Etodolac

ETODOLAC- etodolac tablet, film coated, extended release
California Pharmaceuticals, LLC

Cardiovascular Thrombotic Events

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

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 and Precautions ] .

Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs cause an increased risk of serious gastrointestinal (GI) 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [ see Warnings and Precautions ].

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-01

C 17 H 21 NO 3 M.W. 287.36

Each etodolac extended-release tablet, USP intended for oral administration contains 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 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%)
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%)

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