s and precautions (5.11)]. aspirin clinical impact: controlled clinical studies showed that the concomitant use of nsaids and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of nsaids alone. in a clinical study, the concomitant use of an nsaid and aspirin was associated with a significantly increased incidence of gi adverse reactions as compared to use of the nsaid alone [see warnings and precautions (5.2)]. intervention: concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see warnings and precautions (5.11)]. indomethacin capsules are not substitute for low dose aspirin for cardiovascular protection. ace inhibitors, angiotensin receptor blockers, and beta-blockers clinical impact: • nsaids may diminish the antihypertensive effect of angiotensin converting enzyme (ace) inhibitors, angiotensin receptor blockers (arbs), or beta-blockers (including propranolol). • in patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an nsaid with ace inhibitors or arbs may result in deterioration of renal function, including possible acute renal failure. these effects are usually reversible. intervention: • during concomitant use of indomethacin capsules and ace-inhibitors, arbs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • during concomitant use of indomethacin capsules and ace-inhibitors or arbs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see warnings and precautions (5.6)] . • when these drugs are administered concomitantly, patients should be adequately hydrated. assess renal function at the beginning of the concomitant treatment and periodically thereafter. diuretics clinical impact: clinical studies, as well as post-marketing observations, showed that nsaids reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. this effect has been attributed to the nsaid inhibition of renal prostaglandin synthesis. it has been reported that the addition of triamterene to a maintenance schedule of indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. indomethacin capsules and triamterene should not be administered together. both indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. the potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. intervention: indomethacin and triamterene should not be administered together. during concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see warnings and precautions (5.6)]. digoxin clinical impact: the concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. intervention: during concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. lithium clinical impact: nsaids have produced elevations in plasma lithium levels and reductions in renal lithium clearance. the mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. this effect has been attributed to nsaid inhibition of renal prostaglandin synthesis. intervention: during concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. methotrexate clinical impact: concomitant use of nsaids and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). intervention: during concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. cyclosporine clinical impact: concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. intervention: during concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. nsaids and salicylates clinical impact: concomitant use of indomethacin with other nsaids or salicylates (e.g., diflunisal, salsalate) increases the risk of gi toxicity, with little or no increase in efficacy [see warnings and precautions (5.2)]. combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see clinical pharmacology (12.3)]. in some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. intervention: the concomitant use of indomethacin with other nsaids or salicylates, especially diflunisal, is not recommended. pemetrexed clinical impact: concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and gi toxicity (see the pemetrexed prescribing information). intervention: during concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 ml/min, monitor for myelosuppression, renal and gi toxicity. nsaids with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. in the absence of data regarding potential interaction between pemetrexed and nsaids with longer half-lives (e.g., meloxicam, nabumetone), patients taking these nsaids should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. probenecid clinical impact: when indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. intervention: during the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. when increases in the dose of indomethacin are made, they should be made carefully and in small increments. effects on laboratory tests indomethacin capsules reduces basal plasma renin activity (pra), as well as those elevations of pra induced by furosemide administration, or salt or volume depletion. these facts should be considered when evaluating plasma renin activity in hypertensive patients. false-negative results in the dexamethasone suppression test (dst) in patients being treated with indomethacin have been reported. thus, results of the dst should be interpreted with caution in these patients.

e 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 capsules in patients with a recent mi unless the benefits are expected to outweigh the risk of recurrent cv thrombotic events. if indomethacin capsules is used in patients with a recent mi, monitor patients for signs of cardiac ischemia. 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. 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 capsules in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. if indomethacin capsules is 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, 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.

tis; 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). 2. 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. 3. 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.

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 lightheadedness 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 leukopenia 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).

s and precautions (5.11)]. aspirin clinical impact: controlled clinical studies showed that the concomitant use of nsaids and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of nsaids alone. in a clinical study, the concomitant use of an nsaid and aspirin was associated with a significantly increased incidence of gi adverse reactions as compared to use of the nsaid alone [see warnings and precautions (5.2)]. intervention: concomitant use of indomethacin capsules and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see warnings and precautions (5.11)]. indomethacin capsules are not substitute for low dose aspirin for cardiovascular protection. ace inhibitors, angiotensin receptor blockers, and beta-blockers clinical impact: • nsaids may diminish the antihypertensive effect of angiotensin converting enzyme (ace) inhibitors, angiotensin receptor blockers (arbs), or beta-blockers (including propranolol). • in patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an nsaid with ace inhibitors or arbs may result in deterioration of renal function, including possible acute renal failure. these effects are usually reversible. intervention: • during concomitant use of indomethacin capsules and ace-inhibitors, arbs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. • during concomitant use of indomethacin capsules and ace-inhibitors or arbs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [ see warnings and precautions (5.6)] . • when these drugs are administered concomitantly, patients should be adequately hydrated. assess renal function at the beginning of the concomitant treatment and periodically thereafter. diuretics clinical impact: clinical studies, as well as post-marketing observations, showed that nsaids reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. this effect has been attributed to the nsaid inhibition of renal prostaglandin synthesis. it has been reported that the addition of triamterene to a maintenance schedule of indomethacin capsules resulted in reversible acute renal failure in two of four healthy volunteers. indomethacin capsules and triamterene should not be administered together. both indomethacin capsules and potassium-sparing diuretics may be associated with increased serum potassium levels. the potential effects of indomethacin capsules and potassium-sparing diuretics on potassium levels and renal function should be considered when these agents are administered concurrently. intervention: indomethacin and triamterene should not be administered together. during concomitant use of indomethacin capsules with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects. be aware that indomethacin and potassium-sparing diuretics may both be associated with increased serum potassium levels [see warnings and precautions (5.6)]. digoxin clinical impact: the concomitant use of indomethacin with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. intervention: during concomitant use of indomethacin capsules and digoxin, monitor serum digoxin levels. lithium clinical impact: nsaids have produced elevations in plasma lithium levels and reductions in renal lithium clearance. the mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. this effect has been attributed to nsaid inhibition of renal prostaglandin synthesis. intervention: during concomitant use of indomethacin capsules and lithium, monitor patients for signs of lithium toxicity. methotrexate clinical impact: concomitant use of nsaids and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). intervention: during concomitant use of indomethacin capsules and methotrexate, monitor patients for methotrexate toxicity. cyclosporine clinical impact: concomitant use of indomethacin capsules and cyclosporine may increase cyclosporine’s nephrotoxicity. intervention: during concomitant use of indomethacin capsules and cyclosporine, monitor patients for signs of worsening renal function. nsaids and salicylates clinical impact: concomitant use of indomethacin with other nsaids or salicylates (e.g., diflunisal, salsalate) increases the risk of gi toxicity, with little or no increase in efficacy [see warnings and precautions (5.2)]. combined use with diflunisal may be particularly hazardous because diflunisal causes significantly higher plasma levels of indomethacin [see clinical pharmacology (12.3)]. in some patients, combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. intervention: the concomitant use of indomethacin with other nsaids or salicylates, especially diflunisal, is not recommended. pemetrexed clinical impact: concomitant use of indomethacin capsules and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and gi toxicity (see the pemetrexed prescribing information). intervention: during concomitant use of indomethacin capsules and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 ml/min, monitor for myelosuppression, renal and gi toxicity. nsaids with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. in the absence of data regarding potential interaction between pemetrexed and nsaids with longer half-lives (e.g., meloxicam, nabumetone), patients taking these nsaids should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. probenecid clinical impact: when indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. intervention: during the concomitant use of indomethacin capsules and probenecid, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. when increases in the dose of indomethacin are made, they should be made carefully and in small increments. effects on laboratory tests indomethacin capsules reduces basal plasma renin activity (pra), as well as those elevations of pra induced by furosemide administration, or salt or volume depletion. these facts should be considered when evaluating plasma renin activity in hypertensive patients. false-negative results in the dexamethasone suppression test (dst) in patients being treated with indomethacin have been reported. thus, results of the dst should be interpreted with caution in these patients.

blished studies in pregnant mice, indomethacin produced maternal toxicity and death, increased fetal resorptions, and fetal malformations at 0.1 times the mrhd. when rat and mice dams were dosed during the last three days of gestation, indomethacin produced neuronal necrosis in the offspring at 0.1 and 0.05 times the mrhd, respectively [see data]. based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. in animal studies, administration of prostaglandin synthesis inhibitors such as indomethacin, resulted in increased pre- and post-implantation loss. clinical considerations labor or delivery there are no studies on the effects of indomethacin capsules during labor or delivery. in animal studies, nsaids, including indomethacin, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. data animal data reproductive studies were conducted in mice and rats at dosages of 0.5, 1, 2, and 4 mg/kg/day. except for retarded fetal ossification at 4 mg/kg/day (0.1 times [mice] and 0.2 times [rats] the mrhd on a mg/m2 basis, respectively) considered secondary to the decreased average fetal weights, no increase in fetal malformations was observed as compared with control groups. other studies in mice reported in the literature using higher doses (5 to 15 mg/kg/day, 0.1 to 0.4 times mrhd on a mg/m2 basis) have described maternal toxicity and death, increased fetal resorptions, and fetal malformations. in rats and mice, maternal indomethacin administration of 4 mg/kg/day (0.2 times and 0.1 times the mrhd on mg/m2 basis) during the last 3 days of gestation was associated with an increased incidence of neuronal necrosis in the diencephalon in the live-born fetuses however no increase in neuronal necrosis was observed at 2 mg/kg/day as compared to the control groups (0.1 times and 0.05 times the mrhd on a mg/m2 basis). administration of 0.5 or 4 mg/kg/day to offspring during the first 3 days of life did not cause an increase in neuronal necrosis at either dose level. 8.2 lactation risk summary based on available published clinical data, indomethacin may be present in human milk. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for indomethacin capsules and any potential adverse effects on the breastfed infant from the indomethacin capsules or from the underlying maternal condition. data in one study, levels of indomethacin in breast milk were below the sensitivity of the assay (<20 mcg/l) in 11 of 15 women using doses ranging from 75 mg orally to 300 mg rectally daily (0.94 to 4.29 mg/kg daily) in the postpartum period. based on these levels, the average concentration present in breast milk was estimated to be 0.27% of the maternal weight-adjusted dose. in another study indomethacin levels were measured in breast milk of eight postpartum women using doses of 75 mg daily and the results were used to calculate an estimated infant daily dose. the estimated infant dose of indomethacin from breast milk was less than 30 mcg/day or 4.5 mcg/kg/day assuming breast milk intake of 150 ml/kg/day. this is 0.5% of the maternal weight-adjusted dosage or about 3% of the neonatal dose for treatment of patent ductus arteriosus. 8.3 females and males of reproductive potential infertility females based on the mechanism of action, the use of prostaglandin-mediated nsaids, including indomethacin capsules, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. small studies in women treated with nsaids have also shown a reversible delay in ovulation. consider withdrawal of nsaids, including indomethacin capsules, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 pediatric use safety and effectiveness in pediatric patients 14 years of age and younger has not been established. indomethacin capsules should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk. in experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with indomethacin capsules, side effects in pediatric patients were comparable to those reported in adults. experience in pediatric patients has been confined to the use of indomethacin capsules. if a decision is made to use indomethacin for pediatric patients two years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. there have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. if indomethacin treatment is instituted, a suggested starting dose is 1 to 2 mg/kg/day given in divided doses. maximum daily dosage should not exceed 3 mg/kg/day or 150 to 200 mg/day, whichever is less. limited data are available to support the use of a maximum daily dosage of 4 mg/kg/day or 150 to 200 mg/day, whichever is less. as symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued. 8.5 geriatric use elderly patients, compared to younger patients, are at greater risk for nsaid-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. if the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see warnings and precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. indomethacin may cause confusion or rarely, psychosis [see adverse reactions (6.1)]; physicians should remain alert to the possibility of such adverse effects in the elderly. indomethacin and its metabolites are known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, use caution in this patient population, and it may be useful to monitor renal function [see clinical pharmacology (12.3)].

; 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 co2 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.

0.02 times the mrhd on a mg/m2 basis).

ly and the patients followed very closely for any possible adverse effects.