ETODOLAC TABLETS, USP
400 mg and 500 mg

Etodolac is a pyranocarboxylic acid, chemically designated as (±) 1,8-diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1-acetic acid. The structural formula for etodolac is shown below:

The molecular formula for etodolac is C₁₇H₂₁NO₃. 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. Etodolac, USP is a white crystalline compound, insoluble in water but soluble in alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol.

Each tablet, for oral administration, contains 400 mg or 500 mg of etodolac, USP. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, glyceryl triacetate, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, polysorbate 80, povidone, sodium lauryl sulfate, sodium starch glycolate, and titanium dioxide. The 500 mg tablet also contains D&C Red No. 30 Aluminum Lake.

Etodolac is a non-steroidal 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 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. Both enantiomers are stable and there is no [-]R to [+]S conversion in vivo.

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 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

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 etodolac have been reported in such patients (see WARNINGS: Anaphylactoid Reactions and PRECAUTIONS: General: Preexisting Asthma).

Etodolac is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greater risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Renal pelvic transitional epithelial hyperplasia, a spontaneous change occurring with variable frequency, was observed with increased frequency in treated male rats in a 2 year chronic study.

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 patient's renal function is advisable.

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: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

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.

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: Teratogenic Effects. Pregnancy Category C ).

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 slowly if a 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.

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 bulers, 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.

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 a 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, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, etodolac should be discontinued.

The urine of patients who take etodolac can give a false-positive reaction for urinary bilirubin (urobilin) due to the presence of phenolic metabolites of etodolac. Diagnostic dipstick 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 mg to 1000 mg/day) after 4 weeks of therapy. These levels then remained stable for up to one year of therapy.

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 2 years or 18 months, respectively. Etodolac was not mutagenic in in vitro tests performed with S. typhimurium and mouse lymphoma cells as well as in an in vivo mouse micronucleus test. However, data from the in vitro human peripheral lymphocyte test showed an increase in the number of gaps (3 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%); 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 8 mg/kg group.

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. 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.

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

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).

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 post-marketing 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 uled 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 per day).

Body as a Whole: chills and fever

Digestive System: dyspepsia (10%), abdominal painDrug-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., 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.

(Adverse reactions reported only in worldwide post-marketing experience, not seen in clinical trials, are considered rarer and are italicized.)

Body as a Whole: allergic reaction, anaphylactic/anaphylactoid reaction (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.

(Medical events occurring under circumstances where causal relationship to etodolac is uncertain. These reactions are uled 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

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.

Body as a Whole: sepsis, death

Cardiovascular System: tachycardia

Digestive System: gastric ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis

Hemic and Lymphatic System: lymphadenopathy

Nervous System: anxiety, dream abnormalities, convulsions, coma, hallucinations, meningitis, tremors, vertigo

Respiratory System: respiratory depression, pneumonia

Urogenital System: oliguria/polyuria, proteinuria.

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.

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 initial therapy with etodolac, the dose and frequency should be adjusted to suit an individual patient's 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).

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 clinical trials.

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.

Etodolac Tablets, USP are available containing 400 mg and 500 mg of Etodolac, USP.

The 400 mg tablets are film-coated white, oval-shaped, unscored tablets debossed with MYLAN on one side of the tablet and 237 on the other side. They are available as follows:

NDC 0378-0237-01
bottles of 100 tablets

The 500 mg tablets are film-coated pink, oval-shaped, unscored tablets debossed with MYLAN on one side of the tablet and 242 on the other side. They are available as follows:

NDC 0378-1242-01
bottles of 100 tablets