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ULTRADOL™
Procter & Gamble Pharmaceuticals
Etodolac
Nonsteroidal Anti-inflammatory - Analgesic
 
Action And Clinical Pharmacology: Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory analgesic and antipyretic properties in animal models. The pharmacological actions of etodolac are thought to be related to inhibition of prostaglandin biosynthesis at the site of inflammation.

Ultradol is a racemic mixture of R- and S-etodolac. As with other NSAIDs, it has been demonstrated in animals that the S-form is biologically active and the R-form is not. Both enantiomers are stable and there is no R-to-S conversion in vivo.

According to in vitro studies of human chondrocytes, etodolac may preserve collagen phenotype while still inhibiting prostaglandin (PGE2) biosynthesis. The results demonstrated that normal chondrocyte function remained unaffected by etodolac, as assessed by the rate of DNA synthesis, proteoglycan synthesis, type II collagen production, and collagenase production. Etodolac maintained type II collagen synthesis and partially blocked the effects of interleukin-1 (IL-1). Nevertheless, PGE2 synthesis was significantly decreased in the presence of etodolac. These results need to be verified through in vivo testing.

Pharmacokinetics: Etodolac is well absorbed following oral administration. The systemic availability of etodolac is at least 80%, and the drug does not undergo significant first-pass metabolism. The dose-proportionality based on AUC (the area under the plasma concentration-time curve) is linear following doses up to 600 mg every 12 hours. Etodolac is more than 99% bound to plasma proteins.

Mean peak plasma concentrations range from approximately 14±4 to 37±9 µg/mL after 200 to 600 mg single doses and are reached in 80±30 minutes. The mean plasma clearance of etodolac is 47(±16) mL/h/kg, and terminal disposition half-life is 7.3 (±4) hours.

Etodolac is extensively metabolized in the liver, with renal elimination of etodolac and its metabolites being the primary route of excretion. Approximately 72% of the administered dose is recovered in the urine as the following, indicated as % of the administered dose: etodolac, unchanged 1%, etodolac glucuronide 13%, hydroxylated metabolites (6-, 7- and 8-OH) 5%, hydroxylated metabolite glucuronides 20% and unidentified metabolites 33%.

Fecal excretion accounted for 16% of the dose. Therefore, enterohepatic circulation, if present, is not extensive.

The extent of absorption of etodolac is not affected when it is administered after a meal or with an antacid. 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. Coadministration with an antacid decreases the peak concentration reached by about 15 to 20%, with no measurable effect on time-to-peak.

In studies in the elderly, age was found to have no effect on etodolac half-life or protein binding, and there was no drug accumulation. Etodolac clearance was reduced by about 15%. Because the reduction in clearance is small, no dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics. The elderly may need dosage adjustment, however, on the basis of body size, and they may be more sensitive to antiprostaglandin effects than younger patients.

In studies of the effects of mild to moderate renal impairment, no significant differences in the disposition of total and free etodolac were observed. 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. Nevertheless, etodolac is not dialyzable. No dosage adjustment of etodolac is generally required in patients with mild to moderate renal impairment; however, 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.

In patients with compensated hepatic cirrhosis, the disposition of total and free etodolac is not altered. Although no dosage adjustment is generally required in this patient population, etodolac clearance is dependent on hepatic function and could be reduced in patients with severe hepatic failure.

Clinical Studies: Rheumatoid Arthritis and Osteoarthritis: Etodolac has been studied in double-blind, randomized, parallel-group, multicentre clinical trials in the treatment of rheumatoid arthritis and osteoarthritis. In rheumatoid arthritis studies, etodolac 200 mg twice a day was compared with naproxen 500 mg twice a day, piroxicam 20 mg once a day, or diclofenac 50 mg 3 times a day. In osteoarthritis studies, etodolac 200 mg 3 times a day was compared with diclofenac 50 mg 3 times a day, and etodolac 300 mg twice a day was compared with piroxicam 20 mg once a day, or naproxen 500 mg twice a day.

Results of these rheumatoid arthritis and osteoarthritis studies showed etodolac to be comparable to naproxen, piroxicam and diclofenac. Key efficacy parameters improved significantly (pŁ0.05) in all treatment groups with no significant differences between therapies.

Analgesia: Clinical trials have demonstrated the effectiveness of etodolac when used as an analgesic. In well-controlled, double-blind, randomized, parallel, single-dose acute pain studies in 3 pain models (dental extractions, postgeneral surgery, and postepisiotomy pain), the onset of analgesia occurred approximately 30 minutes after oral administration with the peak effect occurring between 1 and 2 hours. The analgesic effective dose for etodolac established in these acute pain models was 200 to 400 mg. The duration of relief with these doses was generally 4 to 6 hours but persisted for up to 8 to 12 hours in some patients.

Special Studies: Etodolac was compared to other NSAIDs in studies focusing on gastrointestinal microbleeding, endoscopy, and gastroduodenal prostaglandin asseys. The clinical significance of these results is unknown.

In gastrointestinal microbleeding studies of healthy individuals, the GI blood loss observed with etodolac (600 mg to 1 200 mg/day) was similar to that seen with placebo and significantly less than that seen with ASA (2 600 mg/day), ibuprofen (2 400 mg/day), indomethacin (200 mg/day), or naproxen (750 mg/day). In a study of etodolac (600 and 1 000 mg/day) and piroxican (20 mg/day), gastrointestinal blood loss observed with etodolac was comparable with that seen with placebo and significnatly less than that seen with piroxicam.

With endoscopy studies in healthy volunteers, etodolac treatment (up to 1 200 mg/day) resulted in endoscopy scores which were similar to baseline and placebo, and significantly better than following treatment with ASA (3 900 mg/day), ibuprofen (2 400 mg/day), indomethacin (200 mg/day), or naproxen )1 000 mg/day). The effects of etodolac (600 mg to 1 200 mg/day) and diclofenac (150 mg/day) were not significantly different from each other or from baseline, as shown by endoscopy. Gastrointestinal microbleeding and endoscopy studies provide an objective measure of blood loss and lesions.

Prostaglandin assays of the gastroduodenal mucosa of patients with active rheumatoid arthritis were performed in a double-blind randomized study involving therapeutic doses of etodolac (600 mg/day) and naproxen (1 000 mg/day). Biopsies were taken at baseline and after 4 weeks of treatment. The results of this study indicate that etodolac does not appear to affect gastric or duodenal prostaglandin synthesis.

Indications And Clinical Uses: For acute or long-term use in the relief of signs and symptoms of rheumatoid arthritis and osteoarthritis (degenerative joint disease). Etodolac is also indicated for the short-term treatment of mild to moderate pain.

Contra-Indications: Active peptic ulcer, a history of recurrent ulceration or active inflammatory disease of the gastrointestinal system. Known or suspected hypersensitivity to the drug or other NSAIDs. The potential for cross-reactivity between different NSAIDs must be kept in mind.

Etodolac should not be used in patients with the complete or partial syndrome of nasal polyps, or in whom asthma, anaphylaxis, urticaria, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals. As well, individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse effects.

Significant hepatic impairment or active liver disease. Severely impaired or deteriorating renal function (creatinine clearance <30 mL/min or <0.5 mL/sec). Individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored. Etodolac is not recommended for use with other NSAIDs because of the absence of any evidence demonstrating synergistic benefits and the potential for additive side effects.

Manufacturers' Warnings In Clinical States: Gastrointestinal: Serious gastrointestinal toxicity, such as peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal can occur at any time, with or without symptoms in patients treated with NSAIDs including etodolac.

Minor upper gastrointestinal problems, such as dyspepsia, are common, usually developing early in therapy. Physicians should remain alert for ulceration and bleeding in patients treated with NSAIDs, even in the absence of previous gastrointestinal tract symptoms.

In patients observed in clinical trials of such agents, symptomatic upper gastrointestinal ulcers, gross bleeding or perforation appear to occur in approximately 1 % of patients treated for 3 to 6 months and in about 2 to 4 % of patients treated for 1 year. The risk continues beyond 1 year and possibly increases.

The incidence of these complications increases with increasing dose.

In a 3-year double-blind, parallel group, multicentre study, evaluating the long-term effects of 300 mg/day and 1 000 mg/day etodolac vs ibuprofen in patients with rheumatoid arthritis, cumulative rates of less than 1 % for gastrointestinal ulcers and bleeding were reported in both the 300 mg/day and 1 000 mg/day etodolac groups compared to 4.74 % of patients in the 2 400 mg/day ibuprofen group over the 3-year study period.

Etodolac should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, melena, diverticulosis or other inflammatory disease of the gastrointestinal tract such as ulcerative colitis or Crohn's disease. In these cases the physician must weigh the benefits of treatment against the possible hazards (see Contraindications and Adverse Effects).

Physicians should inform patients about the signs and/or symptoms of serious gastrointestinal toxicity and instruct them to contact a physician immediately if they experience persistent dyspepsia or other symptoms or signs suggestive of gastrointestinal ulceration or bleeding.

Because serious gastrointestinal tract ulceration and bleeding can occur without warning symptoms, physicians should follow chronically treated patients by checking their hemoglobin periodically and by being vigilant for the signs and symptoms of ulceration and bleeding and should inform the patients of the importance of this followup.

If ulceration is suspected or confirmed, or if gastrointestinal bleeding occurs, etodolac should be discontinued immediately, appropriate treatment instituted and the patient monitored closely.

No studies, to date, have identified any group of patients not at risk of developing ulceration and bleeding. A prior history of serious gastrointestinal events and other factors such as excess alcohol intake, smoking, age, female gender and concomitant oral steroid and anticoagulant use have been associated with increased risk.

Studies to date show that all NSAIDs can cause gastrointestinal tract adverse events. Although existing data does not clearly identify differences in risk between various NSAIDs, this may be shown in the future.

Geriatrics: Patients older than 65 years and frail or debilitated patients are most susceptible to a variety of adverse reactions from NSAIDs: the incidence of these adverse reactions increases with dose and duration of treatment. In addition, these patients are less tolerant to ulceration and bleeding. Most reports of fatal gastrointestinal events are in this population. Older patients are also at risk of lower esophageal ulceration and bleeding.

For such patients consideration should be given to a starting dose lower than the one usually recommended, with individual adjustment when necessary and under close supervision. See "Precautions" for further advice.

Cross-sensitivity: Patients sensitive to any one of the NSAIDs may be sensitive to any of the other NSAIDs also.

Aseptic Meningitis: In occasional cases, with some NSAIDs, the symptoms of aseptic meningitis (stiff neck, severe headaches, nausea and vomiting, fever or clouding of consciousness) have been observed. Patients with autoimmune disorders (systemic lupus erythematosus, mixed connective tissues diseases, etc.) seem to be predisposed. Therefore, in such patients, the physician must be vigilant to the development of this complication.

Pregnancy , Labor and Lactation: The safety of etodolac during pregnancy and lactation has not been established and therefore, its use during pregnancy and lactation is not recommended.

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 metatarsal 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 intial or repeated studies did not establish a clear drug- or dose-response relationship.

In rat studies with etodolac, 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.

It is not known whether etodolac is excreted in human milk. Caution should be exercised if etodolac is administered to a nursing woman, because many drugs are excreted in human milk.

Children: The safety and effectiveness of etodolac in children have not been established and therefore, the drug is not recommended in this age group.

Precautions: Gastrointestinal: There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow the continuation of etodolac therapy when and if the adverse reactions appear.

Renal Function: Long term administration of NSAIDs to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose dependent reduction in prostaglandin formation and may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and the elderly. Discontinuation of nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pretreatment state.

Etodolac and its metabolites are eliminated primarily by the kidneys; therefore, the drug should be used with great caution in patients with impaired renal function. In these cases, utilization of lower doses of etodolac should be considered and patients carefully monitored. During long-term therapy, kidney function should be monitored periodically.

Genitourinary Tract: Some NSAIDs are known to cause persistent urinary symptoms (bladder pain, dysuria, urinary frequency), hematuria or cystitis. The onset of these symptoms may occur at any time after the initiation of therapy with an NSAID. Some cases have become severe on continued treatment. Should urinary symptoms occur, treatment with etodolac must be stopped immediately to obtain recovery. This should be done before any urological investigations or treatments are carried out.

Hepatic Function: As with other NSAIDs, borderline elevations of one or more liver function tests may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Meaningful (3 times the upper limit of normal) elevations of ALT or AST occurred in controlled clinical trials with etodolac in approximately 1% of patients. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with NSAIDs. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), this drug should be discontinued.

During long-term therapy, liver function tests should be monitored periodically. If this drug is to be used in the presence of impaired liver function, it must be done under strict observation.

Fluid and Electrolyte Balance: Fluid retention and edema have been observed in patients treated with etodolac. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Etodolac should be used with caution in patients with heart failure, hypertension and renal diseases and in those recovering from surgical operations under general anesthesia and other conditions predisposing to fluid retention.

With NSAID treatment there is a potential risk of hyperkalemia, particularly in patients with conditions such as diabetes mellitus or renal failure, elderly patients or in patients receiving concomitant therapy with beta-adrenergic blockers, angiotensin converting enzyme inhibitors or some diuretics.

Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients at risk.

Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to varying degrees; therefore, patients who may be adversely affected by such an action should be carefully observed when etodolac is administered.

Blood dyscrasias (such as neutropenia, leukopenia, thrombocytopenia, aplastic anemia and agranulocytosis) associated with the use of NSAIDs are rare, but could be with severe consequences.

Anemia is commonly observed in rheumatoid arthritis and is sometimes aggravated by NSAIDs, which may produce fluid retention or minor gastrointestinal blood loss in some patients. Therefore, patients with initial hemoglobin values of 10 g/dL or less who are to receive long-term therapy, should have hemoglobin values determined frequently.

Infection: In common with other anti-inflammatory drugs, etodolac may mask the usual signs of infection.

Ophthalmology: Blurred and/or diminished vision has been reported with the use of etodolac and other NSAIDs. If such symptoms develop, this drug should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.

CNS: Some patients may experience drowsiness, dizziness, vertigo, insomnia or depression with the use of etodolac. If patients experience these side effects, they should exercise caution in carrying out activities that require alertness.

Hypersensitivity: As with other nonsteroidal anti-inflammatory drugs, allergic reactions, including anaphylactic/anaphylactoid reactions, can occur without prior exposure to drug; therefore, careful questioning of patients for a history of asthma, nasal polyps, urticaria, and hypotension associated with NSAIDs before starting therapy is important.

Drug Interactions: ASA or other NSAIDs: When etodolac is administered with ASA, its protein binding is reduced although the clearance of free etodolac is not altered. The clinical significance of this interaction is not known; however, the use of etodolac in addition to any other NSAID, including those over the counter ones (such as ASA and ibuprofen), is not recommended due to the possibility of additive side effects.

Cyclosporine, Digoxin, Lithium, 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 digoxin, lithium, and 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 (monitoring of plasma drug levels).

Anticoagulants: Numerous studies have shown that the concomitant use of NSAIDs and anticoagulants increases the risk of gastrointestinal adverse events such as ulceration and bleeding. Concomitant administration of warfarin and etodolac results in reduced protein binding of warfarin, but there is no change in the clearance of free warfarin. There is 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, in postmarketing experience there have been spontaneous reports of prolonged prothrombin times in etodolac-treated patients receiving concomitant warfarin therapy. As well, because prostaglandins play an important role in hemostasis, and NSAIDs affect platelet function, concurrent therapy of etodolac with warfarin requires close monitoring to be certain that no change in anticoagulant dosage is necessary.

Glyburide: Etodolac has no apparent pharmacokinetic or pharmacodynamic interaction when administered with glyburide.

Diuretics: Etodolac has no apparent pharmacokinetic interaction when administered with furosemide or hydrochlorothiazide, nor does etodolac attenuate the diuretic response of either of these drugs in normal volunteers. Etodolac, and other NSAIDs nevertheless, should be used with caution in patients receiving diuretics or who have cardiac, renal or hepatic failure (see Renal Function).

Antihypertensive Agents: NSAIDs can reduce the antihypertensive effect of propranolol and other b-blockers as well as other antihypertensive agents.

Glucocorticoids: Numerous studies have shown that the concomitant use of NSAIDs and oral glucocorticoids increases the risk of gastrointestinal side effects such as ulceration and bleeding. This is especially the case in older (>65 years of age) individuals.

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.

Phenytoin: Etodolac has no apparent pharmacokinetic interaction when administered with phenytoin.

Protein Binding: 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 ibuprofen, acetaminophen, phenytoin, probenecid, indomethacin, chlorpropamide, glyburide, naproxen, glypizide or piroxicam.

In contrast, phenylbutazone causes an increase (by about 80 %) in the free fraction of etodolac. Although in vivo studies have not been done to see if etodolac clearance is changed by coadministration of phenylbutazone, it is not recommended that they be coadministered.

The following drug interactions have been identified for NSAIDs in general on the basis of their potential clinical significance: potassium supplements, insulin, bone marrow depressants, valproic acid, colchicine, nephrotoxic agents and platelet aggregation inhibitors.

These interactions have not been documented with all NSAIDs but have been reported for some NSAIDs and should be considered potential precautions to the use of any NSAID, especially with chronic administration.

Clinical Laboratory Tests: The urine of patients who take etodolac can give a false-positive reaction for urinary bilirubin (urorubin) 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 a small decrease in serum uric acid levels. In clinical trials, mean decreases of 1 to 2 mg/dL were observed in arthritic patients receiving etodolac (600 to 1 000 mg/day) after 4 weeks of therapy. These levels then remained stable for up to 1 year of therapy.

Adverse Reactions: The most common adverse reactions encountered with nonsteroidal anti-inflammatory drugs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred on occasion, particularly in the elderly.

Adverse reaction information for etodolac was derived from 2 629 arthritic patients treated with etodolac in double-blind and open-label clinical trials of 4 to 320 weeks in duration, 2 213 patients treated with etodolac in double-blind, single-dose analgesia clinical trials, and worldwide postmarketing surveillance studies in approximately 60 000 patients. Spontaneous postmarketing reports are also included.

In clinical studies, etodolac was generally well tolerated. Most adverse reactions were mild and transient. The discontinuation rate in controlled clinical trials because of adverse events, was 9% for arthritic patients and 0.6% for analgesic patients treated with etodolac.

Listed below are the patient complaints with an incidence of greater than, equal to, or less than 1% which occurred in clinical trials and postmarketing experience with etodolac at doses up to 1 000 mg/day.

Incidence ł1%: Gastrointestinal: nausea, diarrhea, epigastric pain, heartburn, indigestion, flatulence, abdominal pain, gastrointestinal cramps, abdominal distention, constipation, vomiting, dyspepsia, gastritis, melena.

CNS: headache, dizziness, drowsiness, insomnia, nervousness/anxiety, depression.

Dermatologic: dermatitis manifested as skin rash (erythematous, vesicular, maculopapular, morbilliform, petechial, or eczematous) or pruritus.

General Illness: fatigue, weakness/malaise, chills and fever.

Genitourinary: urinary frequency, dysuria, after-birth pain.

Metabolic: fluid retention/edema.

Eye, Ear, Nose and Throat: tinnitus, blurred vision.

Incidence<1%: Gastrointestinal: dry mouth; peptic ulcer with/without gastrointestinal hemorrhage and/or perforation; hematemesis; rectal bleeding; stool changes (loose, with mucus, or increase in number and/or frequency); taste abnormalities including loss of taste; eructation; stomatitis (including ulcerative stomatitis); hepatitis (including cholestatic hepatitis); hepatic failure; intestinal ulceration; cholestasis; jaundice (including cholestatic jaundice); esophagitis with or without erosions or stricture or cardiospasm; colitis (including ischemic colitis); pancreatitis; duodenitis; entercolitis, anorexia.

CNS: restlessness; confusion; vertigo; syncope; nightmares; listlessness; inability to concentrate, somnolence; paresthesia circumoral; emotional lability; hallucinations; minor hysteria; stupor; hypertonia.

Dermatologic: urticaria; angioedema; alopecia; sore, dry, inflamed or swollen mucous membranes including mouth, tongue, and lips; photosensitivity; peeling; easy bruising; brittle nails; exfoliative dermatitis; Stevens-Johnson syndrome, cutaneous vasculitis with purpura; erythema multiforme; hyperpigmentation; sweating; vesiculobullous rash.

Eye, Ear, Nose and Throat: hearing loss, visual disturbances including teichopsia; epistaxis; earache; pressure/throbbing in ears; burning sensation of eyes/nose; twinging behind eyes; photophobia; conjunctivitis; conjunctival ulcer; lacrimation disorders; edema of gums: gingivitis.

Extremities: paresthesias; muscle cramps; muscle pain; muscular fatigue; involuntary muscle movement; pain in arms/hands/shoulders/back; hand tremor; tenderness; s.c. nodule/first metatarsophalangeal join; pain from fracture; heat at site of fracture; joint discomfort; myasthenia; myelitis.

General Illness: lethargy; vasculitis (including necrotizing and allergic); general deterioration; breast tenderness; infection; pain.

Genitourinary: dysuria; urinary urgency; hematuria; nocturia; vaginal bleeding; difficulty maintaining erection; recto-pubic pain; cystitis; leukorrhea; renal calculus; interstitial nephritis; papillary necrosis; renal insufficiency; renal failure; pyelonephritis; glomerulonephritis; uterine bleeding irregularities; rectal disorder; myomatous uterus; painful testicles; uterine cramps.

Metabolic: change in weight; change in appetite; flushing; excessive thirst; hot flashes; diaphoresis; elevated BUN; hyperglycemia in previously controlled diabetic patients; dehydration.

Cardiovascular: hypertension; congestive heart failure; palpitations; tachycardia; chest pain (costal, costochondral, or retrosternal); arrhythmias; myocardial infarction; and chest tightness or fullness; cerebrovascular accident; postural hypotension.

Respiratory: dyspnea; asthma; bronshospasm; hyperventilation; sneezing and sighing; bronchitis; pharyngitis; rhinitis; sinusitis.

Hypersensitivity: allergic/anaphylactic/anaphylactoid reaction; laryngeal edema.

Hematology: agranulocytosis; pancytopenia; decreased hemoglobin; decreased hematocrit; anemia; hemolytic anemia; thrombocytopenia; leukopenia; neutropenia; eosinophilia; atypical lymphocytes; increased bleeding time; ecchymosis.

Laboratory: elevated hepatic enzymes; increased serum creatinine.

Symptoms And Treatment Of Overdose: Symptoms: Symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain which are generally reversible with supportive care. Gastrointestinal bleeding can occur and coma has occurred following massive ibuprofen or mefenamic acid overdose. Hypertension, acute renal failure, and respiratory depression may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following overdose. tag_Treatment

Treatment: Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Gut decontamination may be indicated in patients seen within 4 hours with symptoms or following a large overdose (5 to 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with an osmotic cathartic. Forced diuresis, alkalinization of the urine, hemodialysis or hemoperfusion would probably not be useful due to etodolac's high protein binding.

There have been infrequent reports of etodolac overdose. One case of intentional etodolac overdosage has been reported (Human Toxicol. 1988; 7: 203-204). This 53-year-old female ingested from 15 to 46 two hundred mg etodolac capsules (3 to 8.6 g). Plasma etodolac concentrations were measured frequently over the next 4 days. At 5 hours after ingestion (3 hours after gastric lavage) the plasma etodolac level was 22 µg/mL. These plasma levels and her subsequent recovery with no signs or symptoms of etodolac toxicity were consistent with systemic absorption of 600 to 800 mg. Her laboratory tests on admission showed a prolonged prothrombin time and a false-positive urine bilirubin (attributed to the phenolic etodolac metabolites).

Dosage And Administration: Rheumatoid Arthritis and Osteoarthritis: Adults: The recommended dosage of etodolac in the treatment of rheumatoid arthritis and osteoarthritis is 200 to 300 mg twice daily. Patients may also respond to single daily (400 or 600 mg) dose administered in the evening.

Geriatrics: As with any NSAID, caution should be exercised in treating the elderly, and when individualizing their dosage, extra care should be taken when increasing the dose because the elderly seem to tolerate NSAID side effects less well than younger patients. In otherwise healthy patients 65 years and older, no substantial differences in the side effects profile of etodolac were seen.

Analgesia: Adults: The usual recommended dose of etodolac in the treatment of short-term acute pain is 200 to 400 mg every 6 to 8 hours, as needed. For this indication, the maximum duration of treatment is 7 days. In some patients, adequate analgesic relief is provided with 12-hour dosing intervals.

The safety of doses in excess of 1 000 mg/day for extended periods has not been established. In order to maximize the effectiveness of therapy, the dosage must be individualized for each patient.



Availability And Storage: 200 mg: Each light grey capsule with a wide red band printed "Ultradol 200"/dark grey with 2 narrow red bands, contains: etodolac 200 mg. Nonmedicinal ingredients: cellulose, lactose, magnesium stearate, povidone, sodium lauryl sulfate and sodium starch glycolate; capsule shell also contains black iron oxide, gelatin and silicon dioxide and titanium dioxide and may contain benzyl alcohol, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium, methylparaben, propylparaben, sodium propionate and yellow iron oxide. Bottles of 100.

300 mg: Each light grey capsule with a wide red band printed "Ultradol 300" and 2 narrow red bands, contains: etodolac 300 mg. Nonmedicinal ingredients: cellulose, lactose, magnesium stearate, povidone, sodium lauryl sulfate and sodium starch glycolate; capsule shell also contains black iron oxide, gelatin and silicon dioxide and titanium dioxide and may contain benzyl alcohol, butylparaben, carboxymethylcellulose sodium, edetate calcium disodium, methylparaben, propylparaben, sodium propionate and yellow iron oxide. Bottles of 100.

Store at room temperature (25°C) and protect from moisture.