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Ethionamide

Class: Antituberculosis Agents
- Antimycobacterial Agents
VA Class: AM500
CAS Number: 536-33-4
Brands: Trecator

Medically reviewed by Drugs.com on Jan 22, 2021. Written by ASHP.

Introduction

Antituberculosis agent; synthetic isonicotinic acid derivative.

Uses for Ethionamide

Tuberculosis

Treatment of active (clinical) tuberculosis (TB) in conjunction with other antituberculosis agents.

Second-line agent used in treatment of drug-resistant TB caused by Mycobacterium tuberculosis known or presumed to be susceptible to ethionamide when isoniazid and/or rifampin cannot be used because of resistance and/or intolerance.

For initial treatment of active TB caused by drug-susceptible M. tuberculosis, recommended multiple-drug regimens consist of an initial intensive phase (2 months) and a continuation phase (4 or 7 months). Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months, ATS, CDC, and IDSA state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy. A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.

Patients with treatment failure or drug-resistant M. tuberculosis, including multidrug-resistant (MDR) TB (resistant to both isoniazid and rifampin) or extensively drug-resistant (XDR) TB (resistant to both isoniazid and rifampin and also resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial such as capreomycin, kanamycin, or amikacin), should be referred to or managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.

Mycobacterium avium Complex (MAC) Infections

Has been used as an alternative agent in multiple-drug regimens used for treatment of M. avium complex (MAC) infections. Evidence of clinical efficacy not available; not included in current ATS, CDC, NIH, or IDSA recommendations for treatment of MAC infections, including macrolide-resistant MAC.

Treatment of MAC infections is complicated and should be directed by clinicians familiar with mycobacterial diseases; consultation with a specialist is particularly important when the patient cannot tolerate first-line drugs or when the infection has not responded to prior therapy or is caused by macrolide-resistant MAC.

Leprosy

Has been used for treatment of multibacillary leprosy in conjunction with other antimycobacterials.

Previously recommended as an alternative agent for use in multiple-drug regimens in leprosy patients who would not accept or could not tolerate clofazimine, but WHO no longer recommends use of ethionamide for leprosy because severe hepatotoxicity has been reported.

Ethionamide Dosage and Administration

Administration

Oral Administration

Administer orally.

May be administered without regard to meals, but should be given at the time of day that the patient finds most suitable to avoid or minimize GI intolerance, which usually is at mealtimes.

Administered as a single daily dose (usually at bedtime or with the main meal). If GI effects occur, give in divided doses with meals.

Since severity of adverse GI effects may diminish as treatment proceeds, patients should be encouraged to persevere with ethionamide treatment if GI effects occur.

Concomitant use of pyridoxine (vitamin B6) is recommended to prevent or relieve neurotoxic effects.

Dosage

Should not be used alone for treatment of TB; must be given in conjunction with other antituberculosis agents.

Data not available to date to support use of ethionamide in intermittent (e.g., 1–3 times weekly) multiple-drug TB regimens.

Pediatric Patients

Tuberculosis
Treatment of Active (Clinical) Tuberculosis
Oral

Children <15 years of age or weighing ≤40 kg: 15–20 mg/kg daily (up to 1 g daily) given in 2 or 3 divided doses recommended by ATS, CDC, IDSA, and AAP. Manufacturer states that optimum dosage has not been established, but that dosages of 10–20 mg/kg daily given in 2 or 3 divided doses or 15 mg/kg daily as a single dose have been recommended.

Adolescents ≥15 years of age: 15–20 mg/kg daily (up to 1 g daily) recommended by ATS, CDC, and IDSA. Usual dosage is 500–750 mg daily as a single dose or in 2 divided doses.

Adults

Tuberculosis
Treatment of Active (Clinical) Tuberculosis
Oral

15–20 mg/kg daily (up to 1 g daily) recommended by ATS, CDC, and IDSA. Usual dosage is 500–750 mg daily as a single dose or 2 divided doses.

Manufacturer states that it may be beneficial to initiate therapy using a dosage of 250 mg daily and then gradually titrate to optimal dosage (up to 1 g daily) as tolerated by the patient. A regimen consisting of ethionamide 250 mg daily for 1–2 days, followed by 250 mg twice daily for 1–2 days with a subsequent increase to 1 g daily in 3 or 4 divided doses, has been used. The minimum effective dosage has not been identified; use highest tolerated dosage (usually 0.5–1 g daily).

Prescribing Limits

Pediatric Patients

Tuberculosis
Treatment of Active (Clinical) Tuberculosis
Oral

Maximum 1 g daily.

Adults

Tuberculosis
Treatment of Active (Clinical) Tuberculosis
Oral

Maximum 1 g daily.

Special Populations

Renal Impairment

Some experts suggest a dosage of 250–500 mg daily for treatment of TB in patients with Clcr <30 mL/minute or undergoing hemodialysis.

Cautions for Ethionamide

Contraindications

  • Known hypersensitivity to ethionamide or any ingredient in the formulation.

  • Severe hepatic impairment.

Warnings/Precautions

General Precautions

Hepatic Effects

Hepatitis (with or without jaundice) reported. Transient increases in serum bilirubin, AST, and ALT have occurred.

Determine serum AST and ALT concentrations at baseline and at monthly intervals. If AST or ALT concentrations become elevated, temporarily discontinue ethionamide and concomitant antituberculosis drugs until laboratory abnormalities resolve. Reintroduce ethionamide and concomitant antituberculosis drugs sequentially to determine which drug(s) are responsible for hepatotoxicity.

Diabetes Mellitus

Measure blood glucose at baseline and periodically during therapy.

Use caution in diabetic patients; must be particularly alert for episodes of hypoglycemia.

Nervous System and Ophthalmic Effects

Psychotic disturbances (including mental depression), drowsiness, dizziness, restlessness, headache, and postural hypotension reported.

Peripheral neuritis, diplopia, optic neuritis, blurred vision, and a pellagra-like syndrome reported rarely.

Perform ophthalmic evaluations (including ophthalmoscopy) at baseline and periodically during therapy.

Manufacturer recommends concomitant use of pyridoxine (vitamin B6) to prevent or relieve neurotoxic effects.

Hypothyroidism

Hypothyroidism (with or without goiter) reported.

Monitor thyroid function.

Some experts recommend determining thyroid-stimulating hormone (TSH) concentrations at baseline and at monthly intervals.

Precautions Related to Treatment of Tuberculosis

Should not be used alone for treatment of TB; must be given in conjunction with other antituberculosis agents.

Clinical specimens for microscopic examination and mycobacterial cultures and in vitro susceptibility testing should be obtained prior to initiation of antituberculosis therapy and periodically during treatment to monitor therapeutic response. The antituberculosis regimen should be modified as needed. Patients with positive cultures after 4 months of treatment should be considered to have failed treatment (usually as the result of noncompliance or drug-resistant TB).

If ethionamide is added as a new drug to a regimen in patients experiencing treatment failure who have proven or suspected drug-resistant TB, at least 2 (preferably 3) new drugs known or expected to be active against the resistant strain should be added at the same time.

Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical. Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.

To ensure compliance, ATS, CDC, IDSA, and AAP recommend that directly observed (supervised) therapy (DOT) be used for treatment of active (clinical) TB whenever possible, especially when intermittent regimens are used, when the patient is immunocompromised or infected with HIV, or when drug-resistant M. tuberculosis is involved.

Specific Populations

Pregnancy

Category C.

ATS, CDC, and IDSA state that ethionamide should not be used in pregnant women.

Lactation

Not known whether ethionamide is distributed into milk. Use with caution and only when benefits outweigh risks; carefully observe breast-fed infants for adverse effects.

Pediatric Use

Limited data are available.

Manufacturer states the drug should not be used in children <12 years of age except when TB is known to be resistant to first-line therapy and systemic dissemination of the disease or other life-threatening complications of TB are judged to be imminent.

Hepatic Impairment

Use caution in patients with hepatic disease; contraindicated in those with severe hepatic impairment.

Renal Impairment

Dosage reduction advised. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia, weight loss.

Interactions for Ethionamide

Specific Drugs

Drug

Interaction

Comments

Alcohol

Psychotic reaction reported

Avoid excessive alcohol ingestion

Cycloserine

Possible increased risk of adverse effects; seizures reported

Use concomitantly with caution

Isoniazid

Increased isoniazid concentrations

Use concomitantly with caution

Ethionamide Pharmacokinetics

Absorption

Bioavailability

Essentially completely absorbed following oral administration; does not undergo any appreciable first-pass metabolism. Peak plasma concentrations attained within about 1 hour.

Peak plasma concentrations are higher and attained more quickly with ethionamide film-coated tablets (Trecator) than with the previously available sugar-coated tablets (Trecator-SC); AUC is similar for both preparations.

Distribution

Extent

Studies using sugar-coated tablets (Trecator-SC; no longer commercially available in the US) indicate ethionamide is rapidly and widely distributed into body tissues and fluids and concentrations in plasma and various organs are approximately equal. Although studies have not been performed to date with ethionamide film-coated tablets (Trecator), distribution of the drug is expected to be the same as that reported with the sugar-coated tablets.

CSF concentrations may be equal to concurrent plasma concentrations.

Crosses placenta.

Not known whether ethionamide is distributed into milk.

Plasma Protein Binding

30%.

Elimination

Metabolism

Metabolized to active and inactive metabolites in the liver.

Elimination Route

Less than 1% of an oral dose is excreted in urine as active drug and metabolites; the remainder is excreted in urine as inactive metabolites.

Only low concentrations removed by hemodialysis.

Half-life

1.9–3 hours.

Stability

Storage

Oral

Tablets

20–25°C in a tight container.

Actions and Spectrum

  • Bactericidal or bacteriostatic in action.

  • Appears to inhibit peptide synthesis in susceptible organisms. Like isoniazid, ethionamide inhibits mycolic acid synthesis in susceptible organisms. May form covalent adducts with nicotinamide adenine dinucleotide (NAD).

  • A highly specific agent; active only against Mycobacterium. Active against M. tuberculosis, M. bovis, M. kansasii, and M. malmoense. Some strains of M. avium complex (MAC) may be susceptible, but high concentrations may be required. Also active against M. leprae.

  • Natural and acquired resistance to ethionamide demonstrated in vitro and in vivo in strains of M. tuberculosis.

  • Cross-resistance may occur between ethionamide and isoniazid or thiosemicarbazones such as thiacetazone (drugs not commercially available in the US). No evidence of cross-resistance between ethionamide and aminosalicylic acid, cycloserine, or streptomycin.

Advice to Patients

  • Advise patients that poor compliance with antituberculosis regimens can result in treatment failure and development of drug-resistant TB, which can be life-threatening and lead to other serious health risks.

  • Importance of completing full course of therapy; importance of not missing any doses.

  • Importance of informing clinicians of any change in visual acuity (with or without eye pain).

  • Importance of avoiding excessive alcohol consumption.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ethionamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

250 mg

Trecator (with povidone)

Wyeth

AHFS DI Essentials™. © Copyright 2021, Selected Revisions February 1, 2008. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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