Ethionamide, a structural analog of isoniazid, is a second-line agent in the treatment of tuberculosis. Ethionamide is used in combination with at least one other antitubercular drug either for disease resistant to rifampin and/or isoniazid or for patients who are intolerant of rifampin and isoniazid. Patients with disease resistance are at high risk for treatment failure and further disease resistance development. Optimum treatment regimens have not been established for drug-resistant tuberculosis, but drug selection should be based on susceptibility testing results. An expert in the treatment of drug-resistant tuberculosis should be consulted. Trecator(R)-SC (ethionamide tablets, USP) sugar-coated tablets have been reformulated to film-coated tablets and renamed Trecator(R). The new formulation was designed to improve stability. Although the mean systemic exposure is not significantly different, the new film-coated tablet is more rapidly absorbed. As a result, higher peak ethionamide concentrations may potentially cause patient intolerance when introduced at the same initial dose as the old sugar-coated tablet. Therefore, patients should be closely monitored and may need dosage adjustments when switching from the sugar-coated tablet to the film-coated tablet. Ethionamide was approved by the FDA in 1962.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Directly observed therapy (DOT) is recommended.
-Concomitant pyridoxine is recommended.
Route-Specific Administration
Oral Administration
-Administer at bedtime or with meals to minimize gastrointestinal intolerance.
The most common adverse reactions reported in patients receiving ethionamide are gastrointestinal related. Side effects include abdominal pain, diarrhea, nausea, vomiting, hypersalivation, metallic taste, stomatitis, anorexia, and weight loss. Measurement of serum transaminases and bilirubin may be advisable. Adverse gastrointestinal effects appear to be dose related with approximately 50% of patients unable to tolerate 1 gram as a single oral dose. Gastrointestinal side effects may be minimized by changing administration times to correlate with meals, decreasing the dosage, administering the daily dosage in divided doses as compared with a single daily dose, or concomitant administration of an antiemetic. Also, adverse gastrointestinal effects may diminish in severity with time.
Adverse central nervous system reactions due to ethionamide include dizziness, drowsiness, headache, and restlessness. Psychotic disturbances, including depression, have occurred in patients taking short and long courses of therapy. In rare instances, peripheral neuropathy and a pellagra-like syndrome have been observed. Optic neuritis and visual impairment, including diplopia and blurred vision, have been rarely reported. Perform ophthalmologic examinations (including ophthalmoscopy) before and periodically during ethionamide treatment. Concurrent administration of pyridoxine has been recommended to prevent or relieve ethionamide-induced neurotoxic effects.
Transient elevated hepatic enzymes, hyperbilirubinemia, and hepatitis with or without jaundice have occurred during treatment with ethionamide. Monitor serum transaminases before initiation of ethionamide therapy and then monthly. If serum transaminases become elevated during therapy, ethionamide and the companion antituberculosis drug or drugs may be discontinued temporarily until the laboratory abnormalities have resolved. Reintroduce ethionamide and the companion antituberculosis medication(s) sequentially to determine the drug(s) responsible for the hepatotoxicity. Most combination therapy for active TB disease includes more than 1 agent that may contribute to hepatotoxicity.
Cases of severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), have been reported with the use of combination antituberculosis therapy that included ethionamide. If symptoms or signs of SCARs develop, discontinue the suspect drug(s) immediately and institute appropriate therapy. Other dermatologic reactions, including the acneiform rash or acne, have also been observed during ethionamide therapy. Hypersensitivity reactions, including rash, photosensitivity, purpura, and thrombocytopenia, have been reported rarely.
Impotence (erectile dysfunction), gynecomastia, orthostatic hypotension, and hypoglycemia have been reported during treatment with ethionamide. The management of diabetes mellitus may be more difficult in patients receiving ethionamide. Blood glucose determinations should be made before and periodically throughout treatment.
The development of hypothyroidism with or without goiter has been documented in patients on ethionamide. Periodic monitoring of thyroid function tests is recommended during ethionamide treatment.
Ethionamide use may cause vitamin B6 deficiency. Supplementation with vitamin B6 may be beneficial in preventing depletion and reducing adverse reactions.
Ethionamide is contraindicated in patients with known hypersensitivity to the drug.
Avoid excessive ethanol ingestion (i.e., ethanol intoxication) with ethionamide because a psychotic reaction has been reported. Persons with alcoholism are at risk for ethionamide-induced neurotoxicity; administer pyridoxine concurrently to protect against the neurological adverse effects of ethionamide.
Monitor blood glucose before and periodically throughout therapy with ethionamide. Advise patients with diabetes mellitus to be particularly alert for episodes of hypoglycemia. The management of patients with diabetes mellitus may become more difficult in those receiving ethionamide. Persons with diabetes mellitus are also at risk for ethionamide-induced neurotoxicity; administer pyridoxine concurrently to protect against the neurological adverse effects of ethionamide.
In persons with concomitant tuberculosis and human immunodeficiency virus (HIV) infection, malabsorption syndrome may be present. Suspect drug malabsorption in patients who adhere to therapy but fail to respond appropriately. In such cases, consider therapeutic drug monitoring. Persons with HIV are also at risk for ethionamide-induced neurotoxicity; administer pyridoxine concurrently to protect against the neurological adverse effects of ethionamide.
The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities. According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions. Geriatric patients are also at risk for ethionamide-induced neurotoxicity; administer pyridoxine concurrently to protect against the neurological adverse effects of ethionamide.
Persons with malnutrition or renal failure are at risk for ethionamide-induced neurotoxicity; administer pyridoxine concurrently to protect against the neurological adverse effects of ethionamide.
Ethionamide is contraindicated in patients with severe hepatic disease. Monitor serum transaminases before initiation of ethionamide therapy and then monthly. If serum transaminases become elevated during therapy, ethionamide and the companion antituberculosis drug or drugs may be discontinued temporarily until the laboratory abnormalities have resolved. Reintroduce ethionamide and the companion antituberculosis medication(s) sequentially to determine the drug(s) responsible for the hepatotoxicity. Most combination therapy for active TB disease includes more than 1 agent that may contribute to hepatotoxicity.
Periodic monitoring of thyroid function tests is recommended as hypothyroidism, with or without goiter, has been reported with ethionamide therapy.
Cases of serious rash, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP), have been reported with the use of combination antituberculosis therapy that included ethionamide. If symptoms or signs of severe cutaneous adverse reactions develop, discontinue the suspect drug(s) immediately and institute appropriate therapy.
There are no adequate and well-controlled studies with ethionamide in human pregnancy. Based on animal data, withhold ethionamide from women who are pregnant, or who are likely to become pregnant while receiving therapy, unless the prescriber considers it to be an essential part of the treatment. Animal studies conducted with ethionamide indicate that the drug has teratogenic potential in rabbits and rats. The doses used in these studies on a mg/kg basis were considerably more than those recommended in humans. Guidelines suggest avoiding ethionamide during pregnancy if alternative agents can be used for effective treatment. The effect of ethionamide on labor and delivery in pregnant women is unknown.
Because no information is available on the excretion of ethionamide in human milk, use ethionamide in breast-feeding mothers only if the benefits outweigh the risks. Monitor newborns who are breast-fed by mothers who are taking ethionamide for adverse effects. Ethionamide use as part of multidrug regimens to treat 2 pregnant women with multidrug-resistant tuberculosis, 1 throughout pregnancy and postpartum and the other postpartum only, has been reported. The infants were breast-fed and developing normally except for a mild speech delay in 1 infant and hyperactivity in the other.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Mycobacterium tuberculosis
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of drug-susceptible tuberculosis infection as part of combination therapy:
NOTE: During the conversion from sugar-coated to film-coated tablets, monitor patients, and retitrate the dosage.
Oral dosage:
Adults: 15 to 20 mg/kg/day (Max: 1 g/day) or 5 days/week PO divided once or twice daily. Start with an initial dose of 250 mg PO once daily and gradually increase as tolerated. Usual dose: 250 to 500 mg PO once or twice daily. Ethionamide is generally recommended as second-line therapy; duration is dependent on the site of involvement.
Infants, Children, and Adolescents: 15 to 20 mg/kg/day (Max: 1 g/day) or 5 days/week PO divided 1 to 3 times daily. The FDA-approved dosage is 10 to 20 mg/kg/day (Max: 1 g/day).
For the treatment of drug-resistant tuberculosis infection as part of combination therapy:
NOTE: During the conversion from sugar-coated to film-coated tablets, monitor patients, and retitrate the dosage.
Oral dosage:
Adults: 15 to 20 mg/kg/day (Max: 1 g/day) PO divided once or twice daily. Start with an initial dose of 250 mg PO once daily and gradually increase as tolerated. Usual dose: 250 to 500 mg PO once or twice daily.
Infants, Children, and Adolescents: 15 to 20 mg/kg/day (Max: 1 g/day) PO divided 1 to 3 times daily. The FDA-approved dosage is 10 to 20 mg/kg/day (Max: 1 g/day).
Maximum Dosage Limits:
-Adults
1 g/day PO.
-Geriatric
1 g/day PO.
-Adolescents
20 mg/kg/day (Max: 1 g/day) PO.
-Children
20 mg/kg/day (Max: 1 g/day) PO.
-Infants
20 mg/kg/day PO.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Ethionamide is contraindicated in patients with severe hepatic impairment.
Patients with Renal Impairment Dosing
Adult*
CrCl 30 mL/minute or more: No dosage adjustment necessary.
CrCl less than 10 to 30 mL/minute: 250 to 500 mg PO once daily or decrease dose by 50%. No dosage adjustment may be necessary.
Intermittent hemodialysis*
250 to 500 mg PO once daily. No dosage adjustment may be necessary.
Peritoneal dialysis*
No dosage is adjustment necessary.
Continuous renal replacement therapy (CRRT)*
NOTE: Various CRRT modalities include continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), continuous venovenous high-flux hemodialysis (CVVHFD), continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), and continuous arteriovenous hemodiafiltration (CAVHDF). Dosing should take into consideration patient-specific factors (e.g., intrinsic renal function), type of infection, the duration of renal replacement therapy, the effluent flow rate, and the replacement solution administered.
No dosage is adjustment necessary.
*non-FDA-approved indication
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and aminosalicylate sodium, aminosalicylic acid. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Urinary concentrations of ethionamide could interfere with the therapeutic effectiveness of BCG. Postpone instillation of BCG if the patient is receiving antibiotics.
Capreomycin: (Moderate) Adverse hepatic effects have been associated with capreomycin, especially with concurrent use of other antituberculosis drugs known to alter hepatic function. Theoretically, coadministration of capreomycin and ethionamide could increase the risk of hepatotoxicity. Monitor patients for changes in liver function if these drugs are coadministered.
Cycloserine: (Moderate) Cycloserine interacts with ethionamide, possibly increasing the risk of developing CNS effects, especially seizures.
Ethambutol: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking ethionamide. A psychotic reaction has been reported with excessive alcohol ingestion. (Moderate) A psychotic reaction has been reported in patients receiving ethionamide and consuming excessive amounts of alcohol. Also, ethionamide appears to be metabolized by the liver. Chronic alcohol ingestion may increase enzymatic activity of the liver whereas acute alcohol ingestion can inhibit liver enzymatic activity.
Isoniazid, INH: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Also, concomitant administration of isoniazid, INH and ethionamide may cause a temporary increase in serum concentrations of isoniazid. Carefully monitor patients for adverse effects of isoniazid. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Also, concomitant administration of isoniazid, INH and ethionamide may cause a temporary increase in serum concentrations of isoniazid. Carefully monitor patients for adverse effects of isoniazid. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Isoniazid, INH; Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Also, concomitant administration of isoniazid, INH and ethionamide may cause a temporary increase in serum concentrations of isoniazid. Carefully monitor patients for adverse effects of isoniazid. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Pyrazinamide, PZA: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Rifabutin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Ethionamide's exact mechanism of action is not known. Similar to isoniazid, ethionamide appears to work by inhibiting mycolic acid synthesis, which disrupts the formation of the mycobacterial cell wall. Susceptible strains of Mycobacterium convert ethionamide to an ethionamide S-oxide metabolite by S-oxidation. Studies have demonstrated that conversion to this active metabolite by susceptible organisms and within the liver is responsible for ethionamide's activity. Ethionamide exhibits bacteriostatic or bactericidal action depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. Cross-resistance between ethionamide and the antitubercular agent isoniazid has been demonstrated in multi-drug resistant strains of M. tuberculosis; however, most M. tuberculosis isolates that are resistant to one are usually susceptible to the other drug. Limited data shows that cross-resistance may exist between ethionamide and thiacetazone. There is no evidence of cross-resistance between ethionamide and para-aminosalicylic acid, streptomycin, or cycloserine.
Ethionamide is administered orally.
Ethionamide does not undergo any significant first pass metabolism. Ethionamide is approximately 30% protein bound. Ethionamide crosses the placenta, but it is unknown whether it distributes into breast milk. Distribution of ethionamide into tissues and fluids, including cerebrospinal fluid (CSF), following administration of the film-coated tablet has not been studied, but is not expected to differ significantly from that of the sugar-coated tablet. After administration of the sugar-coated tablet, ethionamide is rapidly and widely distributed into all body tissues and fluids. Plasma and tissue concentrations are approximately equal. Ethionamide CSF concentrations exceeding the in vitro minimum inhibitory concentration for Mycobacterium tuberculosis (2.5 mcg/mL) were obtained in most patients after a single oral dose of 20 mg/kg/day. Of 18 children (median age 26.5 months) with tuberculous meningitis, an ethionamide spinal fluid concentration of at least 2.5 mcg/mL was reached on 11 of 13 occasions after 20 mg/kg/day but on only 7 of 26 occasions after 15 mg/kg/day.
Ethionamide is extensively metabolized presumably in the liver to active and inactive metabolites. The sulphoxide metabolite has demonstrated antimicrobial activity against Mycobacterium tuberculosis. The mean (SD) plasma half-life observed in 40 healthy volunteers following a single 250 mg oral dose of the film-coated tablet was 1.92 (0.27) hours. Less than 1% of the oral dose is excreted as unchanged drug in the urine.
-Route-Specific Pharmacokinetics
Oral Route
Ethionamide is rapidly and essentially completely absorbed from the gastrointestinal tract. Peak serum concentrations are obtained within 1-2 hours. The mean (SD) ethionamide systemic exposure after a single 250 mg film-coated tablet in 40 healthy, fasting adults was 7.67 (1.69) mcg x hr/mL. The mean systemic exposure is not significantly different from the old sugar-coated tablet. However, the maximum concentration for the film-coated tablets (2.16 mcg/mL) is significantly higher that of the sugar-coated tablets (1.48 mcg/mL).
-Special Populations
Hepatic Impairment
Pharmacokinetic parameters of ethionamide in patients with hepatic insufficiency have not been formally studied. As noted above, ethionamide may be metabolized by the liver.
Renal Impairment
Pharmacokinetic parameters of ethionamide in patients with renal insufficiency have not been formally studied. After a single 500 mg oral dose of the sugar-coated tablet to 8 adults, 0.9-4.8% of the dose was recovered by hemodialysis. Ethionamide was taken 1.9-3.9 hours before dialysis with a high-flux dialyzer. The maximum serum concentration was similar to the value obtained from healthy patients, but the time to the maximum concentration was slightly prolonged (range, 1.9-5.1 hours).