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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Etodolac

Last Update: April 5, 2018.

OVERVIEW

Introduction

Etodolac is a nonsteroidal antiinflammatory drug (NSAID) that is available by prescription only and is used long term for therapy of chronic arthritis and short term for acute pain. Etodolac has been linked to rare instances of clinically apparent drug induced liver disease.

Background

Etodolac (e toe' doe lak) belongs to the acetic acid derivative class of NSAIDs similar to diclofenac, sulindac, ketorolac and indomethacin. Like other NSAIDs, etodolac is a potent cyclo-oxygenase (Cox-1 and -2) inhibitor which blocks the formation of prostaglandins that are important in pain and inflammatory pathways. It has analgesic as well as antipyretic and antiinflammatory activity. Etodolac was approved in the United States in 1991 and is available by prescription only. Currently more than 3 million prescriptions are filled yearly. Current indications include treatment of osteoarthritis and rheumatoid arthritis and for short term treatment of acute pain. Etodolac is available as capsules or tablets in doses of 200, 300, 400 and 500 mg generically and under the trade name Lodine. Extended release formulations of 400, 500 and 600 mg are also available for once or twice daily dosing. The recommended dose is 400 to 1200 mg in 2 to 4 divided doses daily, based upon response and tolerance. Like other NSAIDs, etodolac is generally well tolerated, but side effects can include headache, dizziness, somnolence, dyspepsia, nausea, abdominal discomfort, heartburn, diarrhea, peripheral edema, pruritus and hypersensitivity reactions.

Hepatotoxicity

Prospective studies show that 1% to 2% of patients taking etodolac experience at least transient serum aminotransferase elevations. These may resolve even with drug continuation. Marked aminotransferase elevations (>3 fold elevated) occur in <1% of patients. Clinically apparent liver injury with jaundice from etodolac is rare but several convincing cases have been published. The latency to onset ranged a few days to several months and the pattern of enzyme elevations has been described as cholestatic, hepatocellular and mixed. Perhaps the most typical presentation is with jaundice 3 to 6 months after starting etodolac with a mixed or hepatocellular pattern of injury, and fairly rapid recovery on stopping. Immunoallergic and autoimmune features are uncommon. These features are also typical of diclofenac hepatotoxicity. Several cases of fatal acute liver failure in patients taking etodolac have been described, some of which demonstrate a pattern of hyperacute hepatic necrosis resembling acetaminophen overdose or acute hepatic ischemia. Interestingly, etodolac causes a false positive reaction on dipstick testing for bilirubin in urine.

Likelihood score: C (probable rare cause clinically apparent liver injury).

Mechanism of Injury

The mechanism of etodolac hepatotoxicity is not known, but likely to be due to an idiosyncratic reaction to an intermediate of its metabolism. Etodolac is extensively metabolized by the liver.

Outcome and Management

Severity ranges from asymptomatic elevations in serum aminotransferase levels, to symptomatic hepatitis with or without jaundice. A single fatal case has been described. Patients with etodolac induced clinically apparent liver injury should avoid other acetic acid derivatives such as sulindac, diclofenac, ketorolac, tolmetin and indomethacin.

Drug Class: Nonsteroidal Antiinflammatory Drugs

CASE REPORTS

Case 1. Acute hepatitis attributed to etodolac.

[Modified from Schmeltzer PA, Kosinski AS, Kleiner DE, Hoofnagle JH, Stolz A, Fontana RJ, Russo MW; Drug-Induced Liver Injury Network (DILIN). Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Int 2016; 36: 603-9. PubMed Citation]

A 55 old year woman developed anorexia followed by skin rash 7 months after starting etodolac (400 mg twice daily) for osteoarthritis. She stopped the etodolac, but went on to develop dark urine and jaundice. She had no history of liver disease, alcohol abuse, risk factors for viral hepatitis or drug allergieis. Her other medical conditions included hypothyroidism for which she took levothyroxine and reactive airway disease for which she had taken montelukast daily for several years. She also took multivitamins, but denied exposure to other over-the-counter or herbal products. On examination, she had an erythematous rash over the thorax, but no fever or lymphadenopathy, and no signs of chronic liver disease. Laboratory tests showed total serum bilirubin of 4.0 mg/dL, ALT 661 U/L, AST 501 U/L, alkaline phosphatase 128 U/L and albumin 4.0 g/dL. Tests for hepatitis A, B, C (including HCV RNA) and E were negative as were ANA and SMA. An abdominal ultrasound showed gallstones, but no evidence of biliary obstruction. She was monitored as an outpatient and improved rapidly. Her symptoms resolved within one month and all liver tests were normal within two months of the initial presentation (Table). She did not restart etodolac.

Key Points

Medication:Etodolac
Pattern:Hepatocellular (R=19.3)
Severity:2+ (jaundiced but not hospitalized)
Latency:7 months
Recovery:7 weeks
Other medications:Montelukast, levothyroxine, multivitamins

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
7 months14 days6611284.0Ultrasound normal
21 days3271022.7
30 days114871.6Asymptomatic
8 months37 days56661.3
44 days35581.4
51 days27580.8
10 months3 months16540.8
18 months12 months22460.8
Normal Values<65<136<1.2

Comment

This woman developed a mild, but clinically apparent acute hepatitis 7 months after starting daily etodolac therapy for osteoarthritis. Immunoallergic features were present (rash), but not prominent (eosinophil counts were not available). Other causes of acute hepatitis were excluded. Montelukast can cause acute liver injury, but she had been on this medication for several years. Rechallenge with motelukast with careful monitoring would have been appropriate.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Etodolac – Generic, Lodine®

DRUG CLASS

Nonsteroidal Antiinflammatory Drugs

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Etodolac41340-25-4C17-H21-N-O3
Etodolac chemical structure

ANNOTATED BIBLIOGRAPHY

References updated: 05 April 2018

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    (41 year old woman developed jaundice after intermittent use of etodolac [total bilirubin 17.6 mg/dL, direct 6.8 mg/dL, AST 284 U/L, Alk P 125 U/L, protime 19.8 sec] with hemolytic anemia [hematocrit 18%, positive direct Coombs test], resolving within 2 months but with recurrence of hemolysis on restarting etodolac).
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    (Use of high doses of a R-enanomer of etodolac [1.2 to 4.8 g/day] was associated with decrease in lymphocyte counts in patients with chronic lymphocytic leukemia; the activity was separate from Cox inhibition and not shared by other NSAIDs; in this phase I trial, ALT elevations occurred in 11 of 45 patients [26%], were unrelated to dose, and led to drug withdrawals in 3 [7%]; no mention of hepatitis).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, NSAIDs were implicated as a sole agent in 8 cases [4 diclofenac, 2 celecoxib, 1 meloxicam and 1 oxaprozin] and as one of several agents in 3 cases [1 diclofenac, 1 celecoxib, 1 ibuprofen]; no cases were attributed to etodolac).
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    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, of which 7 were due to NSAIDs, including 4 attributed to bromfenac, 2 to diclofenac and 1 to etodolac).
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    (Review of estimated frequency of drug induced liver injury due to NSAIDs from large published epidemiological studies; mentions that etodolac has been associated with various hepatic reactions).
  • Mehta P, Lukacs M, Abraham SM. Normal in the blood, abnormal in the urine. QJM 2012; 105: 1001-2. [PubMed: 21880696]
    (67 year old woman with rheumatoid arthritis on etodolac had persistent positive urine dipstick reaction for bilirubin despite normal serum bilirubin and liver tests; false positive reaction was due to etodolac).
  • Sampaziotis F, Brais RJ, Griffiths WJ. A case of acute liver failure due to etodolac. Br J Clin Pharmacol 2013; 75: 1156-7. [PMC free article: PMC3612737] [PubMed: 22943552]
    (73 year old woman developed jaundice 6 months after starting etodolac [bilirubin 30.7 mg/dL, ALT 1400 U/L, Alk P 274 U/L, protime 16.7 seconds], developing hepatic encephalopathy, but then recoverying spontaneously within 3 months of stopping).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25 . [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, including 6 attributed to diclofenac [ranking 2nd], but none due to etodolac).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, the most common class of implicated agents being NSAIDS [n=62, 32%], but specific agents were nimesulide [n=53], piroxicam [5], diclofenac [2], gold salts [1], and naproxen [1]; etodolac was not listed]).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 28 were attributed to NSAIDs, including 2 to etodolac [Schmeltzer 2016]).
  • Schmeltzer PA, Kosinski AS, Kleiner DE, Hoofnagle JH, Stolz A, Fontana RJ, Russo MW; Drug-Induced Liver Injury Network (DILIN). Liver injury from nonsteroidal anti-inflammatory drugs in the United States. Liver Int 2016; 36: 603-9. [PMC free article: PMC5035108] [PubMed: 26601797]
    (Among 1221 cases of drug induced liver injury enrolled in a prospective, US database between 2004 and 2014, 30 cases [2.5%] were attributed to NSAIDs, including 2 due to etodolac [Case 1], both of which presented with jaundice 5 and 7 months after starting [bilirubin 3.8 and 4.0 mg/dL, ALT 322 and 661 U/L, Alk P 128 and 341 U/L, INR 1.0 and 1.0], both recovering rapidly upon stopping without residual injury).
  • Taneja S, Kumar P, Rathi S, Duseja A, Singh V, Dhiman RK, Chawla YK. Acute liver failure due to etodolac, a selective cycloxygenase- 2 (COX -2) inhibitor non-steroidal anti-inflammatory drug established by RUCAM-based causality assessment. Ann Hepatol 2017; 16: 818-21. PubMed Citation. [PubMed: 28809737]
    (Two women, ages 27 and 80 years, developed nausea and vomiting within 48 hours of starting a fixed combination of etodolac [400 mg] and acetminophen [500 mg] twice daily followed rapidly by jaundice and confusion [bilirubin 4.3 and 4.4 mg/dL, ALT 6060 and 6896 U/L, Alk P 229 and 78 U/L , INR 6.7 and 4.0] with hyperammonemia and lactic acidosis, one patient dying within 2 days and the other recovering rapidly, a pattern indicative of acute hepatic necrosis).

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