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Lodine

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Lodine

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(Generic versions may still be available.)

Lodine

CLINICAL PHARMACOLOGY

Pharmacodynamics

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

Lodine 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 Lodine (etodolac) 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 g/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 Lodine (etodolac) is 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 Lodine (etodolac) in Normal Healthy Adults and Various Special Populations


PK
Parameters
Normal
Healthy
Adults
(18-65)*
(n=179)
Healthy
Males
(18-65)
(n=176)
Healthy
Females
(27-65)
(n=3)
Elderly
(>65)
(70-84)
Hemodialysis
(24-65)
(n=9)
Renal
Impairment
(46-73)
(n=10)
Hepatic
Impairment
(34-60)
(n=9)
Dialysis On Dialysis Off
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%)
OralClearance, 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%)
% Coefficient of variation
*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 14C-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 a Lodine (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 (t½) 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.

Special Populations

Geriatric

In Lodine (etodolac) clinical studies, no overall differences in safety or effectiveness were observed between these patients and younger patients. In pharmacokinetic studies, age was shown not to have any effect on etodolac half-life or protein binding, and there was no change in expected drug accumulation. Therefore, no dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics (see PRECAUTIONS, Geriatric Use).

Etodolac is eliminated primarily by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see WARNINGS, Renal Effects).

Pediatric

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Race

Pharmacokinetic differences due to race have not been identified. Clinical studies included patients of many races, all of whom responded in a similar fashion.

Hepatic Insufficiency

Etodolac is predominantly metabolized by the liver. In patients with compensated hepatic cirrhosis, the disposition of total and free etodolac is not altered. Patients with acute and chronic hepatic diseases do not generally require reduced doses of etodolac compared to patients with normal hepatic function. However, etodolac clearance is dependent on liver function and could be reduced in patients with severe hepatic failure. Etodolac plasma protein binding did not change in patients with compensated hepatic cirrhosis given Lodine (etodolac) .

Renal Insufficiency

Lodine (etodolac) pharmacokinetics have been investigated in subjects with renal insufficiency. Etodolac renal clearance was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance 37 to 88 mL/min). Furthermore, there were no significant differences in the disposition of total and free etodolac in these patients. However, etodolac should be used with caution in such patients because, as with other NSAIDs, it may further decrease renal function in some patients. In patients undergoing hemodialysis, there was a 50% greater apparent clearance of total etodolac, due to a 50% greater unbound fraction. Free etodolac clearance was not altered, indicating the importance of protein binding in etodolac's disposition. Etodolac is not significantly removed from the blood in patients undergoing hemodialysis.

Clinical Trials

Analgesia

Controlled clinical trials in analgesia were single-dose, randomized, double-blind, parallel studies in three pain models, including dental extractions. The analgesic effective dose for Lodine (etodolac) established in these acute pain models was 200 to 400 mg. The onset of analgesia occurred approximately 30 minutes after oral administration. Lodine (etodolac) 200 mg provided efficacy comparable to that obtained with aspirin (650 mg). Lodine (etodolac) 400 mg provided efficacy comparable to that obtained with acetaminophen with codeine (600 mg + 60 mg). The peak analgesic effect was between 1 to 2 hours. Duration of relief averaged 4 to 5 hours for 200 mg of Lodine (etodolac) and 5 to 6 hours for 400 mg of Lodine (etodolac) as measured by when approximately half of the patients required remedication.

Osteoarthritis

The use of Lodine (etodolac) in managing the signs and symptoms of osteoarthritis of the hip or knee was assessed in double-blind, randomized, controlled clinical trials in 341 patients. In patients with osteoarthritis of the knee, Lodine (etodolac) , in doses of 600 to 1000 mg/day, was better than placebo in two studies. The clinical trials in osteoarthritis used b.i.d. dosage regimens.

Rheumatoid Arthritis

In a 3-month study with 426 patients, Lodine (etodolac) 300 mg b.i.d. was effective in management of rheumatoid arthritis and comparable in efficacy to piroxicam 20 mg/day. In a long-term study with 1,446 patients in which 60% of patients completed 6 months of therapy and 20% completed 3 years of therapy, Lodine (etodolac) in a dose of 500 mg b.i.d. provided efficacy comparable to that obtained with ibuprofen 600 mg q.i.d. In clinical trials of rheumatoid arthritis patients, Lodine (etodolac) has been used in combination with gold, d-penicillamine, chloroquine, corticosteroids, and methotrexate.

Last reviewed on RxList: 9/10/2007
This monograph has been modified to include the generic and brand name in many instances.

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