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EPIC PHARMA LLC
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42806001801

sulindac 150 mg tablet

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Uses

Sulindac is used for anti-inflammatory and analgesic effects in the symptomatic treatment of acute and chronic rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. Sulindac is also used for symptomatic treatment of acute gouty arthritis and acute painful shoulder (bursitis and/or tendinitis).

Sulindac has been used to reduce the number of adenomatous colorectal polyps in adults with familial adenomatous polyposis (FAP).

The potential benefits and risks of sulindac therapy as well as alternative therapies should be considered prior to initiating sulindac therapy. The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.

Inflammatory Diseases

Rheumatoid Arthritis and Osteoarthritis

When used in the treatment of rheumatoid arthritis or osteoarthritis, sulindac has relieved pain and stiffness, reduced swelling and the number of joints involved, and improved mobility and grip strength. In patients with osteoarthritis, sulindac has relieved pain and stiffness, reduced swelling and tenderness, and improved mobility. Sulindac appears to be only palliative in these conditions and has not been shown to permanently arrest or reverse the underlying disease process. Safety and efficacy of sulindac in patients who are incapacitated, largely or wholly bedridden, or confined to a wheelchair with little or no capacity for self care (Functional Class IV rheumatoid arthritis) have not been established.

Most clinical studies have shown that the analgesic and anti-inflammatory effects of usual dosages of sulindac in the management of rheumatoid arthritis or osteoarthritis are greater than those of placebo and about equal to those of usual dosages of salicylates. In patients with osteoarthritis, the therapeutic effects of usual dosages of sulindac are also about equal to those of ibuprofen. Patient response to NSAIAs is variable; patients who do not respond to or cannot tolerate one drug may be successfully treated with a different agent. However, NSAIAs are generally contraindicated in patients in whom sensitivity reactions (e.g., urticaria, bronchospasm, severe rhinitis) are precipitated by aspirin or other NSAIAs.(See Cautions: Precautions and Contraindications.)

In the management of rheumatoid arthritis in adults, NSAIAs may be useful for initial symptomatic treatment; however, NSAIAs do not alter the course of the disease or prevent joint destruction. Disease modifying antirheumatic drugs (DMARDs) (e.g., azathioprine, cyclosporine, etanercept, oral or injectable gold compounds, hydroxychloroquine, infliximab, leflunomide, methotrexate, minocycline, penicillamine, sulfasalazine) have the potential to reduce or prevent joint damage, preserve joint integrity and function, and reduce total health care costs, and all patients with rheumatoid arthritis are candidates for DMARD therapy. DMARDs should be initiated early in the disease course and should not be delayed beyond 3 months in patients with active disease (i.e., ongoing joint pain, substantial morning stiffness, fatigue, active synovitis, persistent elevation of erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], radiographic evidence of joint damage) despite an adequate regimen of NSAIAs. NSAIA therapy may be continued in conjunction with DMARD therapy or, depending on patient response, may be discontinued.

The manufacturers state that, in some patients with rheumatoid arthritis, sulindac has produced additional therapeutic benefit when used in conjunction with gold compounds.

Use of sulindac with aspirin is not recommended by the manufacturers. There is inadequate proof that the combination is more effective than either drug alone, the potential for adverse reactions may be increased, and there is some evidence that aspirin decreases plasma concentrations of sulindac's sulfide metabolite. (See Drug Interactions: Nonsteroidal Anti-inflammatory Agents.)

Other Inflammatory Conditions

When used in patients with ankylosing spondylitis, sulindac has relieved night pain and spinal pain, tenderness, and/or spasm; reduced stiffness; and improved chest expansion and spinal mobility. In a limited number of studies, the anti-inflammatory and analgesic effects of usual dosages of sulindac in the management of ankylosing spondylitis were greater than those of placebo and about equal to those of usual dosages of indomethacin or phenylbutazone (no longer commercially available in the US).

When used in the symptomatic treatment of acute painful shoulder (bursitis and/or tendinitis), the anti-inflammatory and analgesic effects of sulindac are about equal to those of oxyphenbutazone (no longer commercially available in the US).

Colchicine, phenylbutazone (no longer commercially available in the US), or indomethacin are considered the drugs of choice to relieve attacks of acute gouty arthritis. Although the precise role has not been determined, sulindac also has relieved the pain, swelling, and tenderness of acute gouty arthritis. Sulindac is used for its anti-inflammatory and analgesic effects in the short-term management of acute attacks. In short-term clinical studies, the anti-inflammatory and analgesic effects of usual dosages of sulindac were about equal to those of usual dosages of phenylbutazone (no longer commercially available in the US) in relieving attacks of acute gouty arthritis; the drugs were equally well tolerated. Sulindac is not indicated for long-term prophylactic treatment of gouty arthritis.

Colorectal Polyps

Results of observational studies and randomized controlled studies indicate that administration of sulindac is associated with a reduction in the number of polyps in adults with familial adenomatous polyposis (FAP). It is unclear whether the effect of sulindac in reducing the number of polyps persists with long-term therapy.

While sulindac may reduce the number of polyps in patients with FAP, the drug does not appear to prevent the development of adenomatous colorectal polyps in individuals with FAP. In a randomized, placebo-controlled study in children, adolescents, and young adults (8-25 years of age) with the inherited mutation in the adenomatous polyposis coli (APC) gene but no evidence of disease (i.e., no colorectal adenomatous polyps detected on endoscopy at baseline and no prior colonic surgery), administration of sulindac (75 or 150 mg 2 times daily for those weighing 20-44 or greater than 44 kg, respectively) for 4 years was not associated with a difference in number or size of polyps compared with those receiving placebo.

Other Uses

Results from a large, prospective, population-based cohort study in geriatric individuals indicate a lower prevalence of Alzheimer's disease among patients who received an NSAIA for 2 years or longer. Similar findings have been reported from some other, but not all, observational studies.

Dosage and Administration

Administration

The potential benefits and risks of sulindac therapy as well as alternative therapies should be considered prior to initiating sulindac therapy.

Sulindac is administered orally with food.

Dosage

The lowest possible effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed. Dosage of sulindac must be adjusted carefully according to individual requirements and response, using the lowest possible effective dosage.

Inflammatory Diseases

For the symptomatic treatment of rheumatoid arthritis, osteoarthritis, or ankylosing spondylitis, the usual initial adult dosage of sulindac is 150 mg twice daily. Subsequent dosage should be adjusted according to the patient's response and tolerance but should not exceed 400 mg daily. Although higher dosages have been used, pending further clinical experience, the manufacturers do not recommend sulindac dosages greater than 400 mg daily. Symptomatic improvement may occur within 1 week of sulindac therapy, but some patients may require a longer period to respond.

For the symptomatic treatment of acute painful shoulder (bursitis and/or tendinitis) or acute gouty arthritis, the usual adult dosage of sulindac is 200 mg twice daily. When a satisfactory response to sulindac therapy has been achieved, dosage may be reduced according to the patient's response. In acute painful shoulder, 7-14 days of sulindac therapy usually is adequate; in acute gouty arthritis, 7 days is generally adequate.

Colorectal Polyps

Sulindac has been given in a dosage of 150 mg twice daily to reduce the number of adenomatous colorectal polyps in adults with familial adenomatous polyposis (FAP).

Cautions

Cardiovascular Effects

Edema reportedly occurs in 1-3% of patients during sulindac therapy. Congestive heart failure has reportedly occurred in less than 1% of patients and is especially likely in patients with compromised cardiac function. Palpitation and hypertension also have occurred. Arrhythmia has been reported with sulindac therapy, but a direct causal relationship to the drug has not been established.

Nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors and prototypical NSAIAs, increase the risk of serious adverse cardiovascular thrombotic events, including myocardial infarction and stroke (which can be fatal), in patients with or without cardiovascular disease or risk factors for cardiovascular disease. Use of NSAIAs also is associated with an increased risk of heart failure.

The association between cardiovascular complications and use of NSAIAs is an area of ongoing concern and study. Findings of an FDA review of published observational studies of NSAIAs, a meta-analysis of published and unpublished data from randomized controlled trials of these drugs, and other published information indicate that NSAIAs may increase the risk of serious adverse cardiovascular thrombotic events by 10-50% or more, depending on the drugs and dosages studied. Available data suggest that the increase in risk may occur early (within the first weeks) following initiation of therapy and may increase with higher dosages and longer durations of use. Although the relative increase in cardiovascular risk appears to be similar in patients with or without known underlying cardiovascular disease or risk factors for cardiovascular disease, 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.

Results from observational studies utilizing Danish national registry data indicated that patients receiving NSAIAs following a myocardial infarction were at increased risk of reinfarction, cardiovascular-related death, and all-cause mortality beginning in the first week of treatment. Patients who received NSAIAs following myocardial infarction had a higher 1-year mortality rate compared with those who did not receive NSAIAs (20 versus 12 deaths per 100 person-years). Although the absolute mortality rate declined somewhat after the first year following the myocardial infarction, the increased relative risk of death in patients who received NSAIAs persisted over at least the next 4 years of follow-up.

In 2 large controlled clinical trials of a selective COX-2 inhibitor for the management of pain in the first 10-14 days following coronary artery bypass graft (CABG) surgery, the incidence of myocardial infarction and stroke was increased. Therefore, NSAIAs are contraindicated in the setting of CABG surgery.

Findings from some systematic reviews of controlled observational studies and meta-analyses of data from randomized studies of NSAIAs suggest that naproxen may be associated with a lower risk of cardiovascular thrombotic events compared with other NSAIAs. However, limitations of these observational studies and the indirect comparisons used to assess cardiovascular risk of the prototypical NSAIAs (e.g., variability in patients' risk factors, comorbid conditions, concomitant drug therapy, drug interactions, dosage, and duration of therapy) affect the validity of the comparisons; in addition, these studies were not designed to demonstrate superior safety of one NSAIA compared with another. Therefore, FDA states that definitive conclusions regarding relative risks of NSAIAs are not possible at this time.

Data from observational studies also indicate that use of NSAIAs in patients with heart failure is associated with increased morbidity and mortality. Results from a retrospective study utilizing Danish national registry data indicated that use of selective COX-2 inhibitors or prototypical NSAIAs in patients with chronic heart failure was associated with a dose-dependent increase in the risk of death and an increased risk of hospitalization for myocardial infarction or heart failure. In addition, findings from a meta-analysis of published and unpublished data from randomized controlled trials of NSAIAs indicated that use of selective COX-2 inhibitors or prototypical NSAIAs was associated with an approximate twofold increase in the risk of hospitalization for heart failure. Fluid retention and edema also have been observed in some patients receiving NSAIAs.

There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.

GI Effects

Peptic ulceration and GI bleeding have occurred in patients receiving sulindac and rarely have been fatal. GI bleeding is associated with increased morbidity and mortality in patients acutely ill with other conditions, geriatric patients, and patients with hemorrhagic disorders.

The most frequent adverse effects of sulindac involve the GI tract and include GI pain, reportedly occurring in about 10% of patients; dyspepsia, nausea with or without vomiting, diarrhea, and constipation, in about 3-9% of patients; and flatulence, anorexia, and GI cramps, in about 1-3% of patients. Less frequently reported adverse GI effects include gastritis, gastroenteritis, and colitis. Stomatitis, dry mouth, metallic or bitter taste, ageusia, glossitis, and oral mucosal ulcers have also occurred during sulindac therapy. GI perforation has been reported rarely. In addition, a sludge of crystalline sulindac metabolite was recovered at surgery from the common bile duct in some sulindac-treated patients who had developed biliary obstruction.

The frequency of adverse GI effects with usual dosages of sulindac is reportedly less than that with usual dosages of aspirin. The amount of GI bleeding, as determined by fecal blood loss in healthy men, has been reportedly less with 240 or 400 mg of sulindac daily than with 4.8 g of aspirin daily; sulindac (in dosages of 60 or 100 mg 4 times daily for 2 weeks) was associated with only minimal and clinically unimportant GI blood loss. The frequency of adverse GI effects is reportedly similar in patients receiving 200-400 mg of sulindac daily or 0.6-1.2 g of ibuprofen daily and in patients receiving 400 mg of sulindac daily or 600 mg of phenylbutazone (no longer commercially available in the US) daily.

Serious adverse GI effects (e.g., bleeding, ulceration, perforation) can occur at any time in patients receiving NSAIA therapy, and such effects may not be preceded by warning signs or symptoms. Only 1 in 5 patients who develop a serious upper GI adverse event while receiving NSAIA therapy is symptomatic. Therefore, clinicians should remain alert to the possible development of serious GI effects (e.g., bleeding, ulceration) in any patient receiving NSAIA therapy, and such patients should be followed chronically for the development of manifestations of such effects and advised of the importance of this follow-up. In addition, patients should be advised about the signs and symptoms of serious NSAIA-induced GI toxicity and what action to take if they occur. If signs and symptoms of a serious GI event develop, additional evaluation and treatment should be initiated promptly; the NSAIA should be discontinued until appropriate diagnostic studies have ruled out a serious GI event.

Results of studies to date are inconclusive concerning the relative risk of various prototypical NSAIAs in causing serious GI effects. In patients receiving NSAIAs and observed in clinical studies of several months' to 2 years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year. Longer duration of therapy with an NSAIA increases the likelihood of a serious GI event. However, short-term therapy is not without risk. High dosages of any NSAIA probably are associated with increased risk of such effects, although controlled studies documenting this probable association are lacking for most NSAIAs. Therefore, whenever use of relatively high dosages (within the recommended dosage range) is considered, sufficient benefit to offset the potential increased risk of GI toxicity should be anticipated.

Studies have shown that patients with a history of peptic ulcer disease and/or GI bleeding who are receiving NSAIAs have a substantially higher risk of developing GI bleeding than patients without these risk factors. In addition to a history of ulcer disease, pharmacoepidemiologic studies have identified several comorbid conditions and concomitant therapies that may increase the risk for GI bleeding, including concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAIA therapy, smoking, alcoholism, older age, and poor general health status. Patients with rheumatoid arthritis are more likely to experience serious GI complications from NSAIA therapy than are patients with osteoarthritis. In addition, geriatric or debilitated patients appear to tolerate GI ulceration and bleeding less well than other individuals, and most spontaneous reports of fatal GI effects have been in such patients.

For patients at high risk for complications from NSAIA-induced GI ulceration (e.g., bleeding, perforation), concomitant use of misoprostol can be considered for preventive therapy. Alternatively, some clinicians suggest that a proton-pump inhibitor (e.g., omeprazole) may be used concomitantly to decrease the incidence of serious GI toxicity associated with NSAIA therapy. In one study, therapy with high dosages of famotidine (40 mg twice daily) was more effective than placebo in preventing peptic ulcers in NSAIA-treated patients; however, the effect of the drug was modest. In addition, efficacy of usual dosages of H2-receptor antagonists for the prevention of NSAIA-induced gastric and duodenal ulcers has not been established. Therefore, most clinicians do not recommend use of H2-receptor antagonists for the prevention of NSAIA-associated ulcers. Another approach in high-risk patients who would benefit from NSAIA therapy is use of an NSAIA that is a selective inhibitor of COX-2 (e.g., celecoxib), since these agents are associated with a lower incidence of serious GI bleeding than are prototypical NSAIAs. However, while celecoxib (200 mg twice daily) was comparably effective to diclofenac sodium (75 mg twice daily) plus omeprazole (20 mg daily) in preventing recurrent ulcer bleeding (recurrent ulcer bleeding probabilities of 4.9 versus 6.4%, respectively, during the 6-month study) in H. pylori-negative arthritis (principally osteoarthritis) patients with a recent history of ulcer bleeding, the protective efficacy was unexpectedly low for both regimens and it appeared that neither could completely protect patients at high risk. Additional study is necessary to elucidate optimal therapy for preventing GI complications associated with NSAIA therapy in high-risk patients.

Nervous System Effects

Adverse nervous system effects of sulindac include dizziness and headache, which reportedly occur in about 3-9% of patients, nervousness in about 1-3% of patients, and less frequently, anxiety, vertigo, lightheadedness, drowsiness, somnolence, tiredness, insomnia, depression, psychic disturbances (including acute psychosis), seizures, syncope, aseptic meningitis, severe asthenia, and paresthesia. Neuritis has also been reported, but a causal relationship to sulindac has not been established.

Otic and Ocular Effects

Patients receiving sulindac have experienced tinnitus. Blurred vision, visual disturbances (e.g., amblyopia), and decreased hearing have also been reported. Disturbances of the retina and its vasculature have also been reported but not directly attributed to sulindac.

Dermatologic and Sensitivity Reactions

Rash reportedly occurs in about 3-9% of patients during sulindac therapy; pruritus, sore or dry mucous membranes, sweating, photosensitivity, and alopecia occur less frequently. Erythema multiforme, toxic epidermal necrolysis, exfoliative dermatitis, and Stevens-Johnson syndrome have also been reported. Adverse dermatologic effects may occur as part of a potentially fatal, apparent hypersensitivity syndrome. (See Cautions: Sensitivity Reactions.)

Hypersensitivity reactions, including anaphylaxis, angioedema, bronchospasm, and dyspnea have occasionally occurred during sulindac therapy. In a few patients, a potentially fatal, apparent hypersensitivity syndrome has been reported. The apparent hypersensitivity syndrome has resulted in death in a few patients and has included all or some of the following signs and symptoms: fever, chills, diaphoresis, flushing, rash (which may be pruritic or erythematous) or other dermatologic reactions (See Cautions: Dermatologic Effects), abnormalities in liver function test results (See Cautions: Hepatic Effects), hepatic failure, jaundice, pancreatitis, pneumonitis (with or without pleural effusion), tachypnea, cough (which may be nonproductive), rales, leukopenia, leukocytosis, eosinophilia, thrombocytopenia, increased erythrocyte sedimentation rate (ESR), positive antinuclear antibody (ANA) titer, disseminated intravascular coagulation, anemia, conjunctivitis, adenitis, arthralgia, arthritis, myalgia, cyanosis of the fingertips, swelling of the hands, fatigue, malaise, hypotension, chest pain, tachycardia, ECG (ST) changes/ischemia, facial edema, and renal dysfunction (including renal failure). Sulindac therapy should be discontinued if unexplained fever or other evidence of hypersensitivity occurs, and therapy with the drug should not be reinstituted.

Sulindac is contraindicated in patients in whom acute asthmatic attacks, urticaria, or rhinitis is precipitated by aspirin or other NSAIAs. Sensitivity reactions to the structurally different NSAIAs appear to be related mainly to inhibition of prostaglandin synthesis in patients with bronchospastic reactions; however, other mechanisms may be involved. For further discussion of cross-sensitivity of NSAIAs, see .

Hematologic Effects

Adverse hematologic effects of sulindac include thrombocytopenia, ecchymosis, purpura, leukopenia, agranulocytosis, neutropenia, and bone marrow depression (including aplastic anemia). Although hemolytic anemia and pancytopenia have been reported with sulindac therapy, a direct causal relationship to the drug has not been established.

Sulindac inhibits platelet aggregation and may prolong bleeding time but has no effect on prothrombin or whole blood clotting time. Sulindac may prolong prothrombin time in patients receiving oral anticoagulants. (See Drug Interactions: Anticoagulants and Thrombolytic Agents.)

Hepatic Effects

Severe hepatic reactions (sometimes fatal) including hepatitis, hepatic failure, cholestasis, and/or jaundice, with or without fever, have occurred during sulindac therapy, usually within the first 3 months of therapy. Rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure (sometimes fatal), have been reported in patients receiving NSAIAs. Abnormalities in liver function test results, particularly elevated serum alkaline phosphatase, may occur and are usually transient. In one patient receiving sulindac, jaundice, hepatomegaly, fever, facial and oral erythema, thrombocytopenia, and increased serum AST (SGOT), ALT (SGPT), and alkaline phosphatase concentrations occurred. In another patient receiving sulindac, jaundice, malaise, nausea, dark urine, light stools, severe itching (which responded to cholestyramine therapy), centrilobular hepatocellular damage (determined by liver biopsy), and increased serum concentrations of AST, ALT, alkaline phosphatase, and bilirubin occurred; the patient became anicteric and liver function test results returned to within normal limits 7 months after discontinuance of the drug. Rarely, fever and other evidence of a hypersensitivity reaction including abnormalities in one or more liver function test results have also occurred. Evaluation of liver function should be considered whenever a patient receiving sulindac develops unexplained fever, rash or other dermatologic reactions, or constitutional symptoms; therapy with the drug should be discontinued if unexplained fever or other evidence of hypersensitivity occurs. Elevated temperature and abnormalities in liver function test results generally have returned to within normal limits after discontinuance of the drug. Sulindac therapy should not be reinstituted in these patients.

Borderline elevations of one or more liver function test results may occur in up to 15% of patients treated with NSAIAs; meaningful (3 times the upper limit of normal) elevations of serum ALT or AST concentration have occurred in less than 1% of patients receiving NSAIAs in controlled clinical studies. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Patients who experience signs and/or symptoms suggestive of liver dysfunction or an abnormal liver function test result while receiving sulindac should be evaluated for evidence of the development of a severe hepatic reaction. Although such reactions are rare, sulindac should be discontinued if abnormal liver function test results persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash).

Renal Effects

Discoloration of urine, dysuria, proteinuria, and hematuria reportedly occur in less than 1% of patients during sulindac therapy. Renal impairment (including renal failure), interstitial nephritis, and nephrotic syndrome also have occurred during sulindac therapy. Papillary edema and mild interstitial nephritis occurred occasionally and papillary necrosis occurred infrequently during long-term administration of high dosages of sulindac in animals. Results of some studies have suggested that sulindac may be less likely to inhibit renal prostaglandin synthesis and thereby adversely affect renal function than most other currently available NSAIAs, but this has not been clearly established and further evaluation is needed.(See Cautions: Precautions and Contraindications.)

Symptomatic renal calculi consisting of sulindac metabolite concentrations exceeding 10% (range: 10-90%) have been reported rarely in patients receiving the drug. At least one patient continued to pass stones for 9 months after discontinuing the drug. Sulindac-induced renal calculi formation is distinct from the acute toxic renal reaction (i.e., acute flank pain and renal insufficiency) associated with suprofen use. Factors predisposing to urinary crystal formation appear to include increased urinary excretion of sulindac metabolites (related to the 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 exceeds 240 mL/hour or pH exceeds 5.8.

Other Adverse Effects

Although a causal relationship to sulindac has not been established, rarely, fulminant necrotizing fasciitis, which may be fatal and usually is associated with group A β-hemolytic streptococcal infection, has been reported in patients receiving NSAIAs. Pancreatitis (see Cautions: Precautions and Contraindications), vaginal bleeding, muscle weakness and epistaxis reportedly occur in less than 1% of sulindac-treated patients. Gynecomastia has been reported with sulindac therapy, but a direct causal relationship to the drug has not been established.

Precautions and Contraindications

Patients should be advised that sulindac, like other NSAIAs, is not free of potential adverse effects, including some that can cause discomfort, and that more serious effects (e.g., myocardial infarction, stroke, GI bleeding), which may require hospitalization and may even be fatal, also can occur. Patients also should be informed that, while NSAIAs may be commonly employed for conditions that are less serious, NSAIA therapy often is considered essential for the management of some diseases. Clinicians may wish to discuss with their patients the potential risks and likely benefits of NSAIA therapy, particularly when consideration is being given to use of these drugs in less serious conditions for which therapy without an NSAIA may represent an acceptable alternative to both the patient and clinician.

Patients should be advised to read the medication guide for NSAIAs that is provided to the patient each time the drug is dispensed.

NSAIAs increase the risk of serious adverse cardiovascular thrombotic events.(See Cautions: Cardiovascular Effects.) To minimize the potential risk of adverse cardiovascular events, the lowest effective dosage and shortest possible duration of therapy should be employed. Some clinicians suggest that it may be prudent to avoid use of NSAIAs whenever possible in patients with cardiovascular disease. Patients receiving NSAIAs (including those without previous symptoms of cardiovascular disease) should be monitored for the possible development of cardiovascular events throughout therapy. Patients should be informed about the signs and symptoms of serious cardiovascular toxicity (chest pain, dyspnea, weakness, slurring of speech) and instructed to seek immediate medical attention if such toxicity occurs. Sulindac should be avoided in patients with recent myocardial infarction unless the benefits of therapy are expected to outweigh the risk of recurrent cardiovascular thrombotic events; if sulindac is used in such patients, the patient should be monitored for cardiac ischemia.

There is no consistent evidence that concomitant use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs. Concomitant use of aspirin and an NSAIA increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving sulindac should be advised not to take aspirin.

Use of NSAIAs, including sulindac, can result in the onset of hypertension or worsening of preexisting hypertension; either of these occurrences may contribute to the increased incidence of cardiovascular events. Patients receiving NSAIAs may have an impaired response to diuretics (i.e., thiazide or loop diuretics), angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents. NSAIAs, including sulindac, should be used with caution in patients with hypertension. Blood pressure should be monitored closely during initiation of sulindac therapy and throughout therapy.

Because NSAIAs increase morbidity and mortality in patients with heart failure, the manufacturer states that sulindac should be avoided in patients with severe heart failure unless the benefits of therapy are expected to outweigh the risk of worsening heart failure; if sulindac is used in such patients, the patient should be monitored for worsening heart failure. Some experts state that use of NSAIAs should be avoided whenever possible in patients with reduced left ventricular ejection fraction and current or prior symptoms of heart failure. Patients receiving NSAIAs should be advised to inform their clinician if they experience symptoms of heart failure, including dyspnea, unexplained weight gain, and edema. Use of NSAIAs may diminish the cardiovascular effects of certain drugs used to treat heart failure and edema (e.g., diuretics, ACE inhibitors, angiotensin II receptor antagonists).(See Drug Interactions.)

The risk of potentially serious adverse GI effects should be considered in patients receiving sulindac, particularly in patients receiving chronic therapy with the drug.(See Cautions: GI Effects.) Sulindac should be used with caution and under close supervision in patients with a history of upper GI disease Since peptic ulceration and/or GI bleeding have been reported in patients receiving the drug, patients should be advised to promptly report signs or symptoms of GI ulceration or bleeding to their clinician.

Sulindac should be used with extreme caution and under close supervision in patients with a history of GI bleeding or peptic ulceration, and such patients should receive an appropriate ulcer preventive regimen. All patients considered at increased risk of potentially serious adverse GI effects (e.g., geriatric patients, those receiving high therapeutic dosages of NSAIAs, those with a history of peptic ulcer disease, those receiving anticoagulants or corticosteroids concomitantly) should be monitored closely for signs and symptoms of ulcer perforation or GI bleeding.To minimize the potential risk of adverse GI effects, the lowest effective dosage and shortest possible duration of therapy should be employed. For patients who are at high risk, therapy other than an NSAIA should be considered.

If pancreatitis is suspected in patients receiving sulindac, the drug should be discontinued and the patient appropriately evaluated, monitored, and treated; therapy with sulindac should not be reinstituted in these patients. The possibility of other causes of pancreatitis or conditions that may mimic pancreatitis should be ruled out.

Because severe and sometimes fatal hepatotoxic effects have occurred during sulindac therapy, the drug should be discontinued if signs or symptoms of a severe hepatic reaction, unexplained fever, or evidence of hypersensitivity occurs. (See Cautions: Dermatologic and Sensitivity Reactions and also Cautions: Hepatic Effects.)

Renal toxicity has been observed in patients in whom renal prostaglandins have a compensatory role in maintaining renal perfusion. Administration of an NSAIA to such patients may cause a dose-dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those taking an ACE inhibitor or angiotensin II antagonist concomitantly; and geriatric patients. Patients should be advised to consult their clinician promptly if unexplained weight gain or edema occurs. Recovery of renal function to pretreatment levels usually occurs following discontinuance of NSAIA therapy. Some clinicians recommend that renal function be monitored periodically in patients receiving long-term NSAIA therapy.

Sulindac has not been evaluated in patients with severe renal impairment, and the manufacturer states that use of sulindac is not recommended in patients with advanced renal disease. If sulindac is used in patients with severe renal impairment, close monitoring of renal function is recommended.

Symptomatic renal calculi containing sulindac metabolites have been reported rarely in patients receiving sulindac. Sulindac should be used with caution in patients with a history of renal lithiasis; if sulindac is used in these individuals, the patient should be well hydrated.

Sulindac should be used with caution in patients who may be adversely affected by a prolongation of bleeding time (e.g., patients receiving anticoagulant therapy), because the drug may inhibit platelet function. If signs and/or symptoms of anemia occur during therapy with sulindac, hemoglobin concentration and hematocrit should be determined.

Because NSAIAs have caused adverse ocular effects, patients who experience visual disturbances during sulindac therapy should have an ophthalmologic examination.

Sulindac is not a substitute for corticosteroid therapy. Use of corticosteroids during NSAIA therapy may increase the risk of GI ulceration and the drugs should be used concomitantly with caution. If corticosteroid dosage is decreased during sulindac therapy, it should be done gradually and patients should be observed for adverse effects, including adrenocortical insufficiency or symptomatic exacerbation of the inflammatory condition being treated.

The possibility that the antipyretic and anti-inflammatory effects of NSAIAs may mask the usual signs and symptoms of infection or other diseases should be considered. Sulindac should be used with extreme caution in patients with an existing infection, since rarely, fulminant necrotizing fasciitis, which may be fatal and usually is associated with group A β-hemolytic streptococcal infection, has been reported in patients receiving NSAIAs.

Anaphylactoid reactions have been reported in patients receiving NSAIAs. Patients receiving sulindac should be informed of the signs and symptoms of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat) and advised to seek immediate medical attention if an anaphylactoid reaction develops.

Serious skin reactions (e.g., exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis) can occur in patients receiving sulindac. These serious skin reactions may occur without warning; patients should be advised to consult their clinician if skin rash and blisters, fever, or other signs of hypersensitivity reaction (e.g., pruritus) occur. Sulindac should be discontinued at the first appearance of rash or any other sign of hypersensitivity.

Patients receiving long-term NSAIA therapy should have a complete blood cell count and chemistry profile performed periodically.

The manufacturers state that sulindac is contraindicated in patients with known hypersensitivity to the drug. In addition, NSAIAs, including sulindac, generally are contraindicated in patients in whom asthma, urticaria, or other sensitivity reactions are precipitated by aspirin or other NSAIAs, since there is potential for cross-sensitivity between NSAIAs and aspirin, and severe, often fatal, anaphylactic reactions may occur in such patients. Although NSAIAs generally are contraindicated in these patients, the drugs have occasionally been used in NSAIA-sensitive patients who have undergone desensitization. Because patients with asthma may have aspirin-sensitivity asthma, sulindac should be used with caution in patients with asthma. In patients with asthma, aspirin sensitivity is manifested principally as bronchospasm and usually is associated with nasal polyps; the association of aspirin sensitivity, asthma, and nasal polyps is known as the aspirin triad. For a further discussion of cross-sensitivity of NSAIAs,

Sulindac is contraindicated in the setting of CABG surgery.

Pediatric Precautions

Safety and efficacy of sulindac in children have not been established.

Geriatric Precautions

Sulindac should be used with caution in geriatric individuals 65 years of age or older since increasing age may be associated with increased risk of adverse effects. Geriatric individuals appear to tolerate GI ulceration and bleeding less well than other individuals, and many of the spontaneous reports of fatal adverse GI effects in patients receiving NSAIAs involve geriatric individuals. Sulindac is eliminated mainly by the kidneys and individuals with renal impairment may be at increased risk of toxic reactions to the drug. Because geriatric individuals frequently have decreased renal function, particular attention should be paid to sulindac dosage and it may be useful to monitor renal function in these patients.

Mutagenicity and Carcinogenicity

Although it is not known whether sulindac is mutagenic or carcinogenic in humans, studies have shown no evidence of carcinogenicity in animals.

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date in humans, sulindac has decreased fetal weight and increased fetal death in rats when given at dosages of 20 and 40 mg/kg daily (2.5 and 5 times the maximum recommended human dosage, respectively). Visceral and skeletal abnormalities observed in low incidence among rabbits in some teratology studies have not been reproducible in other studies. The drug also prolongs gestation and interferes with parturition in rats, probably as a result of inhibition of prostaglandin synthesis. Sulindac should not be used during the third trimester of pregnancy, since inhibitors of prostaglandin synthesis may have adverse effects on the fetus, including effects on the cardiovascular system (e.g., premature closure of the ductus arteriosus, degenerative myocardial changes, tricuspid incompetence, pulmonary hypertension, postnatal nonclosure of the ductus arteriosus [which may be resistant to medical management]), platelets (e.g., bleeding, including intracranial bleeding), renal function, (e.g., renal injury/dysgenesis which may result in prolonged or permanent renal failure or oligohydramnios), and GI system (e.g., bleeding, perforation, increased risk of necrotizing enterocolitis). Sulindac should be used during early pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

It is not known if sulindac affects fertility in humans.

Lactation

It is not known whether sulindac is distributed into milk in humans; however, the drug is distributed into the milk of lactating rats. Sulindac should not be used in nursing women and a decision should be made to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Protein-bound Drugs

Because sulindac and its sulfide metabolite are highly protein bound, they theoretically could be displaced from binding sites by, or they could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas. Although the manufacturers state that no clinically important interactions occurred in studies in which 400 mg of sulindac daily was given concomitantly with oral anticoagulants or oral antidiabetic agents, patients receiving sulindac with any protein-bound drug, especially patients receiving higher than recommended dosages of sulindac and those with impaired renal function or other metabolic dysfunction that might increase plasma concentrations of sulindac or its sulfide metabolite, should be observed for adverse effects.

Anticoagulants and Thrombolytic Agents

The effects of warfarin and NSAIAs on GI bleeding are synergistic. Concomitant use of sulindac and warfarin is associated with a higher risk of GI bleeding compared with use of either agent alone.

Sulindac reportedly enhances the hypoprothrombinemic effect of oral anticoagulants. If the drugs are used concurrently, prothrombin time should be carefully monitored and dosage of the oral anticoagulant adjusted accordingly; the patient should be observed for adverse effects. In addition, the ulcerogenic potential of sulindac and the effect of the drug on platelet function may further contribute to the hazard of concomitant therapy with any anticoagulant or thrombolytic agent (e.g., streptokinase).

Angiotensin-converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

There is some evidence that concomitant use of NSAIAs with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists may reduce the blood pressure response to the antihypertensive agent.

Diuretics

There is evidence from clinical studies and postmarketing reports that concomitant use of sulindac can reduce the natriuretic effects of furosemide or thiazide diuretics. This effect may be related to inhibition of renal prostaglandin synthesis. Concomitant use of sulindac and diuretics may increase the risk of renal failure.

Nonsteroidal Anti-inflammatory Agents

Administration of aspirin with sulindac decreases plasma concentrations of sulindac's active sulfide metabolite. In a double-blind study comparing the safety and efficacy of sulindac 300 or 400 mg daily given alone or with aspirin 2.4 g daily in patients with osteoarthritis, the addition of aspirin did not alter the types of clinical or laboratory adverse effects of sulindac, but the combination increased the incidence of adverse GI effects. Since the addition of aspirin to a regimen of sulindac also did not result in additional therapeutic benefit, concomitant use of aspirin or other NSAIAs and sulindac is not recommended by the manufacturers.

Concomitant use of aspirin and an NSAIA increases the risk for serious GI events. Because of the potential for increased adverse effects, patients receiving sulindac should be advised not to take aspirin. There is no consistent evidence that use of low-dose aspirin mitigates the increased risk of serious cardiovascular events associated with NSAIAs.

Concurrent administration of sulindac and diflunisal to healthy individuals resulted in a 33% reduction in plasma concentrations of sulindac's active sulfide metabolite.

Dimethylsulfoxide

Concomitant administration of dimethylsulfoxide (DMSO) and sulindac has reportedly decreased the plasma concentration of sulindac's active sulfide metabolite, which potentially could decrease the efficacy of sulindac. Concomitant therapy with the drugs also has reportedly caused peripheral neuropathy. Sulindac and DMSO should not be used concurrently.

Probenecid

Concomitant administration of probenecid and sulindac increases plasma concentrations of sulindac and its sulfone metabolite and slightly decreases peak plasma concentrations of the sulfide metabolite. Sulindac causes a slight reduction in the uricosuric action of probenecid, but this effect is probably not clinically important in most patients.

Methotrexate

The manufacturers state that sulindac and methotrexate should be used concomitantly with caution. Severe, sometimes fatal, toxicity has occurred following administration of an NSAIA concomitantly with methotrexate (principally high-dose therapy) in patients with various malignant neoplasms or rheumatoid arthritis. The toxicity was associated with elevated and prolonged blood concentrations of methotrexate. The exact mechanism of the interaction remains to be established, but it has been suggested that NSAIAs may inhibit renal elimination of methotrexate, possibly by decreasing renal perfusion via inhibition of renal prostaglandin synthesis or by competing for renal elimination. Further studies are needed to evaluate the interaction between NSAIAs and methotrexate.

Cyclosporine

Concomitant administration of an NSAIA and cyclosporine may increase the nephrotoxic effects of cyclosporine; this interaction may be related to inhibition of a renal prostaglandin (e.g., prostacyclin) synthesis. The manufacturers of sulindac state that an NSAIA and cyclosporine should be used concomitantly with caution and renal function should be closely monitored.

Lithium

Unlike other NSAIAs (e.g., diclofenac, indomethacin, mefenamic acid, naproxen, piroxicam), sulindac does not appear to increase serum lithium concentrations. Nevertheless, some clinicians recommend that when sulindac and lithium are used concurrently, patients should be observed for altered responses to lithium during initial stages of combined therapy and when sulindac is discontinued.

Other Drugs

Propoxyphene and acetaminophen reportedly do not affect plasma concentrations of sulindac or its sulfide metabolite.

Pharmacokinetics

Absorption

Approximately 90% of an oral dose of sulindac is absorbed. When sulindac is taken with food, the rate and extent of absorption are reduced, and peak plasma concentrations of the drug and its active sulfide metabolite are delayed. The manufacturers state that an aluminum and magnesium hydroxides antacid (Maalox) does not interfere with the bioavailability of sulindac, as determined by urinary excretion.

Following oral administration of sulindac, peak plasma concentrations of the sulfide metabolite occur in about 2 hours when the drug is administered in the fasting state and in about 3-4 hours when the drug is taken with food. Following oral administration of 200 mg of sulindac twice daily for 5 days in healthy fasting individuals, steady-state mean plasma concentrations of the sulfide metabolite are 3-6 mcg/mL. The manufacturers state that extensive enterohepatic circulation and reversible metabolism probably are principally responsible for sustained plasma concentrations of the sulfide metabolite in humans. (See Pharmacokinetics: Elimination.)

Plasma concentrations of the sulfide metabolite required for anti-inflammatory effect are not known.

Distribution

At concentrations of 1 mcg/mL, approximately 93% of sulindac and 98% of its sulfide metabolite are bound to human albumin.

Studies in rats indicate that radiolabeled sulindac is widely distributed in the body, and concentrations of radioactivity in plasma are greater than those in tissues such as liver, stomach, kidneys, and small intestine. In animals, sulindac and its metabolites distribute into bile; although the extent of biliary distribution varies considerably among various animal species, in all species, sulindac appears in highest concentrations, followed by the sulfone and then the sulfide metabolites. In rats, sulindac and its metabolites cross the placenta to a limited extent.

Although it is not known whether sulindac and/or its metabolites are distributed into human milk, in rats, the concentration of sulindac and its metabolites in milk is approximately 10-20% of that in plasma.

Elimination

The mean plasma half-lives of sulindac and its sulfide metabolite are reported to be 7.8 and 16.4 hours, respectively.

Sulindac is reduced to the sulfide metabolite (a reversible reaction) and oxidized to a pharmacologically inactive sulfone metabolite (an irreversible reaction); glucuronidation of the drug and its sulfide and sulfone metabolites also occurs. To a lesser extent, side chain hydroxylation and hydration of the double bond also occur.

Sulindac and its sulfide and sulfone metabolites undergo extensive enterohepatic circulation in animals and also in humans. In humans, enterohepatic circulation of sulindac and the sulfone metabolite is more extensive than that of the sulfide metabolite. In animals, total biliary excretion of sulindac is 16 times greater than that of the sulfide metabolite. In one study in healthy individuals, about 50% of a single oral dose of C-labeled sulindac was recovered in urine in 4 days, mainly as sulindac, the sulfone metabolite, and their conjugates; approximately 25% was excreted in feces in 4 days, mainly as the sulfone and sulfide metabolites. Less than 1% of a single oral dose of sulindac appears in urine as the sulfide metabolite.

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