Etodolac

Description

DESCRIPTION Etodolac is member of the pyranocarboxylic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each tablet contains etodolac, USP for oral administration. Etodolac is a racemic mixture of [+]S and [-]R-enantiomers. Etodolac, USP is a 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 a pKa of 4.65 and an n-octanol: water partition coefficient of 11.4 at pH 7.4. The molecular formula for etodolac is C 17 H 21 NO 3 , and it has the following structural formula: Each Tablet, for oral administration, contains 400 mg or 500 mg of Etodolac, USP. In addition, each tablet contains the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate and titanium dioxide. Each 400 mg tablet also contains iron oxide red and iron oxide yellow. Each 500 mg tablet also contains D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake and FD&C Red No. 40 Aluminum Lake. formula

What Is Etodolac Used For?

INDICATIONS AND USAGE Carefully consider the potential benefits and risks of etodolac tablets and other treatment options before deciding to use etodolac tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). Etodolac tablets are 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

Dosage and Administration

DOSAGE AND ADMINISTRATION Carefully consider the potential benefits and risks of etodolac tablets and other treatment options before deciding to use etodolac tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ). After observing the response to initial therapy with etodolac tablets, the dose and frequency should be adjusted to suit an individual patient's needs. Dosage adjustment of etodolac tablets 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 to 400 mg every 6 to 8 hours. Doses of etodolac greater than 1000 mg/day have not been adequately evaluated in well-controlled trials. Osteoarthritis and Rheumatoid Arthritis The recommended starting dose of etodolac for the management of the signs and symptoms of osteoarthritis or rheumatoid arthritis is: 300 mg b.i.d., t.i.d., or 400 mg b.i.d., or 500 mg b.i.d. A lower dose of 600 mg/day may suffice for long-term administration. Physicians should be aware that doses above 1000 mg/day have not been adequately evaluated in well-controlled clinical trials. In chronic conditions, a therapeutic response to therapy with etodolac is sometimes seen within one week of therapy, but most often is observed by two weeks. After a satisfactory response has been achieved, the patient's dose should be reviewed and adjusted as required.

Side Effects (Adverse Reactions)

ADVERSE REACTIONS In patients taking etodolac or other NSAIDs, the most frequently reported adverse experiences occurring in approximately 1 to 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 4 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 a whole - Chills and fever. Digestive system - Dyspepsia (10%), abdominal pain 1 , diarrhea 1 , flatulence 1 , nausea 1 , abdominal distension, epigastric pain, abnormal stools, constipation, gastritis, melena, vomiting. Nervous system - Asthenia/malaise 1 , dizziness 1 , depression, nervousness, fatigue. Skin and appendages - Pruritus, rash. Special senses - Blurred vision, tinnitus. Urogenital system - Dysuria, urinary frequency. Musculoskeletal—Arthralgia. 1 Drug-related patient complaints occurring in 3 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 a whole - Allergic reaction, anaphylactic/anaphylactoid reactions (including shock). Cardiovascular system - Hypertension, congestive heart failure, flushing, palpitations, syncope, vasculitis (including necrotizing and allergic). Digestive system - Thirst, dry mouth, ulcerative stomatitis, anorexia, eructation, elevated liver enzymes, cholestatic hepatitis, hepatitis, cholestatic jaundice, duodenitis, jaundice, hepatic failure, liver necrosis, peptic ulcer with or without bleeding and/or perforation, intestinal ulceration, pancreatitis. Hemic and lymphatic system - Ecchymosis, anemia, thrombocytopenia, bleeding time increased, agranulocytosis, hemolytic anemia, aplastic anemia, leukopenia, neutropenia, pancytopenia. Metabolic and nutritional - Edema, serum creatinine increase, hyperglycemia in previously controlled diabetic patients. Nervous system - Insomnia, somnolence. Respiratory system - Asthma, pulmonary infiltration with eosinophilia . Skin and appendages - Angioedema, sweating, urticaria, exfoliative dermatitis, vesiculobullous rash, cutaneous vasculitis with purpura, Stevens-Johnson Syndrome, toxic epidermal necrolysis, fixed drug eruption (FDE), leukocytoclastic vasculitis, hyperpigmentation , erythema multiforme. Special senses - Photophobia, transient visual disturbances. Urogenital system - Elevated BUN, renal failure, renal insufficiency, renal papillary necrosis. Incidence Less Than 1% - Causal Relationship Unknown (Medical events occurring under circumstances where causal relationship to etodolac is uncertain. These reactions are listed as alerting information for physicians.) Body as a whole - Infection, headache. Cardiovascular system - Arrhythmias, myocardial infarction, cerebrovascular accident. Digestive system - Esophagitis with or without stricture or cardiospasm, colitis, GI discomfort, burning...

Drug Interactions

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, such as etodolac, should not be administered prior to or concomitantly with high doses of methotrexate. NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. In general, 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 with possible loss of blood pressure control. 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 insufficiency or failure (see WARNINGS, Renal Effects ), as well as to assure diuretic efficacy. Glyburide Etodolac has no apparent pharmacokinetic interaction when administered with glyburide. Lithium NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. Careful monitoring of lithium levels is advised in the...

Contraindications

CONTRAINDICATIONS Etodolac tablets are contraindicated in patients with known hypersensitivity to etodolac or other ingredients in etodolac tablets. Etodolac tablets 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 ). In the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).

Pregnancy and Breastfeeding

Pregnancy Risk Summary Use of NSAIDs, including etodolac, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of etodolac use between about 20 and 30 weeks of gestation, and avoid etodolac use at about 30 weeks of gestation and later in pregnancy [see WARNINGS; Fetal Toxicity ]. Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including etodolac, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction 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 a clear drug or dose-response relationship. Animal reproduction studies are not always predictive of human response. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as etodolac, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney...

Nursing Mothers Trace amounts of some NSAIDs have been reported in human milk. 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, a decision should be made whether to discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

Overdosage

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

How Supplied

HOW SUPPLIED Product: 50090-3963 NDC: 50090-3963-1 20 TABLET, FILM COATED in a BOTTLE, PLASTIC NDC: 50090-3963-5 60 TABLET, FILM COATED in a BOTTLE, PLASTIC