ETODOLAC TABLETS

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 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 etodolac, 400 mg. In addition, each tablet contains the following inactive ingredients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate and Opadry Pale Yellow, which contains hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol, polysorbate 80, yellow iron oxide and red iron oxide.

Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of etodolac, like that of other NSAIDs, is not known but is believed to be associated with the inhibition of prostaglandin biosynthesis.

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.

Analgesia was demonstrable ½ hour following single doses of 200 to 400 mg etodolac, with the peak effect occurring in 1 to 2 hours. The analgesic effect generally lasted for 4 to 6 hours (see CLINICAL TRIALS).

The pharmacokinetics of etodolac have been evaluated in 267 normal subjects, 44 elderly patients (>65 years old), 19 patients with renal failure (creatinine clearance 37 to 88 mL/min), 9 patients on hemodialysis, and 10 patients with compensated hepatic cirrhosis.

Etodolac, when administered orally, exhibits kinetics that are well described by a two-compartment model with first-order absorption.

Etodolac has no apparent pharmacokinetic interaction when administered with phenytoin, glyburide, furosemide or hydrochlorothiazide.

Etodolac is well absorbed and had a relative bioavailability of 100% when 200 mg capsules were compared with a solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from either the tablet or capsule formulation, is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (±1 SD) 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 (see Table 1 for summary of pharmacokinetic parameters). 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. Peak concentrations are dose-proportional for both total and free etodolac following doses up to 400 mg every 12 hours, but following a 600 mg dose, the peak is about 20% higher than predicted on the basis of lower doses.

Controlled clinical trials in analgesia were single-dose, randomized, double-blind, parallel studies in three pain models, including dental extractions. The analgesic effective dose for etodolac established in these acute pain models was 200 to 400 mg. The onset of analgesia occurred approximately 30 minutes after oral administration. Etodolac 200 mg provided efficacy comparable to that obtained with aspirin (650 mg). Etodolac 400 mg provided efficacy comparable to that obtained with acetaminophen with codeine (600 mg + 60 mg). The peak analgesic effect was between 1 to 2 hours. Duration of relief averaged 4 to 5 hours for 200 mg of etodolac and 5 to 6 hours for 400 mg of etodolac as measured by when approximately half of the patients required remedication.

The use of etodolac in managing the signs and symptoms of osteoarthritis of the hip or knee was assessed in double-bind, randomized, controlled clinical trials in 341 patients. In patients with osteoarthritis of the knee, etodolac, in doses of 600 to 1000 mg/day, was better than placebo in two studies. The clinical trials in osteoarthritis used b.i.d. dosage regimens.

Etodolac is indicated for acute and long-term use in the management of signs and symptoms of osteoarthritis. Etodolac is also indicated for the management of 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).

Anaphylactoid reactions may occur in patients without prior exposure to etodolac. Etodolac should not be given to patients with aspirin triad. The triad 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 nonsteroidal anti-inflammatory drugs. Fatal reactions have been reported in such patients (see CONTRAINDICATIONS and PRECAUTIONS – Pre-existing Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

In cases with advanced kidney disease, as with other NSAIDs, treatment with etodolac should only be initiated with close monitoring of the patient’s kidney function (see PRECAUTIONS – Renal Effects).

In late pregnancy, as with other NSAIDs, etodolac should be avoided because it may cause premature closure of the ductus arteriosus (see PRECAUTIONS – Teratogenic Effects – Pregnancy Category C).

Etodolac, like other drugs of its class, can cause discomfort and, rarely, more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes.

Physicians may wish to discuss with their patients the potential risks (see WARNINGS, PRECAUTIONS,ADVERSE REACTIONS) and likely benefits of nonsteroidal anti-inflammatory drug treatment.

Patients on etodolac should report to their physicians signs or symptoms of gastrointestinal ulceration or bleeding, blurred vision or other eye symptoms, skin rash, weight gain, or edema.

Because serious gastrointestinal tract ulcerations and bleeding can occur without warning symptoms, physicians should follow chronically treated patients for the signs and symptoms of ulcerations and bleeding and should inform them of the importance of this follow-up (see WARNINGS – Risk of GI Ulceration, Bleeding and Perforation with Nonsteroidal Anti-inflammatory Therapy).

Patients should also be instructed to seek medical emergency help in case of an occurrence of anaphylactoid reactions (see WARNINGS).

Patients on long-term treatment with etodolac, as with other NSAIDs, should have their hemoglobin or hematocrit 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 disease develop or if systemic manifestations occur (e.g., eosinophilia, rash, etc.) and if abnormal liver tests are detected, persist or worsen, etodolac should be discontinued.

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 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 mg to 100 mg/day) after 4 weeks of therapy. These levels then remained stable for up to 1 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 (3.0 to 5.3% unstained regions in the chromatid without dislocation) among the etodolac-treated cultures (50 to 200 µg/mL) compared to negative controls (2.0%); no other difference was noted between the controls and drug-treated groups. Etodolac showed no impairment of fertility in male and female rats up to oral doses of 16 mg/kg (94 mg/m²). However, reduced implantation of fertilized eggs occurred in the 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 have not been established.

As with any NSAID, however, 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 patients 65 years and older, no substantial differences in the side effect profile of etodolac were seen compared with the general population (see CLINICAL PHARMACOLOGY – Pharmacokinetics).

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 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 100 mg/day).

Body as a whole – Chills and fever.

Digestive system – Dyspepsia (10%), abdominal pain*, diarrhea*, flatulence*, nausea*, constipation, gastritis, melena, vomiting.

Nervous system – Asthenia/malaise*, dizziness*, depression, nervousness.

Skin and appendages – Pruritus, rash.

Special senses – Blurred vision, tinnitus.

Urogenital system – Dysuria, urinary frequency.

* Drug-related patient complaints occurring in 3 to 9% of patients treated with etodolac.

Drug-related patient complaints occurring in fewer than 3%, but more than 1%, are unmarked.

(Adverse reactions reported only in worldwide postmarketing experience, not seen in clinical trials, are considered rarer and are italicized)

Body as a whole –Allergic reactions, anaphylactoid reaction.

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.

Skin and appendages – Angioedema, sweating, urticaria, vesiculobullous rash, cutaneous vasculitis with purpura, Stevens-Johnson Syndrome, 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.

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. Gut decontamination 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). 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.

As with other NSAIDs, the lowest dose and longest dosing interval should be sought for each patient. Therefore, 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 PRECAUTIONS – General Precautions, Renal Effects).

The recommended total daily dose of etodolac for acute pain is up to 1000 mg, given as 200-400 mg every 6 to 8 hours. In some patients, if the potential benefits outweigh the risks; the dose may be increased to 1200 mg/day in order to achieve a therapeutic benefit that might not have been achieved with 1000 mg/day. 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 is: 300 mg b.i.d., t.i.d., or 400 mg b.i.d., or 500 mg b.i.d. During long-term administration, the dose of etodolac may be adjusted up or down depending on the clinical response of the patient. A lower dose of 600 mg/day may suffice for long-term administration. In patients who tolerate 100 mg/day, the dose may be increased to 1200 mg/day when a higher level of therapeutic activity is required. When treating patients with higher doses, the physician should observe sufficient increased clinical benefit to justify the higher dose. 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 are supplied as follows:

400 mg – oval, pale yellow, unscored tablet debossed with Endo 744 on one side and plain on the other side.

Bottles of 100
Bottles of 500

Store at controlled room temperature 15˚-30˚C (59˚-86˚F).

Dispense in a well-closed container as defined in the USP. Protect from moisture.

Caution: Federal (USA) law prohibits dispensing without prescription.

Manufactured by:
DuPont Pharma
Wilmington, Delaware 19880

6434-01/Rev. April, 1997