Indications and Usage
Carefully consider the potential benefits and risks of etodolac extended-release tablets and other treatment options before deciding to use etodolac extended-release tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS ).
Etodolac extended-release tablets are indicated:
- For relief of signs and symptoms of juvenile arthritis
- For relief of the signs and symptoms of rheumatoid arthritis
- For relief of the signs and symptoms of osteoarthritis
Dosage and Administration
Carefully consider the potential benefits and risks of etodolac extended-release tablets and other treatment options before deciding to use etodolac extended-release 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 extended-release tablets, the dose and frequency should be adjusted to suit an individual patient's needs.
Juvenile Rheumatoid Arthritis
For the relief of the signs and symptoms of juvenile rheumatoid arthritis in patients 6 to 16 years of age, the recommended dose given orally once per day should be based on body weight, according to the following table:
| Body Weight Range (kg) | Dose |
|---|---|
| 20 to 30 | 400 mg Tablet × 1 |
| 31 to 45 | 600 mg Tablet × 1 |
| 46 to 60 | 400 mg Tablet × 2 |
| >60 | 500 mg Tablet × 2 |
Rheumatoid Arthritis and Osteoarthritis
For the relief of the signs and symptoms of osteoarthritis or rheumatoid arthritis, the recommended starting dose of etodolac extended-release tablets is 400 to 1000 mg given orally once per day.
As with other NSAIDs, the lowest effective dose should be sought for each patient. In chronic conditions, a therapeutic response to therapy with etodolac extended-release tablets is sometimes seen within one week of therapy, but most often is observed by two weeks.
Contraindications
Etodolac extended-release tablets are contraindicated in patients with known hypersensitivity to etodolac.
Etodolac extended-release tablets should not be given to patients who have experienced asthma, urticaria, or 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, Preexisting Asthma ).
Etodolac extended-release tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ).
Adverse Reactions
A total of 1552 patients were exposed to etodolac extended-release tablets in controlled clinical studies of at least 4 weeks in length and using daily doses in the range of 400 to 1200 mg. In the tabulations below, adverse event rates are generally categorized based on the incidence of events in the first 30 days of treatment with etodolac extended-release tablets. As with other NSAIDs, the cumulative adverse event rates may increase significantly over time with extended therapy.
In patients taking NSAIDs, including etodolac extended-release tablets, the most frequently reported adverse experiences occurring in approximately 1 to 10% of patients are: gastrointestinal experiences including:
| abdominal pain | constipation | diarrhea |
| dyspepsia | flatulence | GI ulcers (gastric/duodenal) |
| gross bleeding/perforation | nausea | vomiting |
other events including:
| abnormal renal function Adverse events that were observed in < 1% of patients in the first 30 days of treatment with etodolac extended-release tablets in clinical trials. | anemia | asthenia |
| dizziness | edema | elevated liver enzymes |
| headaches | hypertension | increased bleeding time |
| infection | pharyngitis | pruritus |
| rashes | rhinitis | tinnitus |
Additional NSAID Adverse Experiences Reported Occasionally with NSAIDs or Etodolac Extended-Release Tablets Include
Body as a whole - allergic reaction, anaphylactic/anaphylactoid reactions (including shock), chills, fever, sepsis
Cardiovascular system - congestive heart failure, flushing, palpitations, tachycardia, syncope, vasculitis (including necrotizing and allergic)
Digestive system - anorexia, cholestatic hepatitis, cholestatic jaundice, dry mouth, duodenitis, eructation, esophagitis, gastritis, gastric/peptic ulcers, glossitis, hepatic failure, hepatitis, hematemesis, intestinal ulceration, jaundice, liver necrosis, melena, pancreatitis, rectal bleeding, stomatitis
Hemic and lymphatic system - agranulocytosis, ecchymosis, eosinophilia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, purpura, thrombocytopenia
Metabolic and nutritional - hyperglycemia in previously controlled diabetic patients
Nervous system - anxiety, confusion, depression, dream abnormalities, insomnia, nervousness, paresthesia, somnolence, tremors, vertigo
Respiratory system - asthma, dyspnea, pulmonary infiltration with eosinophilia
Skin and appendages - angioedema, cutaneous vasculitis with purpura, erythema multiforme, hyperpigmentation, sweating, urticaria, vesiculobullous rash
Special senses - blurred vision, photophobia, transient visual disturbances
Urogenital system - dysuria, elevated BUN, oliguria/polyuria, proteinuria, renal failure, renal insufficiency, renal papillary necrosis, serum creatinine increase, urinary frequency
Other NSAID Adverse Reactions, Which Occur Rarely Are
Body as a whole - anaphylactic reactions, appetite changes, death
Cardiovascular system - arrhythmia, cerebrovascular accident, hypotension, myocardial infarction
Digestive system - colitis, esophagitis with or without stricture or cardiospasm, thirst, ulcerative stomatitis
Hemic and lymphatic system - aplastic anemia, lymphadenopathy
Metabolic and nutritional - change in weight
Nervous system - coma, convulsions, hallucinations, meningitis
Respiratory - bronchitis, pneumonia, respiratory depression, sinusitis
Skin and appendages - alopecia, exfoliative dermatitis, maculopapular rash, photosensitivity, skin peeling, Stevens-Johnson syndrome, toxic epidermal necrosis (TEN), and fixed drug eruption (FDE) (see WARNINGS)
Special senses - conjunctivitis, deafness, hearing impairment, taste perversion
Urogenital system - cystitis, hematuria, interstitial nephritis, leukorrhea, renal calculus, uterine bleeding irregularities
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.
Aspirin
When etodolac extended-release tablets are 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 extended-release tablets and aspirin is not generally recommended because of the potential of increased adverse effects.
Cyclosporine and Digoxin
Etodolac extended-release tablets, like other NSAIDs, through effects on renal prostaglandins, may cause changes in the elimination of these drugs, leading to elevated serum levels of cyclosporine and digoxin and increased toxicity. Nephrotoxicity associated with cyclosporine may also be enhanced. Patients receiving these drugs who are given etodolac extended-release tablets, 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.
Furosemide
Clinical studies, as well as post marketing observations, have shown that etodolac extended-release tablets can reduce the natriuretic effect of furosemide and thiazides in some patients. 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 failure (see WARNINGS, Renal Effects ), as well as to assure diuretic efficacy.
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.
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. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
Phenylbutazone
Phenylbutazone causes an increase (by about 80%) in the free fraction of etodolac. Although in vivostudies have not been done to see if etodolac clearance is changed by coadministration of phenylbutazone, it is not recommended that they be coadministered.
Warfarin
The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone.
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. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of NSAIDs, and may occur following an 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 may not be useful due to high protein binding.
Description
Etodolac Extended-Release Tablets contain etodolac, which is a member of the pyranocarboxylic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each tablet contains etodolac for oral administration. Etodolac is a racemic mixture of [+]S and [-]R-enantiomers. It 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 is 287.37. Its molecular formula is C 17H 21NO 3and it has the following structural formula:
The inactive ingredients in etodolac extended-release tablets include: HPMC 2910, hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, PEG 8000, polydextrose FCC, povidone, titanium dioxide and triacetin. In addition, the 500 mg and 600 mg tablets contain Indigo Carmine Lake and the 400 mg and 600 mg tablets contain Allura Red AC Lake and Sunset Yellow F.C.F. Lake. In addition, the 500 mg tablets contain yellow iron oxide. Meets USP Dissolution Test 4.
Chemical StructureClinical Pharmacology
Pharmacodynamics
Etodolac extended-release tablets are a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of etodolac extended-release tablets, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition.
Pharmacokinetics
Absorption
Etodolac extended-release tablets and etodolac tablets both contain etodolac, but differ in their release characteristics. The systemic availability of etodolac from etodolac extended-release tablets is generally greater than 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. After oral administration of etodolac extended-release tablets in doses up to 800 mg once daily, peak concentrations occur approximately 6 hours after dosing and are dose proportional for both total and free etodolac.
Table 1shows the comparison of etodolac pharmacokinetic parameters after the administration of etodolac tablets and etodolac extended-release tablets.
Table 2shows the etodolac pharmacokinetic parameters in various populations. The data from patients with renal and hepatic impairment were obtained following administration of (immediate-release) etodolac tablets.
| Mean (CV)% % Coefficient of variation | ||
|---|---|---|
| Pharmacokinetic Parameters | Etodolac Tablets | Etodolac Extended-Release Tablets |
| Extent of Oral Absorption (Bioavailability) [F] | ≥ 80% | ≥ 80% |
| Time to Peak Concentration (T max), h | 1.4 (61%) | 6.7 (47%) |
| Oral Clearance (CL/F), mL/h/kg | 49.1 (33%) | 46.8 (37%) |
| Apparent Volume of Distribution (Vd/F), mL/kg | 393 (29%) | 566 (26%) |
| Terminal Half-Life (t½), h | 6.4 (22%) | 8.4 (30%) |
| Etodolac Extended-Release Tablets | Etodolac Tablets | |||||||
|---|---|---|---|---|---|---|---|---|
| PK Parameters | Normal Healthy Adults | Healthy Males | Healthy Females | Elderly (> 65 yr) | Hemodialysis Pharmacokinetic parameters obtained following administration of etodolac tablets(24 to 65) (n=9) | Renal Impairment | Hepatic Impairment | |
| (18 to 44) Age range (years)(n=116) | (18 to 43) (n=102) | (25 to 44) (n=14) | (66 to 88) (n=24 | Dialysis On | Dialysis Off | (46 to 73) (n=10) | (34 to 60) (n=9) | |
| NA = not available | ||||||||
| T max, h | 6.7
(47%) |
6.8
(45%) |
4.5
(56%) |
6.2
(51%) |
1.7
(88%) |
0.9
(67%) |
2.1
(46%) |
1.1
(15%) |
| Oral Clearance, mL/h/kg (CL/F) | 46.8
(37%) |
46.8
(37%) |
47.2
(38%) |
51.6
(40%) |
NA | NA | 58.3
(19%) |
42.0
(43%) |
| Apparent Volume of Distribution, mL/kg (Vd/F) | 566
(26%) |
580
(26%) |
459
(28%) |
552
(34%) |
NA | NA | NA | NA |
| Terminal Half-Life, h | 8.4
(30%) |
8.4
(29%) |
7.6
(45%) |
7.8
(26%) |
5.1
(22%) |
7.5
(34%) |
NA | 5.7
(24%) |
Food/Antacid Effects
Food has no significant effect on the extent of etodolac extended-release tablets absorption, however, food significantly increased C max(54%) following a 600 mg dose.
The extent of absorption of etodolac is not affected when etodolac is administered with antacid. Coadministration, with an antacid, decreases the peak concentration reached by about 15 to 20% with no measurable effect on time-to-peak.
Distribution
The mean apparent volume of distribution (Vd/F) of etodolac following administration of etodolac extended-release tablets is 566 mL/kg. Etodolac is more than 99% bound to plasma proteins, primarily to albumin, and is independent of etodolac concentration over the dose range studied. It is not known whether etodolac is excreted in human milk. However, based on its physical-chemical properties, excretion into breast milk is expected.
Metabolism
Etodolac metabolites do not contribute significantly to the pharmacological activity of etodolac extended-release tablets.
Following administration of immediate-release etodolac, several metabolites have been identified in human plasma and urine. Other metabolites remain to be identified. The metabolites include 6-, 7-, and 8- hydroxylated etodolac and etodolac glucuronide. After a single dose of 14C-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolites do not accumulate in the plasma of patients with normal renal function. The extent of accumulation of hydroxylated-etodolac metabolites in patients with renal dysfunction has not been studied. The role, if any, of a specific cytochrome P450 system in the metabolism of etodolac is unknown. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces.
Excretion
The mean oral clearance of etodolac following oral etodolac extended-release tablets dosing is 47 (±17) mL/h/kg. The terminal half-life (t ½) of etodolac after etodolac extended-release tablets administration is 8.4 hours compared to 6.4 hours for etodolac tablets. Approximately 1% of an etodolac tablet dose is excreted unchanged in the urine, with 72% of the dose excreted into the urine as parent drug plus metabolites:
| -etodolac, unchanged | 1% |
| -etodolac glucuronide | 13% |
| -hydroxylated metabolites (6-, 7-, and 8-OH) | 5% |
| -hydroxylated metabolite glucuronides | 20% |
| -unidentified metabolites | 33% |
Fecal excretion accounted for 16% of the dose.
Special Populations
Geriatric
In clinical studies, age was not shown to have any effect on half-life or protein binding, and demonstrated no change in expected drug accumulation. No dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics. The elderly may need dosage adjustment, however, as they may be more sensitive to antiprostaglandin effects than younger patients (see PRECAUTIONS, Geriatric Use ).
Pediatric
The pharmacokinetics of etodolac extended-release tablets were assessed in an open-label, 12-week clinical trial which included plasma sampling for population pharmacokinetics. Seventy-two (72) patients, 6 to 16 years of age, with juvenile rheumatoid arthritis, received etodolac extended-release tablets in doses of 13.3 to 21.3 mg/kg given as 400 to 1000 mg once daily. The results from a population pharmacokinetic analysis based on the 59 subjects who completed the trial are as follows:
| Parameter | JRA Mean (CV) of parameter estimates predicted from population pharmacokinetics(Age: 6 to 16) Age range (years)n = 59 |
|---|---|
| Oral Clearance (CL/F), mL/h/kg | 47.8 (38%) |
| Apparent Volume of Distribution (Vd/F), mL/kg | 78.9 (61%) |
| Half-life (t ½), h | 12.1 (75%) |
While similar, the pharmacokinetic parameters for children with juvenile rheumatoid arthritis did not directly correlate with adult pharmacokinetic data in rheumatoid arthritis. In the population pharmacokinetic analysis, body weights below 50 kg were found to correlate with CL/F (see DOSAGE AND ADMINISTRATION ).
Race
Pharmacokinetic differences due to race have not been identified. Clinical studies included patients of many races, all of whom responded in a similar fashion.
Hepatic Insufficiency
The pharmacokinetics of etodolac following administration of etodolac extended-release tablets have not been investigated in subjects with hepatic insufficiency. Following administration of etodolac tablets, the plasma protein binding and disposition of total and free etodolac were unchanged in the presence of compensated hepatic cirrhosis. Although no dosage adjustment is generally required in patients with chronic hepatic diseases, etodolac clearance is dependent on liver function and could be reduced in patients with severe hepatic failure.
Renal Insufficiency
The pharmacokinetics of etodolac following administration of etodolac extended-release tablets have not been investigated in subjects with renal insufficiency. Etodolac renal clearance following administration of etodolac tablets was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance, 37 to 88 mL/min). Although renal elimination is a significant pathway of excretion for etodolac metabolites, no dosing adjustment in patients with mild-to-moderate renal dysfunction is generally necessary. Etodolac plasma protein binding decreases in patients with severe renal deficiency. Etodolac should be used with caution in such patients because, as with other NSAIDs, it may further decrease renal function in some patients. Etodolac is not significantly removed from the blood in patients undergoing hemodialysis.
Clinical Studies
Arthritis
The use of etodolac extended-release tablets in managing the signs and symptoms of osteoarthritis of the knee and rheumatoid arthritis was assessed in double-blind, randomized, parallel, controlled clinical trials in 1552 patients. In these trials, etodolac extended-release tablets, given once daily, provided efficacy comparable to immediate-release etodolac.
The safety, efficacy, and pharmacokinetics of etodolac extended-release tablets were assessed in an open-label, 12-week clinical trial. Seventy-two (72) patients, 6 to 16 years of age, with juvenile rheumatoid arthritis, received etodolac extended-release tablets in doses of 400 to 1000 mg (13.3 to 21.3 mg/kg body weight) once daily. At these doses, etodolac extended-release tablets controlled the signs and symptoms of juvenile rheumatoid arthritis. Based on the results of this study, the safety profile of etodolac extended-release tablets (at doses not exceeding 20 mg/kg) appeared to be similar to that observed in the adult arthritic patients in clinical trials. (See PRECAUTIONS, Pediatric Use ).
How Supplied / Storage and Handling
Etodolac extended-release tablets are available as:
400 mg tablets(pink, round, bi-convex, film coated tablet engraved with "T400" on one side and plain on the other side).
- in bottles of 60, NDC 16714-497-01
- in bottles of 100, NDC 16714-497-02
500 mg tablets(green, oblong, normal convex, film coated tablet engraved with "T500" on one side and plain on the other side).
- in bottles of 60, NDC 16714-498-01
- in bottles of 100, NDC 16714-498-02
600 mg tablets(grey, oval, bi-convex, film coated tablet engraved with "T600" on one side and plain on the other side).
- in bottles of 60, NDC 16714-499-01
- in bottles of 100, NDC 16714-499-02
Store at 20° to 25°C (68° to 77°F)[See USP Controlled Room Temperature].
Protect from excessive heat and humidity.
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
Patient Counseling Information
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.
-
Cardiovascular Thrombotic Events
Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately (see WARNINGS ). - Etodolac extended-release tablets, 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 ).
-
Serious Skin Reactions, including DRESS
Advise patients to stop taking etodolac extended-release tablets immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [ see Warnings ]. -
Heart Failure and Edema
Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur (see WARNINGS ). - 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 ).
-
Fetal Toxicity
Inform pregnant women to avoid use of etodolac extended-release tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with etodolac extended-release tablets is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [ see WARNINGS; Fetal Toxicity, PRECAUTIONS; Pregnancy ].