Etodolac

ETODOLAC- etodolac tablet, film coated, extended release
Teva Pharmaceuticals USA, Inc.

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 are contraindicated 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 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. 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. It has the following structural formula:

chemical structure for etodolac
(click image for full-size original)

C17 H21 NO3 M.W. 287.37

The inactive ingredients in etodolac extended-release tablets are calcium phosphate dibasic anhydrous, carbomer 934P, colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sodium lauryl sulfate, and titanium dioxide. In addition, the following colorants are used: 400 mg tablets — D&C Yellow #10 Lake, FD&C Red #40, and FD&C Yellow #6; 500 mg tablets — D&C Yellow #10 Lake, FD&C Blue No. 2 Indigo Carmine Aluminum Lake, and iron oxide black; 600 mg tablets — FD&C Blue No. 2 Indigo Carmine Lake, iron oxide black, and iron oxide yellow.

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.
*
% Coefficient of variation

Mean (CV)%*

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
*
% Coefficient of variation
Pharmacokinetic parameters obtained following administration of etodolac tablets
Age range (years)

Etodolac Extended-Release Tablets

Etodolac Tablets

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%)

42.0 (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%)

NA = not available

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