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Etodolac XR

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Etodolac XR

CLINICAL PHARMACOLOGY

Pharmacodynamics

Etodolac extended-release tablets are a nonsteroidal anti-inflammatory drug (NSAID) that exhibit 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 1 shows the comparison of etodolac pharmacokinetic parameters after the administration of etodolac tablets and etodolac extended-release tablets.

Table 2 shows the etodolac pharmacokinetic parameters in various populations. The data from patients with renal and hepatic impairment were obtained following administration of (immediaterelease) etodolac tablets.

Table 1.

Pharmacokinetic Parameters Mean (CV) % †
etodolac tablets etodolac extended-release tablets
Extent of Oral Absorption (Bioavailability) [F] ≥ 80% ≥ 80%
Time to Peak Concentration (Tmax), 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%)
† % Coefficient of variation

Table 2. Mean (CV%) † Pharmacokinetic Parameters of Etodolac in Normal Healthy Adults and Various Special Populations

PK Parameters etodolac extended-release tablets etodolac tablets
Normal
Healthy Adults
(18-44)*
(n=116)
Healthy
Males
(18-43)
(n=102)
Healthy
Females
(25-44)
(n=14)
Elderly
( > 65 yr)
(66-88)
(n=24)
Hemodialysis†
(24-65 )
(n=9)
Renal Impairment‡
(46-73)
(n=10)
Hepatic Impairment‡
(34-60)
(n=9)
Dialysis On Dialysis Off
Tmax,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%)
† % Coefficient of variation
* Age range (years)
‡ Pharmacokinetic parameters obtained following administration of etodolac tablets
NA = not available

Food/Antacid Effects

Food has no significant effect on the extent of etodolac extended-release tablets absorption, however, food significantly increased Cmax (54%) following a 600 mg dose.

The extent of absorption of etodolac is not affected when etodolac is administered with an antacid. Co-administration, 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 (t½) 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:

Table 3. Pharmacokinetic Parameter Estimates for Etodolac Extended-release Tablets in Patients with Juvenile Rheumatoid Arthritis

Parameter JRAa
(Age: 6-16)b
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 (t½), h 12.1 (75%)
a: Mean (CV) of parameter estimates predicted from population pharmacokinetics
b: Age range (years)

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 – 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).

Last reviewed on RxList: 12/9/2008
This monograph has been modified to include the generic and brand name in many instances.

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