Apo-Etodolac (Etodolac)

APO®-ETODOLAC

Apotex

Etodolac

Anti-inflammatory

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.

Etodolac 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 g/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 (±4.0) 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.

Geriatrics: 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 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.

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).

Contra-Indications: Should not be used in patients who have previously shown hypersensitivity to etodolac. Due to possible cross-reactivity, etodolac should not be administered to patients who experience asthma, rhinitis, urticaria or other allergic reactions during therapy with ASA or other NSAIDs. Fatal anaphylactoid reactions have occurred in such individuals.

Etodolac should not be used in patients with an active peptic ulcer or inflammatory diseases of the gastrointestinal tract.

Manufacturers’ Warnings In Clinical States: Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal have been reported during therapy with NSAIDs including etodolac.

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).

Patients taking any NSAID including this drug should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur at any time during treatment, without warning symptoms or signs.

Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from NSAIDs. As with other NSAIDs, etodolac should be used with special caution and under close supervision in these patients and consideration should be given to a starting dose lower than usual, with individual adjustment when necessary.

Pregnancy 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 initial 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: If peptic ulceration is suspected or confirmed or if gastrointestinal bleeding or perforation occurs in patients under treatment with etodolac, the drug should be immediately withdrawn, an appropriate treatment initiated and the patient closely monitored.

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 continuation of etodolac therapy when and if the adverse reactions appear.

Renal Function: As with other NSAIDs, long-term administration of etodolac 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.

In patients with prerenal conditions leading to reduction in renal blood flow or blood volume, where renal prostaglandins have a supportive role in the maintenance of renal perfusion, administration of nonsteroidal anti-inflammatory agents may precipitate overt renal decompensation due to a dose-dependent reduction in prostaglandin formation. Patients at greatest risk are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics, and the elderly. Discontinuation of NSAID 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, lower doses of etodolac should be considered and patients carefully monitored. During long-term therapy, kidney function should be monitored periodically.

Hepatic Function: As with other NSAIDs, borderline elevations of one or more liver 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 this drug as with other 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 reported; 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 b-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 and vascular response to bleeding to some degree; therefore, patients who may be adversely affected by such an action should be carefully observed when etodolac is administered.

Blood dyscrasias 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.

Hypersensitivity: As with other NSAIDs, 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: 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.

ASA: 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, as with other NSAIDs, concomitant administration of etodolac and ASA is not generally recommended because of potential of increased adverse effects.

Warfarin: 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. Caution should be exercised, nevertheless, because interactions have been seen with other NSAIDs.

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

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.

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).

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, glipizide 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.

Laboratory Test Interactions : 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% 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 NSAIDs 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 and worldwide postmarketing surveillance studies in approximately 60 000 patients.

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 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 1%: 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.

Genitourinary: urinary frequency, dysuria.

Metabolic System: fluid retention/edema.

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

CNS: restlessness, confusion, vertigo, syncope, nightmares, listlessness, inability to concentrate, somnolence.

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.

Eye, Ear, Nose and Throat: hearing loss, visual disturbances including teichopsia, epistaxis, ear ache, pressure/throbbing in ears, burning sensation of eyes/nose, twinging behind eyes, photophobia, conjunctivitis.

Extremities: paresthesias, muscle cramps, muscular fatigue, involuntary muscle movement, pain in arms/hands/shoulders, hand tremor, tenderness, s.c. nodule/first metatarsophalangeal joint.

General Illness: pyrexia, chills, lethargy, vasculitis, general deterioration, breast tenderness.

Genitourinary: dysuria, urinary urgency, hematuria, nocturia, vaginal bleeding, difficulty maintaining erection, rectopubic pain, cystitis, leukorrhea, renal calculus, interstitial nephritis, papillary necrosis, renal failure, uterine bleeding irregularities.

Metabolic System: change in weight, change in appetite, flushing, anorexia, excessive thirst, hot flashes, diaphoresis.

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

Respiratory: dyspnea, asthma, bronchospasm, hyperventilation, sneezing and sighing, bronchitis, pharyngitis, rhinitis, sinusitis.

Hypersensitivity: anaphylactic/anaphylactoid reaction, laryngeal edema.

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

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.

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.

One case of intentional etodolac overdosage has been reported. 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 g/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: 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 a single daily (400 mg or 600 mg) dose administered in the evening.

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.

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.

Availability And Storage: 200 mg: Each hard gelatin, light grey/dark grey, size #1 capsule, imprinted “APO 200”, contains: etodolac 200 mg. Nonmedicinal ingredients: black iron oxide, colloidal silicon dioxide, croscarmellose sodium, D&C Red No. 7 Calcium Lake, ethylene glycol monoethyl ether, FD&C Yellow No. 6 Aluminum Lake, gelatin, lactose, n-butyl alcohol, pharmaceutical shellac, SDA-3A alcohol, silicon dioxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide and yellow iron oxide. Bottles of 60, 100, 250, 500 and 1 000. Unit dose packages of 30 and 100. Apotex Long-Term Care Packages (Apo-LTC Paks) of 620 and 700.

300 mg: Each hard gelatin, light grey/light grey, size #0 capsule, imprinted APO 300, contains: etodolac 300 mg. Nonmedicinal ingredients: black iron oxide, colloidal silicon dioxide, croscarmellose sodium, D&C Red No. 7 Calcium Lake, ethylene glycol monoethyl ether, FD&C Yellow No. 6 Aluminum Lake, gelatin, lactose, n-butyl alcohol, pharmaceutical shellac, SDA-3A alcohol, silicon dioxide, sodium lauryl sulfate, stearic acid, talc, titanium dioxide and yellow iron oxide. Bottles of 60, 100, 250 and 500. Unit dose packages of 30 and 100. Apotex Long-Term Care Packages (Apo-LTC Paks) of 620 and 700.

Store at room temperature (15 to 30°C) and protect from moisture.

APO®-ETODOLAC Apotex Etodolac Anti-inflammatory

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