ith nsaid use. the concurrent use of aspirin and an nsaid does increase the risk of serious gi events (see warnings: gastrointestinal effects ). two large, controlled, clinical trials of a cox-2 selective nsaid for the treatment of pain in the first 10 to 14 days following cabg surgery found an increased incidence of myocardial infarction and stroke (see contraindications ). hypertension nsaids, including indomethacin, can lead to onset of new hypertension or worsening of preexisting 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 indomethacin, 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. indomethacin should be used with caution in patients with fluid retention or heart failure. in a study of patients with severe heart failure and hyponatremia, indomethacin was associated with significant deterioration of circulatory hemodynamics, presumably due to inhibition of prostaglandin dependent compensatory mechanisms. gastrointestinal effects risk of ulceration, bleeding, and perforation nsaids, including indomethacin, can cause serious gastrointestinal (gi) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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 to 6 months, and in about 2 to 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. rarely, in patients taking indomethacin, intestinal ulceration has been associated with stenosis and obstruction. gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) have occurred. increased abdominal pain in ulcerative colitis patients or the development of ulcerative colitis and regional ileitis have been reported to occur rarely. nsaids should be prescribed with extreme caution in those with a 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. 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 over 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 with volume depletion, and the elderly. discontinuation of nsaid therapy is usually followed by recovery to the pretreatment state. increases in serum potassium concentration, including hyperkalemia, have been reported with use of indomethacin, even in some patients without renal impairment. in patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state (see precautions: drug interactions ). advanced renal disease no information is available from controlled clinical studies regarding the use of indomethacin in patients with advanced renal disease. therefore, treatment with indomethacin is not recommended in these patients with advanced renal disease. if indomethacin 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 indomethacin. indomethacin 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: general: preexisting asthma ). emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs. skin reactions nsaids, including indomethacin, 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. pregnancy in late pregnancy, as with other nsaids, indomethacin should be avoided because it may cause premature closure of the ductus arteriosus. ocular effects corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin. the prescribing physician should be alert to the possible association between the changes noted and indomethacin. it is advisable to discontinue therapy if such changes are observed. blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients where therapy is prolonged. central nervous system effects indomethacin may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. if severe cns adverse reactions develop, indomethacin should be discontinued. indomethacin may cause drowsiness; therefore, patients should be cautioned about engaging in activities requiring mental alertness and motor coordination, such as driving a car. indomethacin may also cause headache. headache which persists despite dosage reduction requires cessation of therapy with indomethacin.

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 values has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with indomethacin. if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), indomethacin should be discontinued. hematological effects anemia is sometimes seen in patients receiving nsaids, including indomethacin. 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 indomethacin, 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 indomethacin 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, indomethacin should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

te to severe ankylosing spondylitis; and moderate to severe osteoarthritis. suggested dosage: indomethacin capsules 25 mg b.i.d. or t.i.d. if this is well tolerated, increase the daily dosage by 25 mg or by 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150 mg to 200 mg is reached. doses above this amount generally do not increase the effectiveness of the drug. in patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. the total daily dose should not exceed 200 mg. in acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily. if minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and observe the patient closely. if severe adverse reactions occur, stop the drug. after the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued. careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions. as advancing years appear to increase the possibility of adverse reactions, indomethacin should be used with greater care in the elderly (see precautions: geriatric use ). • acute painful shoulder (bursitis and/or tendinitis). initial dose: 75 mg to 150 mg daily in 3 or 4 divided doses. the drug should be discontinued after the signs and symptoms of inflammation have been controlled for several days. the usual course of therapy is 7 to 14 days • acute gouty arthritis. suggested dosage: indomethacin capsules 50 mg t.i.d. until pain is tolerable. the dose should then be rapidly reduced to complete cessation of the drug. definite relief of pain has been reported within 2 to 4 hours. tenderness and heat usually subside in 24 to 36 hours, and swelling gradually disappears in 3 to 5 days.

none hematologic none hypersensitivity none genitourinary none miscellaneous none ________________________________________ 1 reactions occurring in 3% to 9% of patients treated with indomethacin. (those reactions occurring in less than 3% of the patients are unmarked.) incidence less than 1% gastrointestinal anorexia bloating (includes distention) flatulence peptic ulcer gastroenteritis rectal bleeding proctitis single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines intestinal ulceration associated with stenosis and obstruction gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) intestinal strictures (diaphragms) central nervous system anxiety (includes nervousness) muscle weakness involuntary muscle movements insomnia muzziness psychic disturbances including psychotic episodes mental confusion drowsiness light-headedness syncope paresthesia aggravation of epilepsy and parkinsonism depersonalization coma peripheral neuropathy convulsions dysarthria special senses ocular-corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin blurred vision diplopia hearing disturbances, deafness cardiovascular congestive heart failure hypertension hypotension tachycardia chest pain arrhythmia; palpitations metabolic edema weight gain fluid retention flushing or sweating hyperglycemia glycosuria hyperkalemia integumentary pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair stevens-johnson syndrome erythema multiforme toxic epidermal necrolysis hematologic leucopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation hypersensitivity acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever genitourinary hematuria vaginal bleeding proteinuria, nephrotic syndrome, interstitial nephritis bun elevation renal insufficiency, including renal failure miscellaneous epistaxis breast changes, including enlargement and tenderness, or gynecomastia causal relationship unknown other reactions have been reported but occurred under circumstances where a causal relationship could not be established. however, in these rarely reported events, the possibility cannot be excluded. therefore, these observations are being listed to serve as alerting information to physicians: cardiovascular: thrombophlebitis hematologic: although there have been several reports of leukemia, the supporting information is weak. genitourinary: urinary frequency 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, including indomethacin, sometimes with fatal outcome (see also precautions: general ).

ords relief of symptoms; it does not alter the progressive course of the underlying disease. indomethacin suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. improvement in patients treated with indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. indomethacin may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. in such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. indomethacin has been reported to diminish basal and co 2 stimulated cerebral blood flow in healthy volunteers following acute oral and intravenous administration. in one study, after one week of treatment with orally administered indomethacin, this effect on basal cerebral blood flow had disappeared. the clinical significance of this effect has not been established. indomethacin capsules have been found effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis (see indications and usage ). following single oral doses of indomethacin capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/ml, respectively, at about 2 hours. orally administered indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. a single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to a 50 mg indomethacin capsule when each was administered with food. indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. indomethacin undergoes appreciable enterohepatic circulation. the mean half-life of indomethacin is estimated to be about 4.5 hours. with a typical therapeutic regimen of 25 mg or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites, all in the unconjugated form. about 60 % of an oral dosage is recovered in urine as drug and metabolites (26 % as indomethacin and its glucuronide), and 33 % is recovered in feces (1.5 % as indomethacin). about 99% of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. indomethacin has been found to cross the blood-brain barrier and the placenta.