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Ethionamide

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

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

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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.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 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: 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 Clcr <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

Interactions for Ethionamide

Specific Drugs

Drug

Interaction

Comments

Alcohol

Psychotic reaction reported127

Avoid excessive alcohol ingestion127

Cycloserine

Possible increased risk of adverse effects; seizures reported127

Use concomitantly with caution127

Isoniazid

Increased isoniazid concentrations127

Use concomitantly with caution127

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.

Ethionamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

250 mg

Trecator (with povidone)

Wyeth

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

100. Drucker D, Eggo MC, Salit IE et al. Ethionamide-induced goitrous hypothyroidism. Ann Intern Med. 1984; 100:837-9. [IDIS 186246] [PubMed 6721300]

101. Gupta DK. Acceptability of thioamides. I. Ethionamide. J Postgrad Med. 1977; 23:175-80. [PubMed 615264]

102. Moulding T, Fraser R. Hypothyroidism related to ethionamide. Am Rev Respir Dis. 1970; 101:90-4. [PubMed 5410078]

103. Schless JM, Allison RF, Inglis RM et al. The use of ethionamide in combined drug regimens in the re-treatment of isoniazid resistant pulmonary tuberculosis. Am Rev Respir Dis. 1965; 91:728-37. [PubMed 14280946]

104. Report of a WHO Study Group. Chemotherapy of leprosy for control programmes. Technical Report Series No. 675. Geneva: World Health Organization; 1982:3-33.

105. Jacobson RR. Treatment. In: Hastings RC, ed. Leprosy. New York: Churchill Livingstone; 1985:193-222.

106. Centers for Disease Control and Prevention. Treatment of tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Recomm Rep. 2003; 52(RR-11):1-77.

107. American Academy of Pediatrics. 2006 Red Book: Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

110. Donald PR, Seifart HI. Cerebrospinal fluid concentrations of ethionamide in children with tuberculous meningitis. J Pediatr. 1989; 115:483-6. [IDIS 259454] [PubMed 2769511]

113. Griffith DE, Aksamit T, Brown-Elliott BA et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007; 175:367-416. [PubMed 17277290]

114. Reviewers’ comments (personal observations) on the Antituberculosis Agents General Statement 8:16.04.

115. Wyeth. Trecator-SC (ethionamide) sugar-coated tablets prescribing information. Philadelphia, PA; 2002 Mar 14.

116. WHO Expert Committee on Leprosy. Seventh Report. WHO Technical Report Series No. 874. Geneva: World Health Organization; 1998:1-43.

117. Whitty CJ, Lockwood DN. Leprosy—new perspectives on an old disease. J Infect. 1999; 38:2-5. [IDIS 424615] [PubMed 10090496]

118. Jacobson RR, Krahenbuhl JL. Leprosy. Lancet. 1999; 353:655-60. [IDIS 421539] [PubMed 10030346]

119. MacDougall AC, Ulrich MI. Mycobacterial Disease: Leprosy. In: Fitzpatrick TB, Eisen AZ, Wolff K et al, eds. Dermatology in General Medicine, 4th ed. New York, NY: McGraw -Hill Inc; 1993:2395-2410.

120. Panda S. Let’s learn some clinical facts on leprosy - before it is eradicated. Bull on Drug Health Information (India). 1998; 5:5-12.

121. Anon. Choice of antibacterial drugs. Med Lett Treat Guid. 2004; 2:18-26.

122. Anon. Essential drugs. WHO Model Formulary. Antibacterials. Antileprosy Drugs. WHO Drug Information. 1997; 11:253.

123. WHO Study Group on Chemotherapy of Leprosy. Seventh Report. WHO Technical Report Series No. 847. Geneva: World Health Organization; 1994:1-24.

124. WHO. Action Programme for the elimination of leprosy (LEP). From WHO Website () 1999 Sept 23.

125. WHO. Reports on individual drugs. Simplified treatment for leprosy. WHO Drug Information. 1997; 11:131.

126. Single-lesion multicentre trial group. Efficacy of single-dose multidrug therapy for the treatment of single-lesion paucibacillary leprosy. Indian J Leprosy. 1997; 69:121-9.

127. Wyeth. Trecator (ethionamide) tablets prescribing information. Philadelphia, PA; 2006 Sept.

128. Tucker HR. Dear healthcare provider letter regarding reformulation of Trecator-SC (ethionamide sugar-coated tablets). Philadelphia, PA: Wyeth Pharmaceuticals; 2005 Mar 10.

129. Malone RS, Fish DN, Spiegel DM et al. The effect of hemodialysis on cycloserine, ethionamide, para-aminosalicylate, and clofazimine. Chest. 1999; 116:984-90. [IDIS 437367] [PubMed 10531163]

a. AHFS Drug Information 2007. McEvoy GK, ed. Ethionamide. American Society of Health-System Pharmacists; 2007:552-4.

b. Heifets LB, Lindholm-Levy JP, Flory M. Comparison of bacteristatic and bactericidal activity of isoniazid and ethionamide against Mycobacterium avium and Mycobacterium tuberculosis. Am Rev Respir Dis. 1991; 143:268-70. [PubMed 1899326]

c. Rastogi N, Bauriaud RM, Bourgoin A et al. French multicenter study involving eight test sites for radiometric determination of activities of 10 antimicrobial agents against Mycobacterium avium complex. Antimicrob Agents Chemother. 1995; 39:638-44. [PubMed 7793865]

d. Wang F, Langley R, Gulten G et al. Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med. 2007; 204:73-8. [PubMed 17227913]

e. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(RR-15):1-112.

f. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(RR-14):1-92.

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