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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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Last Update: April 7, 2014.



Ethionamide is a second line drug in the therapy of tuberculosis used only in combination with other agents and for drug-resistance tuberculosis. Ethionamide has been linked to transient, asymptomatic elevations in serum aminotransferase levels and in uncommon instances of acute liver injury, which can be severe.


Ethionamide (eth" eye on' a mide) is a thio-isonicotinamide somewhat similar in structure to isoniazid. Ethionamide is a prodrug and, like isoniazid, requires activation whereupon it inhibits mycobacterial fatty acid synthesis (enoyl-ACP reductase) that is necessary for cell wall synthesis and repair. Interestingly, there is little cross resistance between isoniazid and ethionamide, probably because they are activated by different mycobacterial enzymes, and therefore can be used together. Ethionamide is currently used only as a secondary agent in the treatment of active tuberculosis, always in combination with other antituberculosis agents such as isoniazid, ethambutol, pyrazinamide and/or rifampin and usually for multidrug resistant mycobacterial infections or in situations where first agents are contraindicated. Ethionamide also has activity against lepromatous leprosy. Ethionamide is available as 250 mg tablets in generic forms and under the brand name Trecator. The typical dose in adults is 250 mg twice daily, but can then be increased gradually to a total dose of 15 to 20 mg/kg per day to a maximum of 1 gram daily. Pyridoxine (vitamin B6: 50 mg daily) is usually administered with ethionamide. Common side effects include gastrointestinal upset, nausea, anorexia, diarrhea, metallic taste, stomatitis, depression, drowsiness and fatigue.


Ethionamide therapy has been linked to elevations in serum aminotransferase levels in a proportion of patients, but these elevations are typically self-limited and asymptomatic. More importantly, ethionamide has been linked to many instances of clinical apparent acute liver injury that arise in up to 5% of patients and can be severe and even fatal. The time to onset and clinical features of hepatic injury due to ethionamide resemble those of isoniazid, the latency ranging from 2 weeks to more than 6 months after starting (most arise within 1 to 3 months), and the pattern of enzyme elevations typically being hepatocellular and resembling acute viral hepatitis. Features of hypersensitivity (rash, fever and eosinophilia) are uncommon. Like isoniazid, ethionamide therapy may be associated with development of autoantibodies (typically ANA), but titers are generally low and rarely accompanied by autoimmune conditions.

Mechanism of Injury

Ethionamide is extensively metabolized by the liver and liver injury likely is due to a toxic or immunologically active intermediate. Rapid recurrence of injury upon rechallenge suggests a hypersensitivity reaction.

Outcome and Management

Serum aminotransferase elevations during ethionamide therapy are generally transient and asymptomatic, but elevations accompanied by symptoms of hepatitis and those above five times ULN should lead to prompt discontinuation. Monitoring of serum aminotransferase levels is indicated in patients with underlying liver disease receiving ethionamide and in those with a high risk of developing hepatotoxicity. Some cases of ethionamide hepatotoxicity have been severe and fatal instances have been reported. Cross reactivity to hepatic injury between isoniazid and ethionamide has not been shown, and several patients with clinically apparent liver injury due to ethionamide have later tolerated isoniazid without difficulty.

[First line medications used in the therapy of tuberculosis in the US include ethambutol, isoniazid, pyrazinamide, rifabutin, rifampin, and rifapentine. Second line medications include streptomycin, capreomycin, cycloserine, ethionamide, fluoroquinolones such as levofloxacin and moxifloxacin, aminoglycosides such as amikacin, and para-aminosalicylic acid (PAS).]

Drug Class: Antituberculosis Agents

Other Drugs in the Class: Bedaquiline, Capreomycin, Cycloserine, Ethambutol, Isoniazid, Pyrazinamide, Rifabutin, Rifampin, Rifapentine, Streptomycin



Ethionamide – Trecator®


Antituberculosis Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Ethionamide Chemical Structure


References updated: 07 April 2014

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    (Among 70 patients with isoniazid or streptomycin resistance treated with ethionamide, 12 developed AST elevations, but abnormalities were attributed to pyrazinamide; one patient died of liver failure but was also taking isoniazid and pyrazinamide and drinking heavily).
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  • Lees AW. Jaundice due to ethionamide. Br J Dis Chest 1963; 57: 158-61. [PubMed: 14043687]
    (3 of 62 patients with tuberculosis treated with ethionamide developed jaundice; all 3 were women, ages 54-72 years with onset 1-4 months after starting ethionamide in combination with either isoniazid or streptomycin [peak bilirubin 3.0-5.8 mg/dL, Alk P 2-3 times ULN], resolving after 1-4 months; one had positive rechallenge with ethionamide; all later tolerated isoniazid without recurrence).
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    (35 year old man with tuberculosis and multiple relapses, developed fatigue 6 weeks after starting ethionamide and cycloserine, improving on stopping and redeveloping symptoms 1 week after restarting [bilirubin 0.7 mg/dL, AST 500, Alk P 6 times ULN], resolving rapidly on stopping ethionamide only; biopsy showed centrolobular necrosis).
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    (22 year old man with leprosy and HBsAg carrier state developed jaundice and pruritus 2 years after starting thalidomide, rifampin, ethionamide and clotazimine [bilirubin 6.4 mg/dL, ALT 15 times ULN, Alk P 287 U/L, prothrombin index 60%], recovering within 4-5 months of stopping ethionamide and rifampin).
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    (Multidrug resistance is defined as an organism resistant to at least isoniazid and rifampin; authors rank second line agents as: 1. levofloxacin, aminoglycosides, and capreomycin, 2. ethionamide, ofloxacin and ciprofloxacin, 3. PAS, 4. cycloserine, 5. amoxicillin/clavulate or ampicillin/sulbactam, 6. clarithromycin, linezolid and clofazimine).
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    (Among 46 patients with leprosy treated with either ethionamide or prothionamide for 6 months, elevations in AST [35-88 U/L] occurred in 18 [39%], often resolving despite continuing medication, and only one patient developed jaundice [on prothionamide]).
  • 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, no case was attributed to ethionamide).
  • Ethionamide. Tuberculosis (Edinb) 2008; 88: 106-8. [PubMed: 18486043]
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  • Abubakar I, Moore J, Drobniewski F, Kruijshaar M, Brown T, Yates M, Anderson C, et al. Extensively drug-resistant tuberculosis in the UK: 1995 to 2007. Thorax 2009; 64: 512-5. [PubMed: 19318348]
    (Among 678 extensively drug resistant isolates of tuberculosis reported in the UK between 2005 and 2008, 14% were also resistant to ethionamide).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (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 and 25 to antituberculosis agents, including 15 to isoniazid alone [ranking first], 6 to isoniazid combined with other agents, 3 to rifampin and pyrazinamide and 1 to dapsone, but none to ethionamide).
  • Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105: 2396-404. [PubMed: 20648003]
    (Among 313 cases of drug induced liver injury seen between 1997 and 2008 at a large hospital in Bangalore, India, 181 [58%] were attributed to antituberculosis agents which accounted for 39 of 54 [72%] fatal cases; ethionamide is not specifically mentioned).
  • Arbex MA, Varella Mde C, Siqueira HR, Mello FA. Antituberculosis drugs: drug interactions, adverse effects, and use in special situations. Part 2: second line drugs. J Bras Pneumol 2010; 36: 641-56. [PubMed: 21085831]
    (Analysis of adverse effects of second line drugs for tuberculosis; states that hepatotoxicity occurs in 4.3% of patients treated with ethionamide, especially in those with liver disease or alcoholism).
  • Caminero JA, Sotgiu G, Zumla A, Migliori GB. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis 2010; 10: 621-9. [PubMed: 20797644]
    (Mentions that ethionamide is a thioamide and belongs to the second line of antituberculosis medications; no discussion of hepatotoxicity).
  • (CDC website with up-to-date recommendations on therapy of tuberculosis).


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