Ethionamide (Monograph)

Brand name: Trecator
Drug class: Antituberculosis Agents
- Antimycobacterial Agents
VA class: AM500
CAS number: 536-33-4

Introduction

Antituberculosis agent; synthetic isonicotinic acid derivative.¹²⁷

Uses for Ethionamide

Tuberculosis

Treatment of active (clinical) tuberculosis (TB) in conjunction with other antituberculosis agents.^{106 107 127}

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.^{106 107}

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).¹⁰⁶ Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months,^{106 107} 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.¹⁰⁶ A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.^{106 107}

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.^{106 127}

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^{† [off-label]}.¹¹³ Evidence of clinical efficacy not available;¹¹³ not included in current ATS, CDC, NIH, or IDSA recommendations for treatment of MAC infections, including macrolide-resistant MAC.^{113 e f}

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.¹¹³

Leprosy

Has been used for treatment of multibacillary leprosy^{† [off-label]} in conjunction with other antimycobacterials.^{104 105}

Previously recommended as an alternative agent for use in multiple-drug regimens in leprosy patients who would not accept or could not tolerate clofazimine,^{104 105} but WHO no longer recommends use of ethionamide for leprosy because severe hepatotoxicity has been reported.^{116 123}

Ethionamide Dosage and Administration

Administration

Oral Administration

Administer orally.¹²⁷

May be administered without regard to meals,¹²⁷ 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.¹²⁷

Administered as a single daily dose (usually at bedtime or with the main meal).^{106 127 a} If GI effects occur, give in divided doses with meals.^{106 127 a}

Since severity of adverse GI effects may diminish as treatment proceeds, patients should be encouraged to persevere with ethionamide treatment if GI effects occur.¹²⁷

Concomitant use of pyridoxine (vitamin B₆) is recommended to prevent or relieve neurotoxic effects.¹²⁷

Dosage

Should not be used alone for treatment of TB; must be given in conjunction with other antituberculosis agents.^{106 107 127}

Data not available to date to support use of ethionamide in intermittent (e.g., 1–3 times weekly) multiple-drug TB regimens.¹⁰⁶

Pediatric Patients

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

Children <15 years of age or weighing ≤40 kg^{† [off-label]}: 15–20 mg/kg daily (up to 1 g daily) given in 2 or 3 divided doses recommended by ATS, CDC, IDSA, and AAP.^{106 107} 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.¹²⁷

Adolescents ≥15 years of age: 15–20 mg/kg daily (up to 1 g daily) recommended by ATS, CDC, and IDSA.¹⁰⁶ Usual dosage is 500–750 mg daily as a single dose or in 2 divided doses.¹⁰⁶

Adults

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

15–20 mg/kg daily (up to 1 g daily) recommended by ATS, CDC, and IDSA.¹⁰⁶ Usual dosage is 500–750 mg daily as a single dose or 2 divided doses.¹⁰⁶

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.¹²⁷ 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.¹²⁷ The minimum effective dosage has not been identified; use highest tolerated dosage (usually 0.5–1 g daily).¹²⁷

Prescribing Limits

Pediatric Patients

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

Maximum 1 g daily.^{106 107}

Adults

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

Maximum 1 g daily.^{106 127}

Special Populations

Renal Impairment

Some experts suggest a dosage of 250–500 mg daily for treatment of TB in patients with Cl_cr <30 mL/minute or undergoing hemodialysis.¹⁰⁶

Cautions for Ethionamide

Contraindications

• Known hypersensitivity to ethionamide or any ingredient in the formulation.¹²⁷

• Severe hepatic impairment.¹²⁷

Warnings/Precautions

General Precautions

Hepatic Effects

Hepatitis (with or without jaundice) reported.¹²⁷ Transient increases in serum bilirubin, AST, and ALT have occurred.¹²⁷

Determine serum AST and ALT concentrations at baseline and at monthly intervals.^{106 127} If AST or ALT concentrations become elevated, temporarily discontinue ethionamide and concomitant antituberculosis drugs until laboratory abnormalities resolve.¹²⁷ Reintroduce ethionamide and concomitant antituberculosis drugs sequentially to determine which drug(s) are responsible for hepatotoxicity.¹²⁷

Diabetes Mellitus

Measure blood glucose at baseline and periodically during therapy.¹²⁷

Use caution in diabetic patients;¹²⁷ must be particularly alert for episodes of hypoglycemia.¹²⁷

Nervous System and Ophthalmic Effects

Psychotic disturbances (including mental depression), drowsiness, dizziness, restlessness, headache, and postural hypotension reported.¹²⁷

Peripheral neuritis, diplopia, optic neuritis, blurred vision, and a pellagra-like syndrome reported rarely.¹²⁷

Perform ophthalmic evaluations (including ophthalmoscopy) at baseline and periodically during therapy.¹²⁷

Manufacturer recommends concomitant use of pyridoxine (vitamin B₆) to prevent or relieve neurotoxic effects.¹²⁷

Hypothyroidism

Hypothyroidism (with or without goiter) reported.¹²⁷

Monitor thyroid function.¹²⁷

Some experts recommend determining thyroid-stimulating hormone (TSH) concentrations at baseline and at monthly intervals.¹⁰⁶

Precautions Related to Treatment of Tuberculosis

Should not be used alone for treatment of TB; must be given in conjunction with other antituberculosis agents.^{106 107 127}

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.^{106 127} The antituberculosis regimen should be modified as needed.¹⁰⁶ 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).¹⁰⁶

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.¹⁰⁶

Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical.¹⁰⁶ Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.¹⁰⁶

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.^{106 107}

Specific Populations

Pregnancy

Category C.¹²⁷

ATS, CDC, and IDSA state that ethionamide should not be used in pregnant women.¹⁰⁶

Lactation

Not known whether ethionamide is distributed into milk.¹²⁷ Use with caution and only when benefits outweigh risks; carefully observe breast-fed infants for adverse effects.¹²⁷

Pediatric Use

Limited data are available.¹²⁷

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.¹²⁷

Hepatic Impairment

Use caution in patients with hepatic disease;¹⁰⁶ contraindicated in those with severe hepatic impairment.¹²⁷

Renal Impairment

Dosage reduction advised.¹⁰⁶ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia, weight loss.¹²⁷

Specific Drugs

Ethionamide Pharmacokinetics

Absorption

Bioavailability

Essentially completely absorbed following oral administration; does not undergo any appreciable first-pass metabolism.¹²⁷ Peak plasma concentrations attained within about 1 hour.¹²⁷

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.¹²⁸

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.¹²⁷ 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.¹²⁷

CSF concentrations may be equal to concurrent plasma concentrations.¹⁰⁶

Crosses placenta.¹⁰⁶

Not known whether ethionamide is distributed into milk.¹²⁷

Plasma Protein Binding

30%.¹²⁷

Elimination

Metabolism

Metabolized to active and inactive metabolites in the liver.¹²⁷

Elimination Route

Less than 1% of an oral dose is excreted in urine¹²⁷ as active drug and metabolites;^a the remainder is excreted in urine as inactive metabolites.^a

Only low concentrations removed by hemodialysis.^{106 129}

Half-life

1.9–3 hours.^{127 129 a}

Stability

Storage

Oral

Tablets

20–25°C in a tight container.¹²⁷

Actions and Spectrum

• Bactericidal or bacteriostatic in action.^{127 b d}

• Appears to inhibit peptide synthesis in susceptible organisms.¹²⁷ Like isoniazid, ethionamide inhibits mycolic acid synthesis in susceptible organisms.^d May form covalent adducts with nicotinamide adenine dinucleotide (NAD).^d

• A highly specific agent; active only against Mycobacterium.^a Active against M. tuberculosis,^{a b d} M. bovis,^a M. kansasii,^{113 a} and M. malmoense.¹¹³ Some strains of M. avium complex (MAC) may be susceptible,^{a b c} but high concentrations may be required.^c Also active against M. leprae.^{a d}

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

• Cross-resistance may occur between ethionamide and isoniazid or thiosemicarbazones such as thiacetazone (drugs not commercially available in the US).¹²⁷ No evidence of cross-resistance between ethionamide and aminosalicylic acid, cycloserine, or streptomycin.¹²⁷

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.^{106 127}

• Importance of completing full course of therapy; importance of not missing any doses.¹²⁷

• Importance of informing clinicians of any change in visual acuity (with or without eye pain).¹²⁷

• Importance of avoiding excessive alcohol consumption.¹²⁷

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹²⁷

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹²⁷

• Importance of informing patients of other important precautionary information.¹²⁷ (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.

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