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Cardiovascular Risk
Gastrointestinal Risk
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Sulindac is a non-steroidal, anti-inflammatory indene derivative designated chemically as (Z)-5-fluoro-2-methyl-1-[[ p -(methylsulfinyl)phenyl]methylene]-1 H -indene-3-acetic acid. It is not a salicylate, pyrazolone or propionic acid derivative. Its empirical formula is C 20 H 17 FO 3 S, 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.
CLINORIL * (Sulindac) is available in 150 and 200 mg tablets for oral administration. Each tablet contains the following inactive ingredients: cellulose, magnesium stearate, 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:
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CLINORIL is a non-steroidal anti-inflammatory drug, also possessing analgesic and antipyretic activities. Its mode of action, like that of other non-steroidal anti-inflammatory agents, is not known; however, its therapeutic action is not due to pituitary-adrenal stimulation. Inhibition of prostaglandin synthesis by the sulfide metabolite may be involved in the anti-inflammatory action of CLINORIL.
Sulindac is approximately 90% absorbed in man after oral administration. The peak plasma concentrations of the biologically active sulfide metabolite are achieved in about two hours when sulindac is administered in the fasting state, and in about three to four hours when sulindac is administered with food. The mean half-life of sulindac is 7.8 hours while the mean half-life of the sulfide metabolite is 16.4 hours. Sustained plasma levels of the sulfide metabolite are consistent with a prolonged anti-inflammatory action which is the rationale for a twice per day dosage schedule.
Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation relative to the sulfide metabolite in animals. Studies in man have also demonstrated that recirculation of the parent drug, sulindac, and its sulfone metabolite, is more extensive than that of the active sulfide metabolite. The active sulfide metabolite accounts for less than six percent of the total intestinal exposure to sulindac and its metabolites.
The primary route of excretion in man is via the urine as both sulindac and its sulfone metabolite (free and glucuronide conjugates). Approximately 50% of the administered dose is excreted in the urine, with the conjugated sulfone metabolite accounting for the major portion. Less than 1% of the administered dose of sulindac appears in the urine as the sulfide metabolite. Approximately 25% is found in the feces, primarily as the sulfone and sulfide metabolites.
The bioavailability of sulindac, as assessed by urinary excretion, was not changed by concomitant administration of an antacid containing magnesium hydroxide 200 mg and aluminum hydroxide 225 mg per 5 mL.
Because CLINORIL is excreted in the urine primarily as biologically inactive forms, it may possibly affect renal function to a lesser extent than other non-steroidal anti-inflammatory drugs, however, renal adverse experiences have been reported with CLINORIL (see ADVERSE REACTIONS ). In a study of patients with chronic glomerular disease treated with therapeutic doses of CLINORIL, no effect was demonstrated on renal blood flow, glomerular filtration rate, or urinary excretion of prostaglandin E 2 and the primary metabolite of prostacyclin, 6-keto-PGF 1 (alpha) . However, in other studies in healthy volunteers and patients with liver disease, CLINORIL was found to blunt the renal responses to intravenous furosemide, i.e., the diuresis, natriuresis, increments in plasma renin activity and urinary excretion of prostaglandins. These observations may represent a differentiation of the effects of CLINORIL on renal functions based on differences in pathogenesis of the renal prostaglandin dependence associated with differing dose-response relationships of different NSAIDs to the various renal functions influenced by prostaglandins. These observations need further clarification and in the interim, sulindac should be used with caution in patients whose renal function may be impaired (see WARNINGS ).
In healthy men, the average fecal blood loss, measured over a two-week period during administration of 400 mg per day of CLINORIL, was similar to that for placebo, and was statistically significantly less than that resulting from 4800 mg per day of aspirin.
In controlled clinical studies CLINORIL was evaluated in the following five conditions:
Carefully consider the potential benefits and risks of CLINORIL and other treatment options before deciding to use CLINORIL. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ).
CLINORIL is indicated for acute or long-term use in the relief of signs and symptoms of the following:
CLINORIL is contraindicated in patients with known hypersensitivity to sulindac or the excipients (see DESCRIPTION ).
CLINORIL 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 WARNINGS - Anaphylactic/Anaphylactoid Reactions , and PRECAUTIONS - Preexisting Asthma ).
CLINORIL is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).
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 GI WARNINGS ).
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 CONTRAINDICATIONS ).
NSAIDs, including CLINORIL, 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 CLINORIL, 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.
Fluid retention and edema have been observed in some patients taking NSAIDs. CLINORIL should be used with caution in patients with fluid retention or heart failure.
NSAIDs, including CLINORIL, 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 prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding 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.
In addition to hypersensitivity reactions involving the liver, in some patients the findings are consistent with those of cholestatic hepatitis. 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 CLINORIL. 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 CLINORIL. 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.), CLINORIL should be discontinued.
In clinical trials with CLINORIL, the use of doses of 600 mg/day has been associated with an increased incidence of mild liver test abnormalities (see DOSAGE AND ADMINISTRATION for maximum dosage recommendation).
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 nonsteroidal 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, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Caution should be used when initiating the treatment with CLINORIL in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with CLINORIL. Caution is also recommended in patients with preexisting kidney disease.
Sulindac metabolites have been reported rarely as the major or a minor component in renal stones in association with other calculus components. CLINORIL should be used with caution in patients with a history of renal lithiasis, and they should be kept well hydrated while receiving CLINORIL.
No information is available from controlled clinical studies regarding the use of CLINORIL in patients with advanced renal disease. Therefore, treatment with CLINORIL is not recommended in these patients with advanced renal disease. If CLINORIL therapy must be initiated, close monitoring of the patient's renal function is advisable.
Since CLINORIL is eliminated primarily by the kidneys, patients with significantly impaired renal function should be closely monitored; a lower daily dosage should be anticipated to avoid excessive drug accumulation.
As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to CLINORIL. CLINORIL 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 CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma ). Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs.
NSAIDs, including CLINORIL, 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.
Rarely, fever and other evidence of hypersensitivity (see ADVERSE REACTIONS ) including abnormalities in one or more liver function tests and severe skin reactions have occurred during therapy with CLINORIL. 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 CLINORIL develops unexplained fever, rash or other dermatologic reactions or constitutional symptoms. If unexplained fever or other evidence of hypersensitivity occurs, therapy with CLINORIL should be discontinued. The elevated temperature and abnormalities in liver function caused by CLINORIL characteristically have reverted to normal after discontinuation of therapy. Administration of CLINORIL should not be reinstituted in such patients.
In late pregnancy, as with other NSAIDs, CLINORIL should be avoided because it may cause premature closure of the ductus arteriosus.
CLINORIL cannot be expected to substitute for corticosteroids or to treate 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 CLINORIL in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Anemia is sometimes seen in patients receiving NSAIDs, including CLINORIL. 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 CLINORIL, 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 CLINORIL who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
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 nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, CLINORIL should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.
Pancreatitis has been reported in patients receiving CLINORIL (see ADVERSE REACTIONS ). 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.
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 CLINORIL have ophthalmologic studies.
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.
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.
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, CLINORIL should be discontinued.
Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors and angiotensin II antagonists. These interactions should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors or angiotensin II antagonists. In some patients with compromised renal function, the co-administration of an NSAID and an ACE-inhibitor or an angiotensin II antagonist may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible.
Acetaminophen had no effect on the plasma levels of sulindac or its sulfide metabolite.
When CLINORIL is administered with aspirin, its protein binding is reduced, although the clearance of free CLINORIL is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of sulindac and aspirin is not generally recommended because of the potential of increased adverse effects.
The concomitant administration of aspirin with sulindac significantly depressed the plasma levels of the active sulfide metabolite. A double-blind study compared the safety and efficacy of CLINORIL 300 or 400 mg daily given alone or with aspirin 2.4 g/day for the treatment of osteoarthritis. The addition of aspirin did not alter the types of clinical or laboratory adverse experiences for CLINORIL; however, the combination showed an increase in the incidence of gastrointestinal adverse experiences. Since the addition of aspirin did not have a favorable effect on the therapeutic response to CLINORIL, the combination is not recommended.
Administration of non-steroidal anti-inflammatory drugs concomitantly with cyclosporine has been associated with an increase in cyclosporine-induced toxicity, possibly due to decreased synthesis of renal prostacyclin. NSAIDs should be used with caution in patients taking cyclosporine, and renal function should be carefully monitored.
The concomitant administration of CLINORIL and diflunisal in normal volunteers resulted in lowering of the plasma levels of the active sulindac sulfide metabolite by approximately one-third.
Clinical studies, as well as post marketing observations, have shown that CLINORIL can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS , Renal Effects ), as well as to assure diuretic efficacy.
DMSO should not be used with sulindac. Concomitant administration has been reported to reduce the plasma levels of the active sulfide metabolite and potentially reduce efficacy. In addition, this combination has been reported to cause peripheral neuropathy.
NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
The concomitant use of CLINORIL with other NSAIDs is not recommended due to the increased possibility of gastrointestinal toxicity, with little or no increase in efficacy.
Although sulindac and its sulfide metabolite are highly bound to protein, studies in which CLINORIL was given at a dose of 400 mg daily have shown no clinically significant interaction with oral anticoagulants. However, patients should be monitored carefully until it is certain that no change in their anticoagulant dosage is required. Special attention should be paid to patients taking higher doses than those recommended and to patients with renal impairment or other metabolic defects that might increase sulindac blood levels. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
Although sulindac and its sulfide metabolite are highly bound to protein, studies in which CLINORIL was given at a dose of 400 mg daily, have shown no clinically significant interaction with oral hypoglycemic agents. However, patients should be monitored carefully until it is certain that no change in their hypoglycemic dosage is required. Special attention should be paid to patients taking higher doses than those recommended and to patients with renal impairment or other metabolic defects that might increase sulindac blood levels.
Probenecid given concomitantly with sulindac had only a slight effect on plasma sulfide levels, while plasma levels of sulindac and sulfone were increased. Sulindac was shown to produce a modest reduction in the uricosuric action of probenecid, which probably is not significant under most circumstances.
Propoxyphene hydrochloride had no effect on the plasma levels of sulindac or its sulfide metabolite.
CLINORIL is not recommended for use in pregnant women, since safety for use has not been established. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women.
Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
The known effects of drugs of this class on the human fetus during the third trimester of pregnancy include: constriction of the ductus arteriosus prenatally, tricuspid incompetence, and pulmonary hypertension; non-closure of the ductus arteriosus postnatally which may be resistant to medical management; myocardial degenerative changes, platelet dysfunction with resultant bleeding, intracranial bleeding, renal dysfunction or failure, renal injury/dysgenesis which may result in prolonged or permanent renal failure, oligohydramnios, gastrointestinal bleeding or perforation, and increased risk of necrotizing enterocolitis.
In reproduction studies in the rat, a decrease in average fetal weight and an increase in numbers of dead pups were observed on the first day of the postpartum period at dosage levels of 20 and 40 mg/kg/day (2 ½ and 5 times the usual maximum daily dose in humans), although there was no adverse effect on the survival and growth during the remainder of the postpartum period. CLINORIL prolongs the duration of gestation in rats, as do other compounds of this class. Visceral and skeletal malformations observed in low incidence among rabbits in some teratology studies did not occur at the same dosage levels in repeat studies, nor at a higher dosage level in the same species.
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 CLINORIL on labor and delivery in pregnant women are unknown.
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 CLINORIL, 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.
Safety and effectiveness in pediatric patients have not been established.
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 WARNINGS , Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation ).
This drug is 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 WARNINGS , Renal Effects ).
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 CLINORIL 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%
The most frequent types of adverse reactions occurring with CLINORIL are gastrointestinal; these include gastrointestinal pain (10%), dyspepsia *** , nausea *** with or without vomiting, diarrhea *** , constipation *** , flatulence, anorexia and gastrointestinal cramps.
Dermatologic
Dizziness *** , headache *** , nervousness.
Special Senses
Miscellaneous
Incidence Less Than 1 in 100
Gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding have been reported. GI perforation and intestinal strictures (diaphragms) have been reported rarely.
Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis; hepatic failure.
There have been rare reports of sulindac metabolites in common bile duct "sludge" and in biliary calculi in patients with symptoms of cholecystitis who underwent a cholecystectomy.
Pancreatitis (see PRECAUTIONS ).
Dermatologic
Stomatitis, sore or dry mucous membranes, alopecia, photosensitivity.
Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis have been reported.
Congestive heart failure, especially in patients with marginal cardiac function; palpitation; hypertension.
Hematologic
Thrombocytopenia; ecchymosis; purpura; leukopenia; agranulocytosis; neutropenia; bone marrow depression, including aplastic anemia; hemolytic anemia; increased prothrombin time in patients on oral anticoagulants (see PRECAUTIONS ).
Urine discoloration; dysuria; vaginal bleeding; hematuria; proteinuria; crystalluria; renal impairment, including renal failure; interstitial nephritis; nephrotic syndrome.
Renal calculi containing sulindac metabolites have been observed rarely.
Depression; psychic disturbances including acute psychosis.
Vertigo; insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis.
Special Senses
Blurred vision; visual disturbances; decreased hearing; metallic or bitter taste.
Anaphylaxis; angioneurotic edema; bronchial spasm; dyspnea.
A potentially fatal apparent hypersensitivity syndrome has been reported. This syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other dermatologic reactions -- see above), conjunctivitis, involvement of major organs (changes in liver function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia, leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia, renal impairment, including renal failure), and other less specific findings (adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest pain, tachycardia).
Causal Relationship Unknown
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A (beta)-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, sometimes with fatal outcome (see also PRECAUTIONS , General ).
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.
Special Senses
Disturbances of the retina and its vasculature.
Miscellaneous
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.
Carefully consider the potential benefits and risks of CLINORIL and other treatment options before deciding to use CLINORIL. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ).
After observing the response to initial therapy with CLINORIL, the dose and frequency should be adjusted to suit an individual patient's needs.
CLINORIL 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.
No. 3360 -- Tablets CLINORIL 150 mg are bright yellow, hexagon-shaped, compressed tablets, coded MSD 941 on one side and CLINORIL on the other. They are supplied as follows:
NDC 0006-0941-68 in bottles of 100
(6505-01-071-5559, 150 mg 100's).
No. 3353 -- Tablets CLINORIL 200 mg are bright yellow, hexagon-shaped, scored, compressed tablets, coded MSD 942 on one side and CLINORIL on the other. They are supplied as follows:
NDC 0006-0942-68 in bottles of 100
(6505-01-072-3426, 200 mg 100's).
Distributed by:
MERCK & CO., INC., Whitehouse Station, NJ 08889, USA
Manufactured by:
MERCK SHARP & DOHME Pty., Ltd.
South Granville, NSW, Australia 2142.
9676101 Issued July 2005
COPYRIGHT © 1988, 2005 MERCK & CO., Inc.
All rights reserved
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(See the end of this Medication Guide for a list of prescription NSAID medicines.)
NSAID medicines may increase the chance of a heart attack or stroke that can lead to death. This chance increases:
NSAID medicines should never be used right before or after a heart surgery called a "coronary artery bypass graft (CABG)."
NSAID medicines can cause ulcers and bleeding in the stomach and intestines at any time during treatment.
NSAID medicines should only be used:
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:
Do not take an NSAID medicine:
Tell your healthcare provider:
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Get emergency help right away if you have any of the following symptoms:
Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.
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This Medication Guide has been approved by the U.S. Food and Drug Administration.