these drugs leading to elevated serum levels of cyclosporine, digoxin, methotrexate, and increased toxicity. nephrotoxicity associated with cyclosporine may also be enhanced. patients receiving these drugs who are given etodolac, or any other nsaid, and particularly those patients with altered renal function, should be observed for the development of the specific toxicities of these drugs. nsaids, such as etodolac, should not be administered prior to or concomitantly with high doses of methotrexate. nsaids have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. this may indicate that they could enhance the toxicity of methotrexate. in general, caution should be used when nsaids are administered concomitantly with methotrexate. diuretics etodolac has no apparent pharmacokinetic interaction when administered with furosemide or hydrochlorothiazide. nevertheless, clinical studies, as well as post-marketing observations have shown that etodolac can reduce the natriuretic effect of furosemide and thiazides in some patients with possible loss of blood pressure control. 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 insufficiency or failure (see warnings , renal effects ), as well as to assure diuretic efficacy. glyburide etodolac has no apparent pharmacokinetic interaction when administered with glyburide. lithium 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. careful monitoring of lithium levels is advised in the event nsaid dosage adjustments are required. phenylbutazone phenylbutazone causes increase (by about 80%) in the free fraction of etodolac. although in vivo studies have not been done to see if etodolac clearance is changed by co-administration of phenylbutazone, it is not recommended that they be co-administered. phenytoin etodolac has no apparent pharmacokinetic interaction when administered with phenytoin. warfarin 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 that of users of either drug alone. short-term pharmacokinetic studies have demonstrated that concomitant administration of warfarin and etodolac results in reduced protein binding of warfarin, but there was no change in the clearance of free warfarin. there was no significant difference in the pharmacodynamic effect of warfarin administered alone and warfarin administered with etodolac as measured by prothrombin time. thus, concomitant therapy with warfarin and etodolac should not require dosage adjustment of either drug. however, caution should be exercised because there have been a few spontaneous reports of prolonged prothrombin times, with or without bleeding, in etodolac-treated patients receiving concomitant warfarin therapy. close monitoring of such patients is therefore recommended.

nimize 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 etodolac, 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 to 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 etodolac tablets in patients with a recent mi unless the benefits are expected to outweigh the risk of recurrent cv thrombotic events. if etodolac tablets are used in patients with a recent mi, monitor patients for signs of cardiac ischemia. hypertension nsaids, including etodolac, 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 etodolac, 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 etodolac 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 etodolac tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. if etodolac tablets 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 etodolac, 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 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. physicians should inform patients about the signs and/or symptoms of serious gi toxicity and what steps to take if they occur. 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 and 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 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 greater 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. renal pelvic transitional epithelial hyperplasia, a spontaneous change occurring with variable frequency, was observed with increased frequency in treated male rats in a 2-year chronic study. caution is recommended in patients with pre-existing kidney disease. advanced renal disease no information is available from controlled clinical studies regarding the use of etodolac in patients with advanced renal disease. therefore, treatment with etodolac is not recommended in these patients with advanced renal disease. if etodolac 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 prior exposure to etodolac. etodolac 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. fatal reactions have been reported in such patients (see contraindications and precautions , general , pre-existing asthma ). emergency help should be sought in cases where an anaphylactoid reaction occurs. skin reactions nsaids, including etodolac, 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. drug reaction with eosinophilia and systemic symptoms (dress) drug reaction with eosinophilia and systemic symptoms (dress) has been reported in patients taking nsaids such as etodolac. some of these events have been fatal or life-threatening. dress typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. sometimes symptoms of dress may resemble an acute viral infection. eosinophilia is often present. because this disorder is variable in its presentation, other organ systems not noted here may be involved. it is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. if such signs or symptoms are present, discontinue etodolac and evaluate the patient immediately. pregnancy fetal toxicity premature closure of fetal ductus arteriosus avoid use of nsaids, including etodolac, in pregnant women at about 30 weeks gestation and later. nsaids including etodolac, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. oligohydramnios/neonatal renal impairment use of nsaids, including etodolac, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. these adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after nsaid initiation. oligohydramnios is often, but not always, reversible with treatment discontinuation. complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. in some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. if nsaid treatment is necessary between about 20 weeks and 30 weeks gestation, limit etodolac use to the lowest effective dose and shortest duration possible. consider ultrasound monitoring of amniotic fluid if etodolac treatment extends beyond 48 hours. discontinue etodolac if oligohydramnios occurs and follow up according to clinical practice (see precautions, pregnancy ) .

ions, 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 etodolac. if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), etodolac should be discontinued. hematological effects anemia is sometimes seen in patients receiving nsaids including etodolac. 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 etodolac, 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 etodolac who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. pre-existing asthma patients with asthma may have aspirin-sensitive asthma. the use of aspirin in patients with aspirin-sensitive asthmas 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, etodolac should not be administered to patients with this form of aspirin sensitivity and should be used with caution in all patients with pre-existing asthma.

ell-controlled trials. osteoarthritis and rheumatoid arthritis the recommended starting dose of etodolac for the management of the signs and symptoms of osteoarthritis or rheumatoid arthritis is: 300 mg b.i.d., t.i.d., or 400 mg b.i.d., or 500 mg b.i.d. a lower dose of 600 mg/day may suffice for long-term administration. physicians should be aware that doses above 1000 mg/day have not been adequately evaluated in well-controlled clinical trials. in chronic conditions, a therapeutic response to therapy with etodolac tablets is sometimes seen within one week of therapy, but most often is observed by two weeks. after a satisfactory response has been achieved, the patient’s dose should be reviewed and adjusted as required.

r than or equal to 1%) are listed below by body system. the incidences were determined from clinical trials involving 465 patients with osteoarthritis treated with 300 mg to 500 mg of etodolac b.i.d. (i.e., 600 mg/day to 1000 mg/day). incidence greater than or equal to 1% - probably causally related body as a whole chills and fever. digestive system dyspepsia (10%), abdominal pain 1 , diarrhea 2 , flatulence 3 , nausea 4 , abdominal distension, epigastric pain, abnormal stools, constipation, gastritis, melena, vomiting. nervous system asthenia/malaise 5 , dizziness 6 , depression, nervousness, fatigue. skin and appendages pruritus, rash. special senses blurred vision, tinnitus. urogenital system dysuria, urinary frequency. musculoskeletal arthralgia 1 drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac. 2 drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac. 3 drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac. 4 drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac. 5 drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac. 6 drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac. drug-related patient complaints occurring in fewer than 3%, but more than 1%, are unmarked. incidence less than 1% - probably causally related (adverse reactions reported only in worldwide post-marketing experience, not seen in clinical trials, are considered rarer and are italicized.) body as a whole allergic reaction, anaphylactic/anaphylactoid reactions (including shock). cardiovascular system hypertension, congestive heart failure, flushing, palpitations, syncope, vasculitis (including necrotizing and allergic). digestive system thirst, dry mouth, ulcerative stomatitis, anorexia, eructation, elevated liver enzymes, cholestatic hepatitis, hepatitis, cholestatic jaundice, duodenitis, jaundice, hepatic failure, liver necrosis, peptic ulcer with or without bleeding and/or perforation , intestinal ulceration, pancreatitis. hemic and lymphatic system ecchymosis, anemia, thrombocytopenia, bleeding time increased, agranulocytosis, hemolytic anemia, aplastic anemia, leukopenia, neutropenia, pancytopenia. metabolic and nutritional edema, serum creatinine increase, hyperglycemia in previously controlled diabetic patients. nervous system insomnia, somnolence. respiratory system asthma, pulmonary infiltration with eosinophilia. skin and appendages angioedema, sweating, urticaria, exfoliative dermatitis, vesiculobullous rash, cutaneous vasculitis with purpura, stevens-johnson syndrome, toxic epidermal necrolysis , leukocytoclastic vasculitis , hyperpigmentation , erythema multiforme. special senses photophobia, transient visual disturbances. urogenital system elevated bun, renal failure, renal insufficiency, renal papillary necrosis. incidence less than 1% - causal relationship unknown (medical events occurring under circumstances where causal relationship to etodolac is uncertain. these reactions are listed as alerting information for physicians.) body as a whole infection, headache. cardiovascular system arrhythmias, myocardial infarction, cerebrovascular accident. digestive system esophagitis with or without stricture or cardiospasm, colitis, gi discomfort, burning sensation, blood in stools, gastralgia, upper abdominal discomfort. metabolic and nutritional change in weight. nervous system paresthesia, confusion, irritability. respiratory system bronchitis, bronchospasm, dyspnea, pharyngitis, rhinitis, sinusitis. skin and appendages alopecia, maculopapular rash, photosensitivity, skin peeling. special senses conjunctivitis, deafness, taste perversion, loss of taste. urogenital system cystitis, hematuria, leukorrhea, renal calculus, interstitial nephritis, uterine bleeding irregularities, renal impairment. musculoskeletal muscle pain. additional adverse reactions reported with nsaids body as a whole sepsis, death cardiovascular system tachycardia digestive system gastric ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis hemic and lymphatic system lymphadenopathy nervous system anxiety, dream abnormalities, convulsions, coma, hallucinations, meningitis, tremors, vertigo respiratory system respiratory depression, pneumonia urogenital system oliguria/polyuria, proteinuria

these drugs leading to elevated serum levels of cyclosporine, digoxin, methotrexate, and increased toxicity. nephrotoxicity associated with cyclosporine may also be enhanced. patients receiving these drugs who are given etodolac, or any other nsaid, and particularly those patients with altered renal function, should be observed for the development of the specific toxicities of these drugs. nsaids, such as etodolac, should not be administered prior to or concomitantly with high doses of methotrexate. nsaids have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. this may indicate that they could enhance the toxicity of methotrexate. in general, caution should be used when nsaids are administered concomitantly with methotrexate. diuretics etodolac has no apparent pharmacokinetic interaction when administered with furosemide or hydrochlorothiazide. nevertheless, clinical studies, as well as post-marketing observations have shown that etodolac can reduce the natriuretic effect of furosemide and thiazides in some patients with possible loss of blood pressure control. 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 insufficiency or failure (see warnings , renal effects ), as well as to assure diuretic efficacy. glyburide etodolac has no apparent pharmacokinetic interaction when administered with glyburide. lithium 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. careful monitoring of lithium levels is advised in the event nsaid dosage adjustments are required. phenylbutazone phenylbutazone causes increase (by about 80%) in the free fraction of etodolac. although in vivo studies have not been done to see if etodolac clearance is changed by co-administration of phenylbutazone, it is not recommended that they be co-administered. phenytoin etodolac has no apparent pharmacokinetic interaction when administered with phenytoin. warfarin 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 that of users of either drug alone. short-term pharmacokinetic studies have demonstrated that concomitant administration of warfarin and etodolac results in reduced protein binding of warfarin, but there was no change in the clearance of free warfarin. there was no significant difference in the pharmacodynamic effect of warfarin administered alone and warfarin administered with etodolac as measured by prothrombin time. thus, concomitant therapy with warfarin and etodolac should not require dosage adjustment of either drug. however, caution should be exercised because there have been a few spontaneous reports of prolonged prothrombin times, with or without bleeding, in etodolac-treated patients receiving concomitant warfarin therapy. close monitoring of such patients is therefore recommended.

ductus arteriosus. oligohydramnios/neonatal renal impairment use of nsaids at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. data from observational studies regarding other potential embryofetal risks of nsaid use in women in the first or second trimesters of pregnancy are inconclusive. animal reproduction studies are not always predictive of human response. there are no adequate and well-controlled studies in pregnant women. etodolac should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. 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 etodolac, resulted in increased pre- and post-implantation loss. prostaglandins also have been shown to have an important role in fetal kidney development. in published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses.

olac does not undergo significant first-pass metabolism following oral administration. mean (± 1 sd) peak plasma concentrations (c max ) range from approximately 14 ± 4 mcg/ml to 37 ± 9 mcg/ml after 200 mg to 600 mg single doses and are reached in 80 ± 30 minutes (see table 1 for summary of pharmacokinetic parameters). the dose-proportionality based on the area under the plasma concentration-time curve (auc) is linear following doses up to 600 mg every 12 hours. peak concentrations are dose proportional for both total and free etodolac following doses up to 400 mg every 12 hours, but following a 600 mg dose, the peak is about 20% higher than predicted on the basis of lower doses. the extent of absorption of etodolac is not affected when etodolac is administered after a meal. food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration by 1.4 to 3.8 hours. table 1: mean (cv%) %coefficient of variation pharmacokinetic parameters of etodolac in normal healthy adults and various special populations pk parameters normal healthy adults (18-65) age range (years) (n=179) healthy males (18-65) (n=176) healthy females (27-65) (n=3) elderly (>65) (70-84) hemodialysis (24-65) (n=9) dialysis dialysis on off renal impairment (46-73) (n=10) hepatic impairment (34-60) (n=9) t max, h 1.4 (61%) 1.4 (60%) 1.7 (60%) 1.2 (43%) 1.7 (88%) 0.9 (67%) 2.1 (46%) 1.1 (15%) oral clearance, ml/h/kg (cl/f) 49.1 (33%) 49.4 (33%) 35.7 (28%) 45.7 (27%) na na 58.3 (19%) 42.0 (43%) apparent volume of distribution, ml/kg (vd/f) 393 (29%) 394 (29%) 300 (8%) 414 (38%) na na na na terminal half-life, h 6.4 (22%) 6.4 (22%) 7.9 (35%) 6.5 (24%) 5.1 (22%) 7.5 (34%) na 5.7 (24%) na = not available distribution the mean apparent volume of distribution (vd/f) of etodolac is approximately 390 ml/kg. etodolac is more than 99% bound to plasma proteins, primarily to albumin. the free fraction is less than 1% and is independent of etodolac total concentration over the dose range studied. it is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. data from in vitro studies, using peak serum concentrations at reported therapeutic doses in humans, show that the etodolac free fraction is not significantly altered by acetaminophen, ibuprofen, indomethacin, naproxen, piroxicam, chlorpropamide, glipizide, glyburide, phenytoin, and probenecid. metabolism etodolac is extensively metabolized in the liver. the role, if any, of a specific cytochrome p450 system in the metabolism of etodolac is unknown. several etodolac metabolites have been identified in human plasma and urine. other metabolites remain to be identified. the metabolites include 6-, 7-, and 8-hydroxylated-etodolac and etodolac glucuronide. after a single dose of 14 c-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. on chronic dosing, hydroxylated-etodolac metabolite does not accumulate in the plasma of patients with normal renal function. the extent of accumulation of hydroxylated-etodolac metabolites in patients with renal dysfunction has not been studied. the hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces. excretion the mean oral clearance of etodolac following oral dosing is 49 (± 16) ml/h/kg. approximately 1% of an etodolac dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite: - etodolac, unchanged 1% - etodolac glucuronide 13% - hydroxylated metabolites (6-, 7- and 8-oh) 5% - hydroxylated metabolite glucuronides 20% - unidentified metabolites 33% although renal elimination is a significant pathway of excretion for etodolac metabolites, no dosing adjustment in patients with mild to moderate renal dysfunction is generally necessary. the terminal half-life (t 1/2 ) of etodolac is 6.4 hours (22% cv). in patients with severe renal dysfunction or undergoing hemodialysis, dosing adjustment is not generally necessary. fecal excretion accounted for 16% of the dose. special populations geriatric in etodolac clinical studies, no overall differences in safety or effectiveness were observed between these patients and younger patients. in pharmacokinetic studies, age was shown not to have any effect on etodolac half-life or protein binding, and there was no change in expected drug accumulation. therefore, no dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics (see precautions , geriatric use ). etodolac is eliminated primarily by the kidney. 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 ). pediatric safety and effectiveness in pediatric patients below the age of 18 years have not been established. race pharmacokinetic differences due to race have not been identified. clinical studies included patients of many races, all of whom responded in a similar fashion. hepatic insufficiency etodolac is predominantly metabolized by the liver. in patients with compensated hepatic cirrhosis, the disposition of total and free etodolac is not altered. patients with acute and chronic hepatic diseases do not generally require reduced doses of etodolac compared to patients with normal hepatic function. however, etodolac clearance is dependent on liver function and could be reduced in patients with severe hepatic failure. etodolac plasma protein binding did not change in patients with compensated hepatic cirrhosis given etodolac. renal insufficiency etodolac pharmacokinetics have been investigated in subjects with renal insufficiency. etodolac renal clearance was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance 37 ml/min to 88 ml/min). furthermore, there were no significant differences in the disposition of total and free etodolac in these patients. however, etodolac should be used with caution in such patients because, as with other nsaids, it may further decrease renal function in some patients. in patients undergoing hemodialysis, there was a 50% greater apparent clearance of total etodolac, due to a 50% greater unbound fraction. free etodolac clearance was not altered, indicating the importance of protein binding in etodolac’s disposition. etodolac is not significantly removed from the blood in patients undergoing hemodialysis.

s with osteoarthritis of the knee, etodolac, in doses of 600 mg/day to 1000 mg/day, was better than placebo in two studies. the clinical trials in osteoarthritis used b.i.d. dosage regimens. rheumatoid arthritis in a 3-month study with 426 patients, etodolac 300 mg b.i.d. was effective in management of rheumatoid arthritis and comparable in efficacy to piroxicam 20 mg/day. in a long-term study with 1,446 patients in which 60% of patients completed 6 months of therapy and 20% completed 3 years of therapy, etodolac in a dose of 500 mg b.i.d. provided efficacy comparable to that obtained with ibuprofen 600 mg q.i.d. in clinical trials of rheumatoid arthritis patients, etodolac has been used in combination with gold, d-penicillamine, chloroquine, corticosteroids and methotrexate.

mptoms 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 ). 3. serious skin reactions, including dress: advise patients to stop taking etodolac immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible (see warnings ). 4. 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 ). 5. 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. 6. 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 ). 7. fetal toxicity: inform pregnant women to avoid use of etodolac and other nsaids starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. if treatment with etodolac is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours (see warnings, fetal toxicity ; precautions, pregnancy ).