ssociated with nsaid use. the concurrent use of aspirin and an nsaid does increase the risk of serious gi events (see warnings, gastrointestinal effects - risk of ulceration, bleeding, and perforation ). 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 (see contraindications ). hypertension nsaids, including etodolac capsules and tablets, usp, 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 capsules and tablets,usp, should be used with caution in patients with hypertension. blood pressure (bp) should be monitored closely during the initiation of nsaid treatment and throughout the course of therapy. congestive heart failure and edema fluid retention and edema have been observed in some patients taking nsaids. etodolac capsules and tablets, usp should be used with caution in patients with fluid retention or heart failure. gastrointestinal effects - risk of ulceration, bleeding, and perforation nsaids, including etodolac capsules and tablets, usp, can cause serious gastrointestinal (gi) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, which can be fatal. these serious adverse events can occur at any time, with or without warning symptoms, in patients treated with nsaids. only one in five patients, who develop a serious upper gi adverse event on nsaid therapy, is symptomatic. upper gi ulcers, gross bleeding, or perforation caused by nsaids occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. these trends continue with longer duration of use, increasing the likelihood of developing a serious gi event at some time during the course of therapy. however, even short-term therapy is not without risk. 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 antiinflammatory 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 capsules and tablets, usp, in patients with advanced renal disease. therefore, treatment with etodolac capsules and tablets, usp is not recommended in these patients with advanced renal disease. if etodolac capsules and tablets, usp 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 capsules and tablets, usp. etodolac capsules and tablets, usp 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 capsules and tablets, usp, 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, the third trimester, as with other nsaids, etodolac capsules and tablets, usp should be avoided because it may cause premature closure of the ductus arteriosus (see precautions, pregnancy, nonteratogenic effects ).

000 mg/day have not been adequately evaluated in wellcontrolled 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 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.

ac. new patient complaints (with an incidence greater 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 to 500 mg of etodolac b.i.d. (i.e., 600 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 1 , flatulence 1 , nausea 1 , abdominal distension, epigastric pain, abnormal stools, constipation, gastritis, melena, vomiting. nervous system - asthenia/malaise 1 , dizziness 1 , depression, nervousness, fatigue. skin and appendages - pruritus, rash. special senses - blurred vision, tinnitus. urogenital system - dysuria, urinary frequency. musculoskeletal—arthralgia. drug-related patient complaints occurring in fewer than 3%, but more than 1%, are unmarked. 1 drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac.incidence less than 1% - probably causally related (adverse reactions reported only in worldwide postmarketing 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

the tablet or capsule formulation is at least 80%. etodolac does not undergo significant first-pass metabolism following oral administration. mean (± 1 sd) peak plasma concentrations (cmax) range from approximately 14 ± 4 to 37 ± 9 µg/ml after 200 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 tablets or capsules are 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%) * pharmacokinetic parameters of etodolac in normal healthy adults and various special populations pk parameters normal healthy adults (18-65) † healthy males (18-65) healthy females (27-65) elderly (>65) (70-84) hemodialysis (24-65) (n=9) renal impairment (46-73) hepatic impairment (34-60) (n=179) (n=176) (n=3) dialysis on dialysis off (n=10) (n=9) na = not available * % coefficient of variation † age range (years) tmax,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%) 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 14c-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 (t1/2) 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 populationsgeriatric 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 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.

atients with osteoarthritis of the knee, etodolac, in doses of 600 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.

. dispense in light-resistant container.