Etodolac

ETODOLAC- etodolac capsule
Denton Pharma, Inc. DBA Northwind Pharmaceuticals

Cardiovascular Thrombotic Events

  • Nonsteroidal anti-inflammatory drugs (NSAIDs 1) 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).
  • Etodolac capsules 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 (GI) events. (See WARNINGS).

1 Throughout this package insert, the term NSAID refers to a non-aspirin nonsteroidal anti-inflammatory drug.

DESCRIPTION

Etodolac is a member of the pyranocarboxylic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each 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 C 17 H 21 NO 3 , and it has the following structural formula:

structure

Each capsule, for oral administration, contains 200 mg or 300 mg of etodolac USP. The inactive ingredients in Etodolac Capsules USP include: lactose monohydrate, povidone, sodium starch glycolate, sodium lauryl sulfate, propylene glycol, colloidal silicon dioxide, magnesium stearate, talc, titanium dioxide, gelatin, D&C Red No. 28, D&C Red No. 33, FD&C Red No. 40, D&C Yellow No. 10, FD&C Blue No. 1, shellac, and black iron oxide.

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 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 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 the capsule formulation is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (± 1 SD) peak plasma concentrations (C max ) 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 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%)a Pharmacokinetic Parameters of Etodolac in Normal Healthy Adults and Various Special Populations

PK Parameters

Normal Healthy Adults (18 to 65) b (n=179)

Healthy Males (18 to 65) (n=176)

Healthy Females (27 to 65) (n=3)

Elderly (>65) (70 to 84)

Hemodialysis (24 to 65) (n=9)

Renal Impairment (46 to 73) (n=10)

Hepatic Impairment (34 to 60) (n=9)

Dialysis On

Dialysis Off

T max , h

1.4

(61%) a

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%)

a % Coefficient of variation
b Age Range (years)
NA = not available

Distribution

The mean apparent volume of distribution (Vd/F) of etodolac is approximately 390 mL/kg. Etodolac is more than 99% bound to plasma proteins, primarily to albumin. The free fraction is less than 1% and is independent of etodolac total 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. Data from in vitro studies, using peak serum concentrations at reported therapeutic doses in humans, show that the etodolac free fraction is not significantly altered by acetaminophen, ibuprofen, indomethacin, naproxen, piroxicam, chlorpropamide, glipizide, glyburide, phenytoin, and probenecid.

Metabolism

Etodolac is extensively metabolized in the liver. The role, if any, of a specific cytochrome P450 system in the metabolism of etodolac is unknown. Several etodolac 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 14 C-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolite does 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 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 dosing is 49 (± 16) mL/h/kg. Approximately 1% of an etodolac dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite:

– etodolac, unchanged

1%

– etodolac glucuronide

13%

– hydroxylated metabolites (6-, 7-, and 8-OH)

5%

– hydroxylated metabolite glucuronides

20%

– unidentified metabolites

33%

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. The terminal half-life (t 1/2 ) of etodolac is 6.4 hours (22% CV). In patients with severe renal dysfunction or undergoing hemodialysis, dosing adjustment is not generally necessary.

Fecal excretion accounted for 16% of the dose.

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