Etodolac

ETODOLAC- etodolac tablet, film coated, extended release
Proficient Rx LP

Cardiovascular Thrombotic Events

Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions ].
Etodolac extended-release tablets arecontraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications and Warnings ].

Gastrointestinal Risk

NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding , ulceration , and perforation of the stomach or intestines , which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS).

DESCRIPTION

Etodolac extended-release tablets, USP contain etodolac, which is a member of the pyranocarboxylic acid group of non-steroidal anti-inflammatory drugs (NSAIDs). Each tablet contains etodolac for oral administration. Etodolac is a racemic mixture of [+]S and [-]R-enantiomers. Etodolac, USP is a white to off-white crystalline powder, 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. It has the following structural formula:

Etodolac Extended-release Tablets, USP
(click image for full-size original)

C17 H21 NO3 M.W. 287.36

Each etodolac extended-release tablet, USP intended for oral administration contains 400 mg or 500 mg or 600 mg of etodolac. In addition, each tablet contains the following inactive ingredients: disodium hydrogen phosphate, ethylcellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, talc, titanium dioxide and triacetin. Additionally each 400 mg tablet contains: D&C yellow # 10 aluminum lake, FD&C Red # 40 aluminum lake and FD&C yellow # 6 aluminum lake and each 500 mg tablet contains: FD&C Blue # 2 aluminum lake, iron oxide black and iron oxide yellow and each 600 mg tablet contains: FD&C blue # 2 aluminum lake, iron oxide red and iron oxide yellow.

The USP Drug Release test complies with USP Dissolution Test 1.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Etodolac extended-release tablets are a non-steroidal 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 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 (immediate-release) etodolac tablets.

Table 1
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 (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 (t1/2), h

6.4 (22%)

8.4 (30%)

Table 2 Mean (CV%)* Pharmacokinetic Parameters of Etodolac in Normal Healthy Adults and Various Special Populations
Etodolac Extended-release Tablets Etodolac Tablets
* % Coefficient of variation
Pharmacokinetic parameters obtained following administration of etodolac tablets
Age range (years)
NA = not available

PK Parameters

Normal Healthy Adults

Healthy Males

Healthy Females

Elderly (> 65 yr)

Hemodialysis (24 to 65) (n = 9)

Renal Impairment

Hepatic Impairment

(18 to 44) (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)

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 (43%)

ApparentVolume ofDistribution,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%)

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