NURSING MOTHERS SECTION.

Nursing Mothers It is not known whether etodolac is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from etodolac, decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS In patients taking etodolac or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1-10% of patients are: Gastrointestinal experiences including: abdominal pain, constipation, diarrhea, dyspepsia, flatulence, gross bleeding/perforation, heartburn, nausea, GI ulcers (gastric/duodenal), vomiting. Other events including: abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritis, rashes, tinnitus. Adverse-reaction information for etodolac was derived from 2,629 arthritic patients treated with etodolac in double-blind and open-label clinical trials of to 320 weeks in duration and worldwide postmarketing surveillance studies. In clinical trials, most adverse reactions were mild and transient. The discontinuation rate in controlled clinical trials, because of adverse events, was up to 10% for patients treated with etodolac. 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 whole Chills and fever. Digestive system Dyspepsia (10%), abdominal pain, diarrhea, flatulence, nausea, constipation, gastritis, melena, vomiting. Nervous system Asthenia/malaise, dizziness, depression, nervousness. Skin and appendages Pruritus, rash. Special senses Blurred vision, tinnitus. Urogenital system Dysuria, urinary frequency. Drug-related patient complaints occurring in 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 postmarketing experience, not seen in clinical trials, are considered rarer and are italicized.) Body as 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, 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, vesiculobullous rash, cutaneous vasculitis with purpura, Stevens-Johnson Syndrome, toxic epidermal necrolysis, 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 whole Infection, headache. Cardiovascular system Arrhythmias, myocardial infarction, cerebrovascular accident. Digestive system Esophagitis with or without stricture or cardiospasm, colitis. Metabolic and nutritional Change in weight. Nervous system Paresthesia, confusion. Respiratory system Bronchitis, dyspnea, pharyngitis, rhinitis, sinusitis. Skin and appendages Alopecia, maculopapular rash, photosensitivity, skin peeling. Special senses Conjunctivitis, deafness, taste perversion. Urogenital system Cystitis, hematuria, leukorrhea, renal calculus, interstitial nephritis, uterine bleeding irregularities. Additional Adverse Reactions Reported with NSAIDS Body as 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.

BOXED WARNING SECTION.

BOXED WARNING. Cardiovascular RiskNSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See WARNINGS).Etodolac is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (See WARNINGS).Gastrointestinal RiskNSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events (See WARNINGS). NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See WARNINGS).. Etodolac is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (See WARNINGS).. NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal (GI) events (See WARNINGS).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, and Impairment of Fertility No carcinogenic effect of etodolac was observed in mice or rats receiving oral doses of 15 mg/kg/day (45 to 89 mg/m2, respectively) or less for periods of years or 18 months, respectively. Etodolac was not mutagenic in in vitro testsperformed with S. typhimurium and mouse lymphoma cells as well as in an in vivo mouse micronucleus test. However, data from the invitro human peripheral lymphocyte test showed an increase in the number of gaps (3.0 to 5.3% unstained regions in the chromatid without dislocation) among the etodolac-treated cultures (50 to 200 mcg/mL) compared to negative controls (2.0%); no other difference was noted between the controls and drug-treated groups. Etodolac showed no impairment of fertility in male and female rats up to oral doses of 16 mg/kg (94 mg/m2). However, reduced implantation of fertilized eggs occurred in the mg/kg group.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY Pharmacodynamics Etodolac is nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of etodolac, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition. Etodolac is racemic mixture of [-]R- and [+]S-etodolac. As with other NSAIDs, it has been demonstrated in animals that the [+]S-form is biologically active. Both enantiomers are stable and there is no [-]R to [+]S conversion in vivo. Pharmacokinetics Absorption The systemic bioavailability of etodolac is 100% as compared to solution and at least 80% as determined from mass balance studies. Etodolac is well absorbed and had relative bioavailability of 100% when 200 mg capsules were compared with solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from either the tablet or capsule formulation is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (+- SD) peak plasma concentrations (Cmax) range from approximately 14 +- to 37 +- ug/mL after 200 to 600 mg single doses and are reached in 80 +- 30 minutes (see Table 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 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 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 +%Coefficient of variation AgeRange (years) NA= not available PKParametersNormalHealthyAdults(18-65)(n=179) HealthyMales(18-65) (n=176) HealthyFemales(27-65) (n=3) Elderly(>65)(70-84) Hemodialysis(24-65)(n=9) RenalImpairment(46-73) (n=10) HepaticImpairment(34-60) (n=9) DialysisOn DialysisOff Tmax, 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%) N/A N/A 58.3(19%) 42.0(43%) Apparent Volume of Distribution, mL/kg (Vd/F) 393(29%) 394(29%) 300(8%) 414(38%) N/A N/A N/A N/A Terminal Half-Life,h 6.4(22%) 6.4(22%) 7.9(35%) 6.5(24%) 5.1(22%) 7.5(34%) N/A 5.7(24%) Distribution The mean apparent volume of distribution (Vd/F) of etodolacis 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 independentof etodolac total concentration over the dose range studied. It is not knownwhether etodolac is excreted in human milk; however, based on its physical-chemicalproperties, excretion into breast milk is expected. Data from invitro studies, using peak serum concentrations at reported therapeuticdoses in humans, show that the etodolac free fraction is not significantlyaltered 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 specific cytochrome P450 system in the metabolism of etodolacis unknown. Several etodolac metabolites have been identified in human plasmaand urine. Other metabolites remain to be identified. The metabolites include6-, 7-, and 8-hydroxylated-etodolac and etodolac glucuronide. After singledose of 14C-etodolac, hydroxylated metabolites accounted for less than 10%of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolitedoes not accumulate in the plasma of patients with normal renal function.The extent of accumulation of hydroxylated-etodolac metabolites in patientswith renal dysfunction has not been studied. The hydroxylated-etodolac metabolitesundergo further glucuronidation followed by renal excretion and partial eliminationin 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 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 theage 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 ina 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 50% greater apparent clearance of total etodolac, due to 50% greater unbound fraction. Free etodolac clearance was not altered, indicating the importance of protein binding in etodolacs disposition. Etodolac is not significantly removed from the blood in patients undergoing hemodialysis.

OVERDOSAGE SECTION.

OVERDOSAGE Symptoms following acute NSAID overdose are usually limitedto lethargy, drowsiness, nausea, vomiting, and epigastric pain, which aregenerally reversible with supportive care. Gastrointestinal bleeding can occurand coma has occurred following massive ibuprofen or mefenamic-acid overdose.Hypertension, acute renal failure, and respiratory depression may occur butare rare. Anaphylactoid reactions have been reported with therapeutic ingestionof NSAIDs, and may occur following overdose. Patientsshould be managed by symptomatic and supportive care following an NSAID overdose.There are no specific antidotes. Emesis and/or activated charcoal (60 to 100 gin adults, to g/kg in children) and/or osmotic catharticmay be indicated in patients seen within hours of ingestion with symptomsor following large overdose (5 to 10 times the usual dose). Forced diuresis,alkalinization of the urine, hemodialysis, or hemoperfusion would probablynot be useful due to etodolacs high protein binding.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL ETODOLAC 400 MG TABLETS. Etodolac 400 mg Label Image.

PEDIATRIC USE SECTION.

Pediatric Use Safety and effectiveness in pediatric patients below theage of 18 years have not been established.

CLINICAL STUDIES SECTION.

CLINICAL TRIALS Analgesia Controlled clinical trials in analgesia were single-dose, randomized, double-blind, parallel studies in three pain models, including dental extractions. The analgesic effective dose for etodolac established in these acute pain models was 200 to 400 mg. The onset of analgesia occurred approximately 30 minutes after oral administration. Etodolac 200 mg provided efficacy comparable to that obtained with aspirin (650 mg). Etodolac 400 mg provided efficacy comparable to that obtained with acetaminophen with codeine (600 mg 60 mg). The peak analgesic effect was between to hours. Duration of relief averaged to hours for 200 mg of etodolac and to hours for 400 mg of etodolac as measured by when approximately half of the patients required remedication. Osteoarthritis The use of etodolac in managing the signs and symptoms of osteoarthritis of the hip or knee was assessed in double-blind, randomized, controlled clinical trials in 341 patients. In patients 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 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 long-term study with 1,446 patients in which 60% of patients completed months of therapy and 20% completed years of therapy, etodolac in 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.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS Etodolac is contraindicated in patients with known hypersensitivity to etodolac. Etodolac should not be given to patients who have experienced asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS, Anaphylactoid Reactions and PRECAUTIONS, Pre-existing Asthma ). Etodolac is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

DESCRIPTION SECTION.

DESCRIPTION. Etodolac is member of the pyranocarboxylic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Etodolac is racemic mixture of [+]S and [-]R-enantiomers. Etodolac is white crystalline compound, insoluble in water but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol. The chemical name is (+-) 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid. The molecular weight of the base is 287.37. It has pKa of 4.65 and an n-octanol:water partition coefficient of 11.4 at pH 7.4. The molecular formula for etodolac is C17H21NO3, and it has the following structural formula: Each tablet, for oral administration, contains 400 mg or 500 mg of etodolac. In addition, each tablet contains the following inactive ingredients: crospovidone, hydroxypropyl cellulose, hypromellose, magnesium stearate, methylcellulose, polyethylene glycol and titanium dioxide.. etodolac-01.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of etodolac and other treatment options before deciding to use etodolac. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). After observing the response to the initial therapy with etodolac, the dose and frequency should be adjusted to suit an individual patients needs. Dosage adjustment of etodolac is generally not required in patients with mild to moderate renal impairment. Etodolac should be used with caution in such patients, because, as with other NSAIDs, it may further decrease renal function in some patients with impaired renal function (see WARNINGS, Renal Effects ). Analgesia The recommended total daily dose of etodolac for acute pain is up to 1000 mg, given as 200-400 mg every to hours. Doses of etodolac greater than 1000 mg/day have not been adequately evaluated in well-controlled clinical 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. 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, therapeutic response to therapy with etodolac is sometimes seen within one week of therapy, but most often is observed by two weeks. After satisfactory response has been achieved, the patients dose should be reviewed and adjusted as required.

DRUG & OR LABORATORY TEST INTERACTIONS SECTION.

Drug/Laboratory Test Interactions The urine of patients who take etodolac can give false-positive reaction for urinary bilirubin (urobilin) due to the presence of phenolic metabolites of etodolac. Diagnostic dip-stick methodology, used to detect ketone bodies in urine, has resulted in false-positive findings in some patients treated with etodolac. Generally, this phenomenon has not been associated with other clinically significant events. No dose relationship has been observed. Etodolac treatment is associated with small decrease in serum uric acid levels. In clinical trials, mean decreases of to mg/dL were observed in arthritic patients receiving etodolac (600 mg to 1000 mg/day) after weeks of therapy. These levels then remained stable for up to year of therapy.

DRUG INTERACTIONS SECTION.

Drug Interactions ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors (see WARNINGS ). Antacids The concomitant administration of antacids has no apparent effect on the extent of absorption of etodolac. However, antacids can decrease the peak concentration reached by 15% to 20% but have no detectable effect on the time-to-peak. Aspirin When etodolac is administered with aspirin, its protein binding is reduced, although the clearance of free etodolac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of etodolac and aspirin is not generally recommended because of the potential of increased adverse effects. Cyclosporine, Digoxin, Methotrexate Etodolac, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of 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 have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. 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 postmarketing observations have shown that etodolac can reduce the natriuretic effect of furosemide and thiazides in some patients. 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 failure (see WARNINGS, Renal Effects ), as well as to assure diuretic efficacy. Glyburide Etodolac has no apparent pharmacokinetic interaction whenadministered with glyburide. Lithium NSAIDs have produced an elevation of plasma lithium levelsand reduction in renal lithium clearance. The mean minimum lithium concentrationincreased 15% and the renal clearance was decreased by approximately 20%.These effects have been attributed to inhibition of renal prostaglandin synthesisby the NSAID. Thus, when NSAIDs and lithium are administered concurrently,subjects should be observed carefully for signs of lithium toxicity. Phenylbutazone Phenylbutazone causes increase (by about 80%) in the freefraction of etodolac. Although in vivo studieshave not been done to see if etodolac clearance is changed by coadministrationof phenylbutazone, it is not recommended that they be coadministered. Phenytoin Etodolac has no apparent pharmacokinetic interaction whenadministered with phenytoin. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have 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 few spontaneous reports of prolonged prothrombin times, with or without bleeding, in etodolac-treated patients receiving concomitant warfarin therapy.

PHARMACODYNAMICS SECTION.

Pharmacodynamics Etodolac is nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of etodolac, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition. Etodolac is racemic mixture of [-]R- and [+]S-etodolac. As with other NSAIDs, it has been demonstrated in animals that the [+]S-form is biologically active. Both enantiomers are stable and there is no [-]R to [+]S conversion in vivo.

PHARMACOKINETICS SECTION.

Pharmacokinetics Absorption The systemic bioavailability of etodolac is 100% as compared to solution and at least 80% as determined from mass balance studies. Etodolac is well absorbed and had relative bioavailability of 100% when 200 mg capsules were compared with solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from either the tablet or capsule formulation is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (+- SD) peak plasma concentrations (Cmax) range from approximately 14 +- to 37 +- ug/mL after 200 to 600 mg single doses and are reached in 80 +- 30 minutes (see Table 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 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 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 +%Coefficient of variation AgeRange (years) NA= not available PKParametersNormalHealthyAdults(18-65)(n=179) HealthyMales(18-65) (n=176) HealthyFemales(27-65) (n=3) Elderly(>65)(70-84) Hemodialysis(24-65)(n=9) RenalImpairment(46-73) (n=10) HepaticImpairment(34-60) (n=9) DialysisOn DialysisOff Tmax, 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%) N/A N/A 58.3(19%) 42.0(43%) Apparent Volume of Distribution, mL/kg (Vd/F) 393(29%) 394(29%) 300(8%) 414(38%) N/A N/A N/A N/A Terminal Half-Life,h 6.4(22%) 6.4(22%) 7.9(35%) 6.5(24%) 5.1(22%) 7.5(34%) N/A 5.7(24%) Distribution The mean apparent volume of distribution (Vd/F) of etodolacis 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 independentof etodolac total concentration over the dose range studied. It is not knownwhether etodolac is excreted in human milk; however, based on its physical-chemicalproperties, excretion into breast milk is expected. Data from invitro studies, using peak serum concentrations at reported therapeuticdoses in humans, show that the etodolac free fraction is not significantlyaltered 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 specific cytochrome P450 system in the metabolism of etodolacis unknown. Several etodolac metabolites have been identified in human plasmaand urine. Other metabolites remain to be identified. The metabolites include6-, 7-, and 8-hydroxylated-etodolac and etodolac glucuronide. After singledose of 14C-etodolac, hydroxylated metabolites accounted for less than 10%of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolitedoes not accumulate in the plasma of patients with normal renal function.The extent of accumulation of hydroxylated-etodolac metabolites in patientswith renal dysfunction has not been studied. The hydroxylated-etodolac metabolitesundergo further glucuronidation followed by renal excretion and partial eliminationin 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 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.

PRECAUTIONS SECTION.

PRECAUTIONS General Etodolac cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered solely if decision is made to discontinue corticosteroids. The pharmacological activity of etodolac in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including etodolac. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes, have been reported. 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 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. Information For Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.Etodolac, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). Etodolac, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects. Risk of Ulceration, Bleeding, and Perforation). Etodolac, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and flu-like symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). In late pregnancy, the third trimester, as with other NSAIDs, etodolac should be avoided because it may cause premature closure of the ductus arteriosus. Etodolac, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). Etodolac, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects. Risk of Ulceration, Bleeding, and Perforation). Etodolac, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and flu-like symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). In late pregnancy, the third trimester, as with other NSAIDs, etodolac should be avoided because it may cause premature closure of the ductus arteriosus. Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and chemistry profile checked periodically for signs or symptoms of anemia. Appropriate measures should be taken in case such signs of anemia occur. If clinical signs and symptoms consistent with liver or renal disease develop or if systemic manifestations occur (e.g., eosinophilia, rash, etc.) and if abnormal liver tests are detected, persist or worsen, etodolac should be discontinued.. Drug Interactions ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors (see WARNINGS ). Antacids The concomitant administration of antacids has no apparent effect on the extent of absorption of etodolac. However, antacids can decrease the peak concentration reached by 15% to 20% but have no detectable effect on the time-to-peak. Aspirin When etodolac is administered with aspirin, its protein binding is reduced, although the clearance of free etodolac is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of etodolac and aspirin is not generally recommended because of the potential of increased adverse effects. Cyclosporine, Digoxin, Methotrexate Etodolac, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of 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 have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. 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 postmarketing observations have shown that etodolac can reduce the natriuretic effect of furosemide and thiazides in some patients. 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 failure (see WARNINGS, Renal Effects ), as well as to assure diuretic efficacy. Glyburide Etodolac has no apparent pharmacokinetic interaction whenadministered with glyburide. Lithium NSAIDs have produced an elevation of plasma lithium levelsand reduction in renal lithium clearance. The mean minimum lithium concentrationincreased 15% and the renal clearance was decreased by approximately 20%.These effects have been attributed to inhibition of renal prostaglandin synthesisby the NSAID. Thus, when NSAIDs and lithium are administered concurrently,subjects should be observed carefully for signs of lithium toxicity. Phenylbutazone Phenylbutazone causes increase (by about 80%) in the freefraction of etodolac. Although in vivo studieshave not been done to see if etodolac clearance is changed by coadministrationof phenylbutazone, it is not recommended that they be coadministered. Phenytoin Etodolac has no apparent pharmacokinetic interaction whenadministered with phenytoin. Warfarin The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have 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 few spontaneous reports of prolonged prothrombin times, with or without bleeding, in etodolac-treated patients receiving concomitant warfarin therapy. Drug/Laboratory Test Interactions The urine of patients who take etodolac can give false-positive reaction for urinary bilirubin (urobilin) due to the presence of phenolic metabolites of etodolac. Diagnostic dip-stick methodology, used to detect ketone bodies in urine, has resulted in false-positive findings in some patients treated with etodolac. Generally, this phenomenon has not been associated with other clinically significant events. No dose relationship has been observed. Etodolac treatment is associated with small decrease in serum uric acid levels. In clinical trials, mean decreases of to mg/dL were observed in arthritic patients receiving etodolac (600 mg to 1000 mg/day) after weeks of therapy. These levels then remained stable for up to year of therapy. Carcinogenesis, Mutagenesis, and Impairment of Fertility No carcinogenic effect of etodolac was observed in mice or rats receiving oral doses of 15 mg/kg/day (45 to 89 mg/m2, respectively) or less for periods of years or 18 months, respectively. Etodolac was not mutagenic in in vitro testsperformed with S. typhimurium and mouse lymphoma cells as well as in an in vivo mouse micronucleus test. However, data from the invitro human peripheral lymphocyte test showed an increase in the number of gaps (3.0 to 5.3% unstained regions in the chromatid without dislocation) among the etodolac-treated cultures (50 to 200 mcg/mL) compared to negative controls (2.0%); no other difference was noted between the controls and drug-treated groups. Etodolac showed no impairment of fertility in male and female rats up to oral doses of 16 mg/kg (94 mg/m2). However, reduced implantation of fertilized eggs occurred in the mg/kg group. Pregnancy Teratogenic Effects Pregnancy Category . In teratology studies, isolated occurrences of alterations in limb development were found and included polydactyly, oligodactyly, syndactyly, and unossified phalanges in rats and oligodactyly and synostosis of metatarsals in rabbits. These were observed at dose levels (2 to 14 mg/kg/day) close to human clinical doses. However, the frequency and the dosage group distribution of these findings in initial or repeated studies did not establish clear drug or dose-response relationship. Animal reproduction studies are not always predictive of human response. There are no adequate or well-controlled studies in pregnant women. Etodolac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nonteratogenic Effects Etodolac should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Because of the known effects of NSAIDs on parturition and on the human fetal cardiovascular system with respect to closure of the ductus arteriosus, use during late pregnancy should be avoided.. Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of etodolac on labor and delivery in pregnant women are unknown. Nursing Mothers It is not known whether etodolac is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from etodolac, decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients below theage of 18 years have not been established. Geriatric Use As with any NSAID, caution should be exercised in treating the elderly (65 years and older) and when increasing the dose (see WARNINGS). 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 CLINICAL PHARMACOLOGY, Special Populations). Elderly patients may be more sensitive to the antiprostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients (see WARNINGS). In particular, elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. 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 ).

GENERAL PRECAUTIONS SECTION.

General Etodolac cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered solely if decision is made to discontinue corticosteroids. The pharmacological activity of etodolac in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions. Hepatic Effects Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including etodolac. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of them with fatal outcomes, have been reported. 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 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.

GERIATRIC USE SECTION.

Geriatric Use As with any NSAID, caution should be exercised in treating the elderly (65 years and older) and when increasing the dose (see WARNINGS). 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 CLINICAL PHARMACOLOGY, Special Populations). Elderly patients may be more sensitive to the antiprostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients (see WARNINGS). In particular, elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. 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 ).

HOW SUPPLIED SECTION.

HOW SUPPLIED Etodolac Tablets USP are available as:400 mg tablets (White to off-white, oval, unscored, film-coated tablets, imprinted APO 041 on one side and 400 on the other side.)- in bottles of 30, NDC 42549-511-30 in bottles of 60, NDC 42549-511-60 Store at 20 to 25C (68 to 77F); excursions permitted to 15C to 30 (59 to 86F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container [see USP]. APOTEX INC. ETODOLAC TABLETS USP 400 mg and 500 mg Manufactured by: Manufactured for: Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L 1T9 33326 Revised: January 2006 Rev. Relabeling and Repackaging by:STAT Rx USA LLCGainesville, GA 30501.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE Carefully consider the potential benefits and risks of etodolac and other treatment options before deciding to use etodolac. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS). Etodolac is indicated: For acute and long-term use in the management of signs and symptoms of the following:Osteoarthritis Rheumatoid arthritis For the management of acute pain For acute and long-term use in the management of signs and symptoms of the following:Osteoarthritis Rheumatoid arthritis Osteoarthritis Rheumatoid arthritis For the management of acute pain.

INFORMATION FOR PATIENTS SECTION.

Information For Patients Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.Etodolac, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). Etodolac, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects. Risk of Ulceration, Bleeding, and Perforation). Etodolac, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and flu-like symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). In late pregnancy, the third trimester, as with other NSAIDs, etodolac should be avoided because it may cause premature closure of the ductus arteriosus. Etodolac, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS, Cardiovascular Effects). Etodolac, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS, Gastrointestinal Effects. Risk of Ulceration, Bleeding, and Perforation). Etodolac, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible. Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians. Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and flu-like symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy. Patients should be informed of the signs of an anaphylactoid reaction (e.g., difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS). In late pregnancy, the third trimester, as with other NSAIDs, etodolac should be avoided because it may cause premature closure of the ductus arteriosus.

LABOR & DELIVERY SECTION.

Labor and Delivery In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of etodolac on labor and delivery in pregnant women are unknown.

LABORATORY TESTS SECTION.

Laboratory Tests Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and chemistry profile checked periodically for signs or symptoms of anemia. Appropriate measures should be taken in case such signs of anemia occur. If clinical signs and symptoms consistent with liver or renal disease develop or if systemic manifestations occur (e.g., eosinophilia, rash, etc.) and if abnormal liver tests are detected, persist or worsen, etodolac should be discontinued.

NONTERATOGENIC EFFECTS SECTION.

Nonteratogenic Effects Etodolac should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Because of the known effects of NSAIDs on parturition and on the human fetal cardiovascular system with respect to closure of the ductus arteriosus, use during late pregnancy should be avoided.

PREGNANCY SECTION.

Pregnancy Teratogenic Effects Pregnancy Category . In teratology studies, isolated occurrences of alterations in limb development were found and included polydactyly, oligodactyly, syndactyly, and unossified phalanges in rats and oligodactyly and synostosis of metatarsals in rabbits. These were observed at dose levels (2 to 14 mg/kg/day) close to human clinical doses. However, the frequency and the dosage group distribution of these findings in initial or repeated studies did not establish clear drug or dose-response relationship. Animal reproduction studies are not always predictive of human response. There are no adequate or well-controlled studies in pregnant women. Etodolac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Nonteratogenic Effects Etodolac should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Because of the known effects of NSAIDs on parturition and on the human fetal cardiovascular system with respect to closure of the ductus arteriosus, use during late pregnancy should be avoided.

SPL UNCLASSIFIED SECTION.

Absorption The systemic bioavailability of etodolac is 100% as compared to solution and at least 80% as determined from mass balance studies. Etodolac is well absorbed and had relative bioavailability of 100% when 200 mg capsules were compared with solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from either the tablet or capsule formulation is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (+- SD) peak plasma concentrations (Cmax) range from approximately 14 +- to 37 +- ug/mL after 200 to 600 mg single doses and are reached in 80 +- 30 minutes (see Table 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 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 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 +%Coefficient of variation AgeRange (years) NA= not available PKParametersNormalHealthyAdults(18-65)(n=179) HealthyMales(18-65) (n=176) HealthyFemales(27-65) (n=3) Elderly(>65)(70-84) Hemodialysis(24-65)(n=9) RenalImpairment(46-73) (n=10) HepaticImpairment(34-60) (n=9) DialysisOn DialysisOff Tmax, 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%) N/A N/A 58.3(19%) 42.0(43%) Apparent Volume of Distribution, mL/kg (Vd/F) 393(29%) 394(29%) 300(8%) 414(38%) N/A N/A N/A N/A Terminal Half-Life,h 6.4(22%) 6.4(22%) 7.9(35%) 6.5(24%) 5.1(22%) 7.5(34%) N/A 5.7(24%).

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects Pregnancy Category . In teratology studies, isolated occurrences of alterations in limb development were found and included polydactyly, oligodactyly, syndactyly, and unossified phalanges in rats and oligodactyly and synostosis of metatarsals in rabbits. These were observed at dose levels (2 to 14 mg/kg/day) close to human clinical doses. However, the frequency and the dosage group distribution of these findings in initial or repeated studies did not establish clear drug or dose-response relationship. Animal reproduction studies are not always predictive of human response. There are no adequate or well-controlled studies in pregnant women. Etodolac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

USE IN SPECIFIC POPULATIONS SECTION.

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 theage 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 ina 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 50% greater apparent clearance of total etodolac, due to 50% greater unbound fraction. Free etodolac clearance was not altered, indicating the importance of protein binding in etodolacs disposition. Etodolac is not significantly removed from the blood in patients undergoing hemodialysis.

WARNINGS SECTION.

WARNINGS CARDIOVASCULAR EFFECTS Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or 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 does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects Risk of Ulceration, Bleeding, and Perforation). Two large, controlled, clinical trials of 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, 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. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Etodolac should be used with caution in patients with fluid retention or heart failure. Gastrointestinal (GI) Effects Risk of GI 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 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 to months, and in about 2% to 4% of patients treated for year. These trends continue with longer duration of use, increasing the likelihood of developing 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 prior history of ulcer disease or gastrointestinal bleeding. Patients with prior history of peptic ulcer disease, and/or gastrointestinal bleeding, and who use NSAIDs have greater than 10-fold risk for developing GI bleed than 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 of debilitated patients, and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event, 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 serious GI adverse event is suspected. This should include discontinuation of the NSAID until 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 compensatory role in the maintenance of renal perfusion. In these patients, administration of nonsteroidal anti-inflammatory drug may cause 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, spontaneous change occurring with variable frequency, was observed with increased frequency in treated male rats in 2-year chronic study. 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 patients 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. Pregnancy In late pregnancy, the third trimester, as with other NSAIDs, etodolac should be avoided because it may cause premature closure of the ductus arteriosus (see PRECAUTIONS, Pregnancy, Non-teratogenic Effects ).