ents followed very closely for any possible adverse effects. the use of indomethacin in conjunction with aspirin or other salicylates is not recommended. controlled clinical studies have shown that the combined use of indomethacin and aspirin does not produce any greater therapeutic effect than the use of indomethacin alone. furthermore, in one of these clinical studies, the incidence of gastrointestinal side effects was significantly increased with combined therapy. (see precautions, drug interactions ).

inimize the potential risk for an adverse cv event in nsaid-treated patients, use the lowest effective dose for the shortest duration possible. physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous cv symptoms. patients should be informed about the 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, such as indomethacin, increases the risk of serious gastrointestinal (gi) events (see warnings ). status post coronary artery bypass graft (cabg) surgery 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. nsaids are contraindicated in the setting of cabg (see contraindications ). post-mi patients observational studies conducted in the danish national registry have demonstrated that patients treated with nsaids in the post-mi period were at increased risk of reinfarction, cv-related death, and all-cause mortality beginning in the first week of treatment. in this same cohort, the incidence of death in the first year post mi was 20 per 100 person years in nsaid-treated patients compared to 12 per 100 person years in non-nsaid exposed patients. although the absolute rate of death declined somewhat after the first year post-mi, the increased relative risk of death in nsaid users persisted over at least the next four years of follow-up. avoid the use of indomethacin extended-release capsules in patients with a recent mi unless the benefits are expected to outweigh the risk of recurrent cv thrombotic events. if indomethacin extended-release capsules are used in patients with a recent mi, monitor patients for signs of cardiac ischemia. hypertension nsaids, including indomethacin extended-release capsules, 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 extended-release capsules, 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. heart failure and edema the coxib and traditional nsaid trialists’ collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in cox-2 selective-treated patients and nonselective nsaid-treated patients compared to placebo-treated patients. in a danish national registry study of patients with heart failure, nsaid use increased the risk of mi, hospitalization for heart failure, and death. additionally, fluid retention and edema have been observed in some patients treated with nsaids. use of indomethacin may blunt the cv effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ace inhibitors, or angiotensin receptor blockers (arbs)] (see drug interactions ). avoid the use of indomethacin extended-release capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. if indomethacin extended-release capsules are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. gastrointestinal effects-risk of ulceration, bleeding, and perforation nsaids, including indomethacin extended-release capsules, 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 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 a 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 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. advanced renal disease no information is available from controlled clinical studies regarding the use of indomethacin extended-release capsules in patients with advanced renal disease. therefore, treatment with indomethacin extended-release capsules is not recommended in these patients with advanced renal disease. if indomethacin extended-release capsules therapy must be initiated, close monitoring of the patient’s renal function is advisable. anaphylactoid reactions as with other nsaids, anaphylactoid reactions may occur in patients without known prior exposure to indomethacin extended-release capsules. indomethacin extended-release capsules 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 anaphylactoid reaction occurs. skin reactions nsaids, including indomethacin extended-release capsules, 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 extended-release capsules should be avoided because it may cause premature closure of the ductus arteriosus.

reactions appear to correlate with the size of the dose of indomethacin in most patients, but not all. therefore, every effort should be made to determine the smallest effective dosage for the individual patient. always give indomethacin extended-release capsules usp 75 mg with food, immediately after meals, or with antacids to reduce gastric irritation. pediatric use: indomethacin extended-release capsules usp 75 mg ordinarily should not be prescribed for children 14 years of age and under (see warnings ). adult use: dosage recommendations for active stages of the following: moderate to severe rheumatoid arthritis including acute flares of chronic disease; moderate to severe ankylosing spondylitis; and moderate to severe osteoarthritis. the following information is provided as background only and refers to immediate-release indomethacin capsules (25 mg or 50 mg): suggested dosage: the following recommendations on dosing pertain to immediate-release indomethacin capsules usp, and provide important information regarding the dosage and administration of indomethacin. the prescriber should be aware of this information when considering and prescribing indomethacin extended-release capsules usp 75 mg. indomethacin capsules 25 mg b.i.d. or t.i.d. if this is well tolerated, increase the daily dosage by 25 or 50 mg, if required by continuing symptoms, at weekly intervals until a satisfactory response is obtained or until a total daily dose of 150-200 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, either orally or by rectal suppositories, 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. the following information refers to indomethacin extended-release capsules usp 75 mg: if indomethacin extended-release capsules usp 75 mg are used for initiating indomethacin treatment, one capsule daily should be the usual starting dose in order to observe patient tolerance since 75 mg per day is the maximum recommended starting dose for indomethacin (see above). if indomethacin extended-release capsules usp 75 mg are used to increase the daily dose, patients should be observed for possible signs and symptoms of intolerance since the daily increment will exceed the daily increment recommended for other dosage forms. for patients who require 150 mg of indomethacin per day and have demonstrated acceptable tolerance, indomethacin extended-release capsules usp 75 mg may be prescribed as one capsule twice 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 extended-release capsules should be used with greater care in the aged. 2. acute painful shoulder (bursitis and/or tendinitis): initial dose: 75 mg to 150 mg daily. when 150 mg is prescribed, give as one capsule twice daily. 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.

with or without vomiting dyspepsia (including indigestion, heartburn and epigastric pain) diarrhea abdominal distress or pain constipation anorexia bloating (includes distension) 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 pre-existing sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis ulcerative stomatitis toxic hepatitis and jaundice (some fatal cases have been reported) central nervous system headache (11.7%) dizziness vertigo somnolence depression and fatigue (including malaise and listlessness) 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 convulsion dysarthria special senses tinnitus 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 none hypertension hypotension tachycardia chest pain congestive heart failure arrhythmia; palpitations metabolic none edema weight gain fluid retention flushing or sweating hyperglycemia glycosuria hyperkalemia integumentary none pruritus rash; urticaria petechiae or ecchymosis exfoliative dermatitis erythema nodosum loss of hair stevens-johnson syndrome erythema multiforme toxic epidermal necrolysis hematologic none leukopenia bone marrow depression anemia secondary to obvious or occult gastrointestinal bleeding aplastic anemia hemolytic anemia agranulocytosis thrombocytopenic purpura disseminated intravascular coagulation hypersensitivity none acute anaphylaxis acute respiratory distress rapid fall in blood pressure resembling a shock-like state angioedema dyspnea asthma purpura angiitis pulmonary edema fever genitourinary none hematuria vaginal bleeding proteinuria nephrotic syndrome interstitial nephritis bun elevation renal insufficiency including renal failure miscellaneous none 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: a rare occurrence of fulminant necrotizing fasciitis, particularly in association with group a β-hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome (see also precautions, general ). cardiovascular: thrombophlebitis hematologic: although there have been several reports of leukemia, the supporting information is weak. genitourinary: urinary frequency

ymptoms; 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 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 extended-release capsules usp 75 mg are designed to release 25 mg of drug initially and the remaining 50 mg over approximately 12 hours (90% of dose absorbed by 12 hours). plasma concentrations of indomethacin fluctuate less and are more sustained following administration of indomethacin extended-release capsules usp 75 mg than following administration of 25 mg indomethacin capsules given at 4 to 6 hour intervals. in multiple-dose comparisons, the mean daily steady state plasma level of indomethacin attained with daily administration of indomethacin extended-release capsules usp 75 mg was indistinguishable from that following indomethacin 25 mg capsules given at 0, 6, and 12 hours daily. however, there was a significant difference in indomethacin plasma levels between the two dosage regimens especially after 12 hours. controlled clinical studies of safety and efficacy in patients with osteoarthritis have shown that one capsule of indomethacin extended-release capsules usp 75 mg was clinically comparable to one 25 mg indomethacin capsule t.i.d.; and in controlled clinical studies in patients with rheumatoid arthritis, one capsule of indomethacin extended-release capsules usp 75 mg taken in the morning and one in the evening were clinically indistinguishable from one 50 mg capsule of indomethacin t.i.d. 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 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 percent of an oral dosage is recovered in urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent is recovered in feces (1.5 percent 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.

indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. patients should be apprised of the importance of this follow-up (see warnings, gastrointestinal effects: risk of ulceration, bleeding, and perforation ). indomethacin extended-release capsules, like other nsaids, can cause serious skin side effects such as exfoliative dermatitis, sjs, and ten, which may result in hospitalization and even death. although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. heart failure and edema advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see warnings ). patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). if these occur, patients should be instructed to stop therapy and seek immediate medical therapy. patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). if these occur, patients should be instructed to seek immediate emergency help (see warnings ). in late pregnancy, as with other nsaids, indomethacin extended-release capsules should be avoided because it will cause premature closure of the ductus arteriosus.