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 extended-release tablets in patients with a recent mi unless the benefits are expected to outweigh the risk of recurrent cv thrombotic events. if etodolac extended-release tablets are used in patients with a recent mi, monitor patients for signs of cardiac ischemia. hypertension nsaids, including etodolac extended-release tablets, 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 etodolac extended-release tablets, 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 extended-release tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. if etodolac extended-release 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 extended-release tablets, 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. 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 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. 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 extended-release tablets in patients with advanced renal disease. therefore, treatment with etodolac extended-release tablets is not recommended in these patients with advanced renal disease. if etodolac extended-release tablet 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 etodolac extended-release tablets. etodolac extended-release tablets 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 etodolac extended-release tablets, 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 extended-release tablets. 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 extended-release tablets and evaluate the patient immediately. fetal toxicity premature closure of fetal ductus arteriosus avoid use of nsaids, including etodolac extended-release tablets, in pregnant women at about 30 weeks gestation and later. nsaids including etodolac extended-release tablets, 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 extended-release tablets, 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 extended-release tablets use to the lowest effective dose and shortest duration possible. consider ultrasound monitoring of amniotic fluid if etodolac extended-release tablets treatment extends beyond 48 hours. discontinue etodolac extended-release tablets if oligohydramnios occurs and follow up according to clinical practice [see precautions; pregnancy].

arthritis, the recommended starting dose of etodolac extended-release tablets is 400 to 1000 mg given orally once per day. as with other nsaids, the lowest effective dose should be sought for each patient. in chronic conditions, a therapeutic response to therapy with etodolac extended-release tablets is sometimes seen within one week of therapy, but most often is observed by two weeks.

time* infection pharyngitis pruritus rashes rhinitis tinnitus* *adverse events that were observed in < 1% of patients in the first 30 days of treatment with etodolac extended-release tablets in clinical trials. additional nsaid adverse experiences reported occasionally with nsaids or etodolac extended-release tablets include body as a whole - allergic reaction, anaphylactic/anaphylactoid reactions (including shock), chills, fever, sepsis cardiovascular system - congestive heart failure, flushing, palpitations, tachycardia, syncope, vasculitis (including necrotizing and allergic) digestive system - anorexia, cholestatic hepatitis, cholestatic jaundice, dry mouth, duodenitis, eructation, esophagitis, gastritis, gastric/peptic ulcers, glossitis, hepatic failure, hepatitis, hematemesis, intestinal ulceration, jaundice, liver necrosis, melena, pancreatitis, rectal bleeding, stomatitis hemic and lymphatic system - agranulocytosis, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, purpura, thrombocytopenia metabolic and nutritional - hyperglycemia in previously controlled diabetic patients nervous system - anxiety, confusion, depression, dream abnormalities, insomnia, nervousness, paresthesia, somnolence, tremors, vertigo respiratory system - asthma, dyspnea, pulmonary infiltration with eosinophilia skin and appendages - angioedema, cutaneous vasculitis with purpura, erythema multiforme, hyperpigmentation, sweating, urticaria, vesiculobullous rash special senses - blurred vision, photophobia, transient visual disturbances urogenital system - dysuria, elevated bun, oliguria/polyuria, proteinuria, renal failure, renal insufficiency, renal papillary necrosis, serum creatinine increase, urinary frequency other nsaid adverse reactions, which occur rarely are body as a whole - anaphylactic reactions, appetite changes, death cardiovascular system - arrhythmia, cerebrovascular accident, hypotension, myocardial infarction digestive system - colitis, esophagitis with or without stricture or cardiospasm, thirst, ulcerative stomatitis hemic and lymphatic system - aplastic anemia, lymphadenopathy metabolic and nutritional - change in weight nervous system - coma, convulsions, hallucinations, meningitis respiratory - bronchitis, pneumonia, respiratory depression, sinusitis skin and appendages - alopecia, exfoliative dermatitis, maculopapular rash, photosensitivity, skin peeling, stevens-johnson syndrome, toxic epidermal necrosis special senses - conjunctivitis, deafness, hearing impairment, taste perversion urogenital system - cystitis, hematuria, interstitial nephritis, leukorrhea, renal calculus, uterine bleeding irregularities

harmacokinetic parameters after the administration of etodolac tablets and etodolac extended-release tablets. table 2 shows the etodolac pharmacokinetic parameters in various populations. the data from patients with renal and hepatic impairment were obtained following administration of (immediate-release) etodolac tablets. table 1. mean (cv)%* pharmacokinetic parameters etodolac tablets etodolac extended-release tablets *% coefficient of variation extent of oral absorption (bioavailability) [f] ≥ 80% ≥ 80% time to peak concentration (tmax), h 1.4 (61%) 6.7 (47%) oral clearance (cl/f), ml/h/kg 49.1 (33%) 46.8 (37%) apparent volume of distribution (vd/f), ml/kg 393 (29%) 566 (26%) terminal half-life (t½), h 6.4 (22%) 8.4 (30%) table 2. mean (cv%)* pharmacokinetic parameters of etodolac in normal healthy adults and various special populations etodolac extended-release tablets etodolac tablets pk parameters normal healthy adults healthy males healthy females elderly (> 65 yr) hemodialysis†(24 to 65) (n=9) renal impairment† hepatic impairment† (18 to 44)‡(n=116) (18 to 43) (n=102) (25 to 44) (n=14) (66 to 88) (n=24 dialysis on dialysis off (46 to 73) (n=10) (34 to 60) (n=9) na = not available *% coefficient of variation†pharmacokinetic parameters obtained following administration of etodolac tablets‡age range (years) tmax, h 6.7 (47%)* 6.8 (45%) 4.5 (56%) 6.2 (51%) 1.7 (88%) 0.9 (67%) 2.1 (46%) 1.1 (15%) oral clearance, ml/h/kg (cl/f) 46.8 (37%) 46.8 (37%) 47.2 (38%) 51.6 (40%) na na 58.3 (19%) 42.0 (43%) apparent volume of distribution, ml/kg (vd/f) 566 (26%) 580 (26%) 459 (28%) 552 (34%) na na na na terminal half-life, h 8.4 (30%) 8.4 (29%) 7.6 (45%) 7.8 (26%) 5.1 (22%) 7.5 (34%) na 5.7 (24%) food/antacid effects food has no significant effect on the extent of etodolac extended-release tablets absorption, however, food significantly increased cmax (54%) following a 600 mg dose. the extent of absorption of etodolac is not affected when etodolac is administered with antacid. coadministration, with an antacid, decreases the peak concentration reached by about 15 to 20% with no measurable effect on time-to-peak. distribution the mean apparent volume of distribution (vd/f) of etodolac following administration of etodolac extended-release tablets is 566 ml/kg. etodolac is more than 99% bound to plasma proteins, primarily to albumin, and is independent of etodolac 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. metabolism etodolac metabolites do not contribute significantly to the pharmacological activity of etodolac extended-release tablets. following administration of immediate-release etodolac, several 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 14c-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. on chronic dosing, hydroxylated-etodolac metabolites do 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 role, if any, of a specific cytochrome p450 system in the metabolism of etodolac is unknown. 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 etodolac extended-release tablets dosing is 47 (±17) ml/h/kg. the terminal half-life (t½) of etodolac after etodolac extended-release tablets administration is 8.4 hours compared to 6.4 hours for etodolac tablets. approximately 1% of an etodolac tablet dose is excreted unchanged in the urine, with 72% of the dose excreted into the urine as parent drug plus metabolites: -etodolac, unchanged 1% -etodolac glucuronide 13% -hydroxylated metabolites (6-, 7-, and 8-oh) 5% -hydroxylated metabolite glucuronides 20% -unidentified metabolites 33% fecal excretion accounted for 16% of the dose. special populations geriatric in clinical studies, age was not shown to have any effect on half-life or protein binding, and demonstrated no change in expected drug accumulation. no dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics. the elderly may need dosage adjustment, however, as they may be more sensitive to antiprostaglandin effects than younger patients (see precautions, geriatric use). pediatric the pharmacokinetics of etodolac extended-release tablets were assessed in an open-label, 12-week clinical trial which included plasma sampling for population pharmacokinetics. seventy-two (72) patients, 6 to 16 years of age, with juvenile rheumatoid arthritis, received etodolac extended-release tablets in doses of 13.3 to 21.3 mg/kg given as 400 to 1000 mg once daily. the results from a population pharmacokinetic analysis based on the 59 subjects who completed the trial are as follows: table 3. pharmacokinetic parameter estimates for etodolac extended-release tablets in patients with juvenile rheumatoid arthritis parameter jra* (age: 6 to 16)† n = 59 *mean (cv) of parameter estimates predicted from population pharmacokinetics†age range (years) oral clearance (cl/f), ml/h/kg 47.8 (38%) apparent volume of distribution (vd/f), ml/kg 78.9 (61%) half-life (t½), h 12.1 (75%) while similar, the pharmacokinetic parameters for children with juvenile rheumatoid arthritis did not directly correlate with adult pharmacokinetic data in rheumatoid arthritis. in the population pharmacokinetic analysis, body weights below 50 kg were found to correlate with cl/f (see dosage and administration). 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 the pharmacokinetics of etodolac following administration of etodolac extended-release tablets have not been investigated in subjects with hepatic insufficiency. following administration of etodolac tablets, the plasma protein binding and disposition of total and free etodolac were unchanged in the presence of compensated hepatic cirrhosis. although no dosage adjustment is generally required in patients with chronic hepatic diseases, etodolac clearance is dependent on liver function and could be reduced in patients with severe hepatic failure. renal insufficiency the pharmacokinetics of etodolac following administration of etodolac extended-release tablets have not been investigated in subjects with renal insufficiency. etodolac renal clearance following administration of etodolac tablets was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance, 37 to 88 ml/min). 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. etodolac plasma protein binding decreases in patients with severe renal deficiency. etodolac should be used with caution in such patients because, as with other nsaids, it may further decrease renal function in some patients. etodolac is not significantly removed from the blood in patients undergoing hemodialysis.

observed in the adult arthritic patients in clinical trials. (see precautions, pediatric use).