VA Class:AM500

AHFS Class:

• Antituberculosis Agents 8:16.04

Generic Name(s):

• Ethionamide

Ethionamide is a synthetic, isonicotinic acid-derivative antituberculosis agent.

Tuberculosis

Active Tuberculosis

Ethionamide is used in conjunction with other antituberculosis agents in the treatment of clinical tuberculosis.106,127

The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) currently recommend several possible multiple-drug regimens for the treatment of culture-positive pulmonary tuberculosis.106 These regimens have a minimum duration of 6 months (26 weeks), and consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).106 Ethionamide is considered a second-line antituberculosis agent for use in these regimens.106 The drug usually is used in the treatment of drug-resistant tuberculosis caused by Mycobacterium tuberculosis known or presumed to be susceptible to the drug, especially when isoniazid and/or rifampin cannot be used because of resistance and/or intolerance.106,127 If ethionamide is added as a new drug to a regimen in patients experiencing treatment failure who have proven or suspected drug-resistant tuberculosis, 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 After results of in vitro susceptibility testing are available, the regimen can be adjusted accordingly.106 For information on general principles used in the treatment of tuberculosis, see the Antituberculosis Agents General Statement 8:16.04.

Mycobacterium avium Complex (MAC) Infections

Ethionamide has been used in conjunction with other antituberculosis or anti-infective agents in the treatment of Mycobacterium avium complex (MAC) infections†. Some clinicians suggest that ethionamide be included in one alternative multiple-drug regimen for the treatment of MAC pulmonary infections in patients whose disease has failed to respond to therapy with a macrolide-containing regimen (e.g., clarithromycin or azithromycin, rifabutin or rifampin, and ethambutol).113 In such patients, subsequent therapy is complicated, may be associated with a high incidence of adverse effects, and should be undertaken only under the guidance of clinicians experienced in handling these patients.113,114 (See Treatment of Pulmonary and Localized Extrapulmonary MAC Infections, under Management of Other Mycobacterial Disease: Mycobacterium avium Complex [MAC] Infections, in the Antituberculosis Agents General Statement 8:16.04.)

Leprosy

Although ethionamide has been used in the treatment of multibacillary leprosy† and previously was recommended as an alternative agent for use in multiple-drug regimens in patients who would not accept or could not tolerate clofazimine,104,105 the World Health Organization (WHO) no longer recommends use of ethionamide for the treatment of leprosy because severe hepatotoxicity has been associated with use of the drug.116,123 The WHO and most clinicians currently recommend that multibacillary leprosy be treated with a multiple-drug regimen that includes rifampin, dapsone, and clofazimine, and that paucibacillary leprosy be treated with a multiple-drug regimen that includes rifampin and dapsone.116,117,118,119,120,121,122,123,124,125,126 If an alternative agent is needed for these regimens in patients who will not accept or cannot tolerate clofazimine or in patients who cannot receive rifampin because of adverse effects, intercurrent disease (e.g., chronic hepatitis), or infection with rifampin-resistant M. leprae , the WHO and other clinicians generally recommend use of ofloxacin and minocycline.116,121,124 For additional information on the treatment of leprosy, see Rifampin 8:16.04, Dapsone 8:16.92, and Clofazimine 8:16.92.

Administration

Ethionamide is administered orally without regard to meals.106,127

Ethionamide usually is administered once daily, but may be given in divided doses if GI intolerance occurs.127 If ethionamide is given as a single daily dose, the dose should be given at the time of day that the patient finds most suitable in order to avoid or minimize GI intolerance, which usually is at mealtimes.127 (See Cautions: GI Effects.) Patients should be encouraged to persevere with the ethionamide regimen if GI effects occur, since these effects may diminish in severity as treatment proceeds.127

Dosage

Beginning in 2005, ethionamide became commercially available in the US as film-coated tablets (Trecator^®), instead of the previously available sugar-coated tablets (Trecator^®-SC).128 The film-coated tablets are more rapidly absorbed than the sugar-coated tablets and may provide higher peak ethionamide concentrations (see Pharmacokinetics: Absorption) which potentially could lead to patient intolerance if introduced at the same initial dosage as the previously available formulation.128 Therefore, when switching from the sugar-coated tablets to the film-coated tablets, patients should be monitored and have their dosages retitrated to optimal dosage based on tolerance.128

Active Tuberculosis

Ethionamide should not be given alone for the treatment of clinical tuberculosis.106,127 The drug is considered a second-line agent for use in daily multiple-drug regimens for the treatment of active tuberculosis.106 Data are not available to date regarding use of ethionamide in intermittent multiple-drug regimens used in the treatment of tuberculosis.106

Therapy for tuberculosis should be continued long enough to prevent relapse.106 The minimum duration of treatment currently recommended for patients with culture-positive pulmonary tuberculosis is 6 months (26 weeks), and recommended regimens consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).106 However, completion of treatment is determined more accurately by the total number of doses and is not based solely on the duration of therapy.106 For information on general principles of antituberculosis therapy and recommendations regarding specific multiple-drug regimens and duration of therapy, see the Antituberculosis Agents General Statement 8:16.04.

Adult Dosage

For use in conjunction with other antituberculosis agents for the treatment of active tuberculosis in adults, the usual dosage of ethionamide is 15-20 mg/kg (up to 1 g) daily.106,127 The manufacturer recommends an initial dosage of 250 mg daily, with gradual titration to optimal dosage based on patient tolerance.127 A regimen 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 Because data are insufficient to date to indicate the lowest effective dosage, the strategy of using the highest tolerated dosage (based on GI intolerance) has been used to minimize the risk of developing resistance to ethionamide or other drugs in the regimen.127 In adults, this usually is a dosage of 0.5-1 g daily (average 0.75 g daily).127

The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that the usual dosage of ethionamide for use in conjunction with other antituberculosis agents in adults and children 15 years of age or older is 15-20 mg/kg (up to 1 g) daily; a dosage of 500-750 mg daily usually is recommended given as a single daily dose or in 2 divided doses.106

Pediatric Dosage

The manufacturer states that optimum pediatric dosage has not been established, but dosages of 10-20 mg/kg daily given in 2 or 3 divided doses after meals or 15 mg/kg once daily have been recommended for children.127

The ATS, CDC, IDSA, and American Academy of Pediatrics (AAP) recommend a pediatric dosage of 15-20 mg/kg (up to 1 g) daily106,107 given in 2 or 3 divided doses.107 Limited evidence suggests that an ethionamide dosage of 20 mg/kg daily given as a single dose in children is more likely to produce CSF concentrations exceeding the minimum inhibitory concentration of 2.5 mcg/mL for Mycobacterium tuberculosis .110

Dosage in Renal Impairment

Although some clinicians state that dosage adjustments are not necessary in patients with renal impairment,129 others state that ethionamide dosage should be reduced to 250-500 mg daily in patients with creatinine clearance less than 30 mL/minute and in those undergoing hemodialysis.106

GI Effects

Adverse GI effects, including nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia, and weight loss, are the most common adverse effects reported with ethionamide.127 Nausea and vomiting may be severe enough to necessitate discontinuance of ethionamide. GI effects appear to be dose related, and approximately 50% of patients are unable to tolerate a single 1-g dose of the drug.127

Adverse GI effects may be minimized by decreasing the dosage, changing the time of drug administration, administering with meals, or concomitant antiemetic therapy.106,127 Some patients tolerate ethionamide best when it is administered in a single dose at bedtime; others tolerate the drug best when it is administered in equally divided doses with meals.106,127

Nervous System and Special Senses Effects

Psychotic disturbances,127 mental depression,127 restlessness,127 drowsiness,127 dizziness,127 headache,127 postural hypotension,127 and asthenia occur occasionally with ethionamide. Rarely, peripheral neuritis,127 paresthesia, seizures, tremors, a pellagra-like syndrome,127 hallucinations, diplopia,127 optic neuritis,127 blurred vision,127 and olfactory disturbances have been reported.

The manufacturer of ethionamide recommends concomitant use of pyridoxine to prevent or relieve neurotoxic effects during ethionamide treatment.127

Hepatic Effects

Transient increases in serum bilirubin, AST (SGOT), and ALT (SGPT) concentrations have been reported in patients receiving ethionamide.127 Hepatitis (with or without jaundice) also has been reported.127 Hepatotoxicity generally is reversible following discontinuance of the drug.

Hypersensitivity Reactions

Hypersensitivity reactions including rash, photosensitivity, thrombocytopenia, and purpura have been reported rarely with ethionamide.127

Other Adverse Effects

Hypothyroidism, with or without goiter, has been reported rarely in patients receiving ethionamide.100,101,102,103,127

Hypoglycemia,127 gynecomastia,127 impotence,127 menorrhagia, joint pain, acute rheumatic symptoms, and acne127 also have been reported.

Precautions and Contraindications

Ethionamide is contraindicated in patients hypersensitive to the drug.127

Ethionamide is contraindicated in patients with severe hepatic impairment127 and should be used with caution in patients with less severe hepatic impairment.106

Serum AST (SGOT) and ALT (SGPT) concentrations should be determined prior to and at monthly intervals during ethionamide therapy.127 If serum transaminases become elevated during ethionamide therapy, the drug and concomitant antituberculosis agents may be discontinued temporarily until laboratory abnormalities resolve.127 Ethionamide and concomitant antituberculosis drugs should then be reintroduced sequentially to determine which drug(s) is responsible for the hepatotoxicity.127

Ophthalmologic examinations (including ophthalmoscopy) should be performed prior to and periodically during ethionamide therapy.127 Patients should be advised to consult their clinician if blurred vision or any loss of vision, with or without ocular pain, occurs.127

Blood glucose concentrations should be determined prior to and periodically during ethionamide therapy.127 The management of patients with diabetes mellitus may become more difficult during ethionamide therapy.127 Diabetic patients should be particularly alert for hypoglycemia episodes.127

Thyroid function tests should be monitored periodically (e.g., at baseline and at monthly intervals) since hypothyroidism, with or without goiter, has been reported during ethionamide therapy.106,127

Patients should be informed of the importance of adhering to the prescribed antituberculosis regimen for the full duration of treatment.127 Nonadherence can result in treatment failure and development of drug-resistant tuberculosis, which can be life-threatening and lead to other serious health risks.127 Therefore, directly observed therapy (DOT) is recommended for patients being treated for tuberculosis.127 If multi-drug resistant M. tuberculosis (MDMT) is isolated, the patients should be managed in consultation with an expert in the treatment of such infections.127

Patients with tuberculosis who also have human immunodeficiency virus (HIV) infection may have malabsorption syndrome.127 Drug malabsorption should be suspected in patients who adhere to treatment but fail to have an appropriate response to the regimen.127 In such cases, therapeutic drug monitoring should be considered.127

Pediatric Precautions

Limited information is available on the use of ethionamide in neonates, infants, and children.127 The manufacturer states that the drug should not be used in children younger than 12 years of age except when M. tuberculosis known to be resistant to first-line therapy are present and when systemic dissemination of the disease or other life-threatening complications of tuberculosis are judged to be imminent.127

Pregnancy and Lactation

Pregnancy

Safe use of ethionamide during pregnancy has not been established.127 The drug has caused teratogenic effects in rabbits and rats when administered in high doses.127 There are no adequate and controlled studies to date using ethionamide in pregnant women, and the manufacturer states that the drug should not be used in women who are or may become pregnant unless the clinician considers the drug essential to treatment.127 The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that ethionamide should not be used during pregnancy because it crosses the placenta and is teratogenic in animals.106

The effect of ethionamide on labor and delivery in pregnant women is unknown.127

Lactation

Because it is not known whether ethionamide is distributed into human milk, the drug should be administered to nursing mothers only if the benefits of therapy outweigh the potential risks to the infant.127 The manufacturer states that if ethionamide is administered during breastfeeding, the infant should be monitored for adverse effects.127

Alcohol

Patients receiving ethionamide should avoid excessive ingestion of alcohol because a psychotic reaction has been reported in this situation.127

Antituberculosis Agents

Serum concentrations of isoniazid may increase temporarily during concomitant ethionamide therapy.127

Ethionamide may potentiate the adverse effects of other antituberculosis agents included in the treatment regimen.127 There is some evidence that adverse nervous system effects of ethionamide, cycloserine, and isoniazide may be additive. Seizures have been reported in patients receiving regimens that included both ethionamide and cycloserine and caution is advised if these drugs are used concomitantly.127

Acute Toxicity

If overdosage of ethionamide occurs, standard procedures to evacuate gastric contents and supportive care should be employed.127 Only low concentrations of ethionamide are removed by hemodialysis.129

Mechanism of Action

Ethionamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism.127 The exact mechanism of action of ethionamide has not been fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms.127

Spectrum

Ethionamide is a highly specific agent and is active only against Mycobacterium .

Ethionamide is active in vitro and in vivo against M. tuberculosis ,127 M. bovis , M. kansasii , and some strains of M. avium complex (MAC), and M. intracellulare . The drug also is active against M. leprae in experimental leprosy in mice.

In vitro, the minimum inhibitory concentration (MIC) of ethionamide for susceptible Mycobacterium has ranged from 0.6-10 mcg/mL.

Resistance

Natural and acquired resistance to ethionamide have been demonstrated in vitro and in vivo in strains of M. tuberculosis .127 Resistant strains of initially susceptible M. tuberculosis develop rapidly if ethionamide is used alone, but emergence of resistant strains may be delayed or prevented when ethionamide is used in conjunction with other antituberculosis agents.127

Although most M. tuberculosis isolates resistant to ethionamide or isoniazid usually are susceptible to the other drug,127 multi-drug resistant M. tuberculosis (MDMT) may have acquired resistance to both isoniazid and ethionamide.127 Limited data suggest that cross-resistance also may occur between ethionamide and thiosemicarbazones such as thiacetazone (drugs not commercially available in the US).127 There is no evidence to date of cross-resistance between ethionamide and cycloserine, aminosalicylic acid, or streptomycin.127

Strains of M. leprae resistant to ethionamide have been reported rarely.104,105

Pharmacokinetics

Absorption

Ethionamide is essentially completely absorbed following oral administration and does not undergo any appreciable first-pass metabolism.127

Following a single 250-mg oral dose of ethionamide given as film-coated tablets in fasting adults, peak plasma concentrations of ethionamide average 2.16 mcg/mL and are attained within 1 hour.127,128 When a single 250-mg oral dose of ethionamide is given as sugar-coated tablets (Trecator^®-SC; no longer commercially available in the US) in healthy adults, peak plasma concentrations average 1.48 mcg/mL and are attained within 1.5 hours.127,128

Although peak plasma concentrations are higher and attained more quickly with ethionamide film-coated tablets than with the previously available sugar-coated tablets, the area under the plasma-concentration time curve (AUC) is similar for both preparations.128

Distribution

The mean apparent oral volume of distribution reported in healthy adults following a single 250-mg dose of ethionamide film-coated tablets is 93.5 L.127

Studies using ethionamide sugar-coated tablets (Trecator^®-SC; no longer commercially available in the US) indicate that ethionamide is rapidly and widely distributed into body tissues and fluids and that concentrations in plasma and various organs are approximately equal.127 Although studies have not been performed to date with ethionamide film-coated tablets, distribution of the drug is expected to be the same as that reported with the sugar-coated tablets.127

Ethionamide is distributed into CSF106,127 in concentrations approximately equal to concurrent plasma concentrations of the drug.106 In a study in children with tuberculous meningitis, peak concentrations of ethionamide in CSF generally occurred 1.5-2.5 hours after oral doses of 15 or 20 mg/kg but showed considerable interindividual and intraindividual variation.110

Ethionamide readily crosses the placenta. It is not known if ethionamide is distributed into milk.127

Ethionamide is about 30% bound to plasma proteins.127

Elimination

The plasma half-life of ethionamide following a 250-mg oral dose given as film-coated tablets is 1.92 hours.127

Ethionamide is extensively metabolized to active and inactive metabolites, probably in the liver.127 At least 6 metabolites have been identified;127 the sulfoxide metabolite is active against Mycobacterium tuberculosis .127

Less than 1% of an oral dose of ethionamide is excreted in urine127 as active drug and metabolites; the remainder is excreted in urine as inactive metabolites. Only low concentrations of ethionamide are removed by hemodialysis.129

Chemistry and Stability

Chemistry

Ethionamide is a synthetic, isonicotinic acid-derivative antituberculosis agent. The drug occurs as a yellow, crystalline nonhygroscopic powder with a faint to moderate sulfide-like odor.127 Ethionamide is slightly soluble in water and sparingly soluble in alcohol.

Stability

Ethionamide film-coated tablets should be stored in tight containers at 20-25°C.127

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