Sulindac Information
Sulindac ()
Sulindac () Description
Sulindac () is a non-steroidal, anti-inflammatory indene derivative designated chemically as (Z)-5-fluoro-2-methyl-1-[[-(methylsulfinyl)phenyl]methylene]-1-indene-3-acetic acid. It is not a salicylate, pyrazolone or propionic acid derivative. Its empirical formula is CHFOS, with a molecular weight of 356.42. Sulindac () , a yellow crystalline compound, is a weak organic acid practically insoluble in water below pH 4.5, but very soluble as the sodium salt or in buffers of pH 6 or higher.
Sulindac () tablets are available in 150 and 200 mg tablets for oral administration. Each tablet contains the following inactive ingredients: magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
Following absorption, Sulindac () undergoes two major biotransformations — reversible reduction to the sulfide metabolite, and irreversible oxidation to the sulfone metabolite. Available evidence indicates that the biological activity resides with the sulfide metabolite.
The structural formulas of Sulindac () and its metabolites are:
Sulindac () Clinical Pharmacology
Pharmacodynamics
Sulindac () tablets are a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activities in animal models. The mechanism of action, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
Pharmacokinetics
Sulindac () Indications And Usage
Carefully consider the potential benefits and risks of Sulindac () tablets and other treatment options before deciding to use Sulindac () tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ).
Sulindac () tablets are indicated for acute or long-term use in the relief of signs and symptoms of the following:
Sulindac () Contraindications
Sulindac () tablets are contraindicated in patients with known hypersensitivity to Sulindac () or the excipients (see ).
Sulindac () tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions to NSAIDs have been reported in such patients (see and ).
Sulindac () tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see ).
Sulindac () Warnings
CARDIOVASCULAR EFFECTS
Cardiovascular Thrombotic Events
Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (see ).
Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see ).
Hypertension
NSAIDs, including Sulindac () tablets, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including Sulindac () tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
Congestive Heart Failure and Edema
Fluid retention and edema have been observed in some patients taking NSAIDs. Sulindac () tablets should be used with caution in patients with fluid retention or heart failure.
Gastrointestinal Effects – Risk of Ulceration, Bleeding, and Perforation
NSAIDs, including Sulindac () tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3–6 months, and in about 2–4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Hepatic Effects
In addition to hypersensitivity reactions involving the liver, in some patients the findings are consistent with those of cholestatic hepatitis (see). As with other non-steroidal anti-inflammatory drugs, borderline elevations of one or more liver tests without any other signs and symptoms may occur in up to 15% of patients taking NSAIDs including Sulindac () tablets. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with Sulindac () tablets. Although such reactions as described above are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Sulindac () tablets should be discontinued.
In clinical trials with Sulindac () tablets, the use of doses of 600 mg/day has been associated with an increased incidence of mild liver test abnormalities (see for maximum dosage recommendation).
Renal Effects
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume-depleted, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Advanced Renal Disease
No information is available from controlled clinical studies regarding the use of Sulindac () tablets in patients with advanced renal disease. Therefore, treatment with Sulindac () tablets is not recommended in these patients with advanced renal disease. If Sulindac () tablets therapy must be initiated, close monitoring of the patient's renal function is advisable.
Anaphylactic/Anaphylactoid Reactions
As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to Sulindac () tablets. Sulindac () tablets should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see and ). Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs.
Skin Reactions
NSAIDs, including Sulindac () tablets, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
Hypersensitivity
Rarely, fever and other evidence of hypersensitivity (see ) including abnormalities in one or more liver function tests and severe skin reactions have occurred during therapy with Sulindac () tablets. Fatalities have occurred in these patients. Hepatitis, jaundice, or both, with or without fever, may occur usually within the first one to three months of therapy. Determinations of liver function should be considered whenever a patient on therapy with Sulindac () tablets develops unexplained fever, rash or other dermatologic reactions or constitutional symptoms. If unexplained fever or other evidence of hypersensitivity occurs, therapy with Sulindac () tablets should be discontinued. The elevated temperature and abnormalities in liver function caused by Sulindac () tablets characteristically have reverted to normal after discontinuation of therapy. Administration of Sulindac () tablets should not be reinstituted in such patients.
Pregnancy
In late pregnancy, as with other NSAIDs, Sulindac () tablets should be avoided because it may cause premature closure of the ductus arteriosus.
Sulindac () Precautions
General
Sulindac () tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of Sulindac () tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Hematological Effects
Anemia is sometimes seen in patients receiving NSAIDs, including Sulindac () tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Sulindac () tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Sulindac () tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Preexisting Asthma
Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, Sulindac () tablets should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Renal Calculi
Sulindac () metabolites have been reported rarely as the major or a minor component in renal stones in association with other calculus components. Sulindac () tablets should be used with caution in patients with a history of renal lithiasis, and they should be kept well hydrated while receiving Sulindac () tablets.
Pancreatitis
Pancreatitis has been reported in patients receiving Sulindac () tablets (see ). Should pancreatitis be suspected, the drug should be discontinued and not restarted, supportive medical therapy instituted, and the patient monitored closely with appropriate laboratory studies (e.g., serum and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, lipase, etc.). A search for other causes of pancreatitis as well as those conditions which mimic pancreatitis should be conducted.
Ocular Effects
Because of reports of adverse eye findings with non-steroidal anti-inflammatory agents, it is recommended that patients who develop eye complaints during treatment with Sulindac () tablets have ophthalmologic studies.
Hepatic Insufficiency
In patients with poor liver function, delayed, elevated and prolonged circulating levels of the sulfide and sulfone metabolites may occur. Such patients should be monitored closely; a reduction of daily dosage may be required.
SLE and Mixed Connective Tissue Disease
In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease, there may be an increased risk of aseptic meningitis (see ).
Information for Patients
Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
Laboratory Tests
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, Sulindac () tablets should be discontinued.
Drug Interactions
Pregnancy
Labor and Delivery
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Sulindac () tablets on labor and delivery in pregnant women are unknown.
Nursing Mothers
It is not known whether this drug is excreted in human milk; however, it is secreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Sulindac () tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population (see ).
Sulindac () tablets are known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function (see ).
Sulindac () Adverse Reactions
The following adverse reactions were reported in clinical trials or have been reported since the drug was marketed. The probability exists of a causal relationship between Sulindac () tablets and these adverse reactions. The adverse reactions which have been observed in clinical trials encompass observations in 1,865 patients, including 232 observed for at least 48 weeks.
Incidence Greater Than 1%
Incidence Less Than 1 in 100
Causal Relationship Unknown
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, sometimes with fatal outcome (see also ).
Other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians.
Sulindac () Management Of Overdosage
Cases of overdosage have been reported and rarely, deaths have occurred. The following signs and symptoms may be observed following overdosage: stupor, coma, diminished urine output and hypotension.
In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment.
Animal studies show that absorption is decreased by the prompt administration of activated charcoal and excretion is enhanced by alkalinization of the urine.
Sulindac () Dosage And Administration
Carefully consider the potential benefits and risks of Sulindac () tablets and other treatment options before deciding to use Sulindac () tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ).
After observing the response to initial therapy with Sulindac () tablets, the dose and frequency should be adjusted to suit an individual patient's needs.
Sulindac () tablets should be administered orally twice a day with food. The maximum dosage is 400 mg per day. Dosages above 400 mg per day are not recommended.
In osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, the recommended starting dosage is 150 mg twice a day. The dosage may be lowered or raised depending on the response.
A prompt response (within one week) can be expected in about one-half of patients with osteoarthritis, ankylosing spondylitis, and rheumatoid arthritis. Others may require longer to respond.
In acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis) and acute gouty arthritis, the recommended dosage is 200 mg twice a day. After a satisfactory response has been achieved, the dosage may be reduced according to the response. In acute painful shoulder, therapy for 7–14 days is usually adequate. In acute gouty arthritis, therapy for 7 days is usually adequate.
Sulindac () How Supplied
Sulindac () tablets USP are supplied as follows:
Sulindac () tablets, 150 mg, yellow, round, unscored, debossed MP 112
Sulindac () tablets, 200 mg, yellow, round, scored, debossed MP 116
Sulindac ()
Sulindac ()
Sulindac () Principal Display Panel - Mg Tablet Bottle Label
Sulindac () Principal Display Panel - Mg Tablet Bottle Label
