Etodolac

ETODOLAC- etodolac tablet, film coated
Blenheim Pharmacal, Inc.

Rx only

Cardiovascular Risk

NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI), and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. (See WARNINGS).
Etodolac capsules USP, 200 mg and 300 mg, and Etodolac tablets USP, 400 mg and 500 mg are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (See 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 (GI) events. (See WARNINGS).

DESCRIPTION

Etodolac capsules and tablets, USP are members of the pyranocarboxylic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each tablet and capsule contains etodolac for oral administration. Etodolac is a racemic mixture of [+]S and [-]R-enantiomers. Etodolac 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 of the base is 287.37. It has a pKa of 4.65 and an n-octanol: water partition coefficient of 11.4 at pH 7.4. The molecular formula for etodolac is C17 H21 NO3 , and it has the following structural formula:

Chemical Structure

Each Capsule, for oral administration, contains 200 or 300 mg of Etodolac. In addition, each capsule contains the following inactive ingredients: Ammonium Hydroxide USP, Black Iron Oxide USP, Colloidal Silicone Dioxide NF, Erythrosine (200 mg only), Ethyl Alcohol USP, Gelatin, Isopropyl Alcohol USP, Lactose Monohydrate NF, Magnesium Stearate NF, Microcrystalline Cellulose NF, N-Butyl Alcohol USP, Povidone USP, Propylene Glycol USP, Purified Water USP, Shellac, Titanium Dioxide.

Each Tablet, for oral administration, contains 400 mg or 500 mg of Etodolac. In addition, each tablet contains the following inactive ingredients: Hydroxypropyl Methylcellulose USP, Lactose Monohydrate NF, Magnesium Stearate, Microcrystalline Cellulose NF, Polyethylene Glycol, Povidone USP, Sodium Starch Glycolate NF and Titanium Dioxide. Also, each 400 mg tablet contains Iron Oxide Red and Iron Oxide Yellow. Each 500 mg tablet contains D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake, and FD&C Red #40 Aluminum Lake.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of etodolac, like that of other NSAIDs, is not completely understood, but may be related to the prostaglandin synthetase inhibition.

Etodolac is a racemic mixture of [-]R- and [+]S-etodolac. As with other NSAIDs, it has been demonstrated in animals that the [+]S-form is biologically active. Both enantiomers are stable and there is no [-]R to [+] S conversion in vivo.

Pharmacokinetics

Absorption

The systemic bioavailability of etodolac from etodolac capsules and tablets, USP is 100% as compared to solution and at least 80% as determined from mass balance studies. Etodolac is well absorbed and had a relative bioavailability of 100% when 200 mg capsules were compared with a solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from either the tablet or capsule formulation is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (± 1 SD) peak plasma concentrations (Cmax ) range from approximately 14 ± 4 to 37 ± 9 µg/mL after 200 to 600 mg single doses and are reached in 80 ± 30 minutes (see Table 1 for summary of pharmacokinetic parameters). The dose-proportionality based on the area under the plasma concentration-time curve (AUC) is linear following doses up to 600 mg every 12 hours. Peak concentrations are dose proportional for both total and free etodolac following doses up to 400 mg every 12 hours, but following a 600 mg dose, the peak is about 20% higher than predicted on the basis of lower doses. The extent of absorption of etodolac is not affected when etodolac tablets or capsules are administered after a meal. Food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration by 1.4 to 3.8 hours.

Table 1. Mean (CV%)* Pharmacokinetic Parameters of etodolac in Normal Healthy Adults and Various Special Populations
PK Parameters Normal Healthy Adults (18-65) Healthy Males (18-65) Healthy Females (27-65) Elderly (>65) (70-84) Hemodialysis (24-65) (n=9) Renal Impair-ment (46-73) Hepatic Impair-ment (34-60)
(n=179) (n=176) (n=3) Dialysis On Dialysis Off (n=10) (n=9)
*
% Coefficient of variation
Age Range (years)

Tmax ,h

1.4(61%)*

1.4(60%)

1.7(60%)

1.2(43%)

1.7(88%)

0.9(67%)

2.1(46%)

1.1(15%)

Oral Clearance, mL/h/kg (CL/F)

49.1(33%)

49.4(33%)

35.7(28%)

45.7(27%)

NA

NA

58.3(19%)

42.0(43%)

Apparent Volume of Distribution, mL/kg (Vd/F)

393(29%)

394(29%)

300(8%)

414(38%)

NA

NA

NA

NA

Terminal Half-Life,h

6.4(22%)

6.4(22%)

7.9(35%)

6.5(24%)

5.1(22%)

7.5(34%)

NA

5.7(24%)

NA = not available

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