (32), at least when it is used in low dosages, but there is some disagreement on this point (33-35), and five cases of nephrotic syndrome and renal insufficiency have been described (36,37). 

Breton JC, Pibouin M, Allain H, et al. Toxic epidermal necrolysis induced by sulindac. Therapie 1985 40 67. 

Small RE, Garnett WR. Sulindac-induced toxic epidermal necrolysis. Clin Pharm 1988 7(10) 766-71. 

Indole-acetic acid derivatives with NSAID action include etodolac, indomethacin and sulindac. The first produced was indomethacin which, though very powerful as an antirheumatic and antiosteoarthritic agent, has serious toxic GI effects. The more recently introduced members seem better and show promise. 

Indomethacin was the product of a laboratory search for drugs with antiinflammatory properties. It was introduced in 1963 for the treatment of rheumatoid arthritis and related disorders. It is a nonselective COX inhibitor. Although indomethacin still is used clinically and is effective, toxicity and the availability of safer alternatives have limited its use. Sulindac was developed in an attempt to find a less toxic, but effective, congener of indomethacin and also is a nonselective COX inhibitor. 

Most of the renal tubular reabsorption ofU occurs in the proximal tubule. Nevertheless, Id retention can be increased by any diuretic that leads to depletion of Na, particularly the thiazides (see Chapter 28). Renal excretion can be increased by administration of osmotic diuretics, aceta-zolamide or aminophylline, and triamterene. Spironolactone does not increase the excretion of LiL Some nonsteroidal anti-inflammatory agents can facilitate renal proximal tubular resorption of Id and thereby increase concentrations in plasma to toxic levels. This interaction appears to be particularly prominent with indomethacin, but also may occur with ibuprofen, naproxen, and COX-2 inhibitors, and possibly less so with sulindac and aspirin. A potential drug interaction can occur with angiotensin-converting enzyme inhibitors, causing lithium retention (see Chapter 29). 

Sulindac, which is less than half as potent as indomethacin, is a prodrug whose anti-inflammatory activity resides in its sulfide metabolite. The same precautions that apply to other NSAlDs regarding patients at risk for GI toxicity or renal impairment also apply to sulindac. 

Whereas the toxicity of sulindac is lower than that observed for indomethacin and other NSAIDs, the spectrum of adverse reactions is very similar. The most frequent side effects reported are associated with irritation of the Gl tract (e.g., nausea, dyspepsia, and diarrhea), although these effects generally are mild. Effects on the CNS (e.g., dizziness and headache) are less common. Dermatological effects are less frequently encountered. 

Naproxen sodium Anaprox, Aleve, Naprelan Oxaprozin Daypro Piroxicam Feldene Sulindac Clinoril Tolmetin sodium Tolectin Adverse reactions Abdominal pain, bleeding, anorexia, ulcers, liver toxicity, dyspepsia, heartburn (minimized if taken with meals) flank pain may indicate nephrotoxicity drowsiness, headache, dizziness, confusion, tinnitus, vertigo, depression, bladder infections, blood in urine and kidney necrosis... 

Probenecid reduces the clearance of dexketoprofen, diflunisal, in-dometacin (toxicity seen), ketoprofen, ketorolac, naproxen, sodium meclofenamate, tenoxicam and tiaprofenic acid and raises their levels. Ketorolac and probenecid are specifically contraindicated. The uricosuric effects of probenecid are not affected by in-dometacin but may be slightly reduced by sulindac. 

NSAIDs may increase serum-lithium levels leading to toxicity, but there is great variability between different NSAIDs and also between individuals taking the same NSAID. For example, studies have found that celecoxib causes a modest 17% increase in lithium levels, yet case reports describe increases of up to 344%. Similar effects occur with other NSAIDs, and it seems likely that all NSAIDs will interact similarly. However, note that sulindac seems unique in that it is the only NSAID that has also been reported to cause a decrease in lithium levels. 

Lithium levels increased. Two patients developed increased serum-lithium levels apparently due to the use of sulindac. In one case the lithium levels rose from 1 to 2 mmol/L after 19 days of treatment with sulindac 150 mg twice daily, and symptoms of toxicity were seen. The levels fell to 0.8 mmol/L within 5 days of stopping the sulindac. The other patient had a rise from 0.9 to 1.7 mmol/L within a week of adding sulindac 150 mg twice daily. The sulindac was continued and the lithium dosage was reduced from 1.8 to 1.5 g daily. The serum-lithium levels fell and were 1.2 mmol/L at 37 days and 1 mmol/L at 70 days. No symptoms of lithium toxicity occurred. ... 

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