Etodolac

ETODOLAC- etodolac tablet, film coated
Amneal Pharmaceuticals NY LLC

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 tablets, 400 mg and 500 mg 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).

DESCRIPTION

Etodolac is member of the pyranocarboxylic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs). Each tablet contains etodolac, USP for oral administration. Etodolac is a racemic mixture of [+]S and [-]R-enantiomers. Etodolac, USP 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:

formula
(click image for full-size original)

Each Tablet, for oral administration, contains 400 mg or 500 mg of Etodolac, USP. In addition, each tablet contains the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, sodium starch glycolate and titanium dioxide. Each 400 mg tablet also contains iron oxide red and iron oxide yellow. Each 500 mg tablet also contains D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake and FD&C Red No. 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 tablet 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 tablet 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 mcg/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 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

PKParameters

NormalHealthy Adults (18 to 65)

Healthy Males (18 to 65)

Healthy Females (27 to 65)

Elderly (>65) (70 to 84)

Hemodialysis (24 to 65) (n=9)

Renal Impairment (46 to 73)

Hepatic Impairment (34 to 60)

(n=179)

(n=176)

(n=3)

Dialysis

On

Dialysis

Off

(n=10)

(n=9)

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

(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

* % Coefficient of variation

Age Range (years)

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 (t1/2 ) 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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