Trecator

Ethionamide is an antibiotic that fights bacteria.

Ethionamide is used to treat tuberculosis (TB). Ethionamide must be given in combination with other tuberculosis medications and it should not be used alone.

Ethionamide may also be used for purposes not listed in this medication guide.

You should not use ethionamide if you have severe liver disease.

You should not use ethionamide if you are allergic to it, or if you have:

• severe liver disease.

To make sure ethionamide is safe for you, tell your doctor if you have:

• liver disease;
• vision problems;
• diabetes; or
• a thyroid disorder.

FDA pregnancy category C. It is not known whether ethionamide will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether ethionamide passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Do not give this medicine to a child without medical advice.

Trecator is a prescription medication used to treat tuberculosis. Tuberculosis is a disease caused by bacteria that attack the lungs.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Serious side effects have been reported with Trecator. See the "Drug Precautions" section.

Common side effects of Trecator include the following:

• nausea
• vomiting
• diarrhea
• stomach pain
• metallic taste
• weight loss
• increased saliva
• inflammation of the mouth

This is not a complete list of Trecator side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Ethionamide is an antibiotic that fights bacteria.

Ethionamide is used to treat tuberculosis (TB). Ethionamide must be given in combination with other tuberculosis medications and it should not be used alone.

Ethionamide may also be used for purposes not listed in this medication guide.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• numbness, tingling, or burning pain in your hands or feet;

• confusion; unusual thoughts or behavior;

• eye pain, blurred vision, double vision;

• a light-headed feeling, like you might pass out;

• seizure (convulsions); or

• upper stomach pain, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Common side effects may include:

• nausea, vomiting, diarrhea;

• stomach pain, loss of appetite;

• increased salivation, metallic taste in your mouth;

• blisters or ulcers in your mouth, red or swollen gums, trouble swallowing;

• headache, dizziness; or

• drowsiness, depressed mood, restless feeling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Contraindications

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

• Severe hepatic impairment.127

Warnings/Precautions

General Precautions

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

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

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 (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

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

Category C.127

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

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

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

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

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

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Absorption

Ethionamide is essentially completely absorbed following oral administration and is not subjected to any appreciable first pass metabolism. Ethionamide tablets may be administered without regard to the timing of meals.

The pharmacokinetic parameters of ethionamide following single oral-dose administration of 250 mg of Trecator film-coated tablets under fasted conditions to 40 healthy adult volunteers are provided in Table 1.

Trecator tablets have been reformulated from a sugar-coated tablet to a film-coated tablet. The Cmax for the film-coated tablets (2.16 µg/mL) was significantly higher than that of sugar-coated tablets (1.48 µg/mL) (see DOSAGE AND ADMINISTRATION).

Distribution

Ethionamide is rapidly and widely distributed into body tissues and fluids following administration of a sugar-coated tablet, with concentrations in plasma and various organs being approximately equal. Significant concentrations are also present in cerebrospinal fluid following administration of a sugar-coated tablet. Distribution of ethionamide into the same body tissues and fluids, including cerebrospinal fluid 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. The drug is approximately 30% bound to proteins. The mean (SD) apparent oral volume of distribution observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 93.5 (19.2) L.

Metabolism

Ethionamide is extensively metabolized to active and inactive metabolites. Metabolism is presumed to occur in the liver and thus far 6 metabolites have been isolated: 2-ethylisonicotinamide, carbonyl-dihydropyridine, thiocarbonyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso-nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis.

Elimination

The mean (SD) half-life observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 1.92 (0.27) hours. Less than 1% of the oral dose is excreted as ethionamide in urine.

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. The exact mechanism of action of ethionamide has not been fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms.

Microbiology

Ethionamide exhibits bacteriostatic activity against extracellular and intracellular Mycobacterium tuberculosis organisms. The development of ethionamide resistant M. tuberculosis isolates can be obtained by repeated subculturing in liquid or on solid media containing increasing concentrations of ethionamide. Multi-drug resistant strains of M. tuberculosis may have acquired resistance to both isoniazid and ethionamide. However, the majority of M. tuberculosis isolates that are resistant to one are usually susceptible to the other. There is no evidence of cross-resistance between ethionamide and para-aminosalicylic acid (PAS), streptomycin, or cycloserine. However, limited data suggest that cross-resistance may exist between ethionamide and thiosemicarbazones (i.e., thiacetazone) as well as isoniazid.

Ethionamide administered orally initially decreased the number of culturable Mycobacterium tuberculosis organisms from the lungs of H37Rv infected mice. Drug resistance developed with continued ethionamide monotherapy, but did not occur when mice received ethionamide in combination with streptomycin or isoniazid.

Ethionamide is contraindicated in patients with severe hepatic impairment and in patients who are hypersensitive to the drug.

In the treatment of tuberculosis, a major cause of the emergence of drug-resistant organisms, and thus treatment failure, is patient nonadherence to prescribed treatment. Treatment failure and drug-resistant organisms can be life-threatening and may result in other serious health risks. It is, therefore, important that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended when patients are receiving treatment for tuberculosis. Consultation with an expert in the treatment of drug-resistant tuberculosis is advised for patients in whom drug-resistant tuberculosis is suspected or likely. Ethionamide should be administered with at least one, sometimes two, other drugs to which the organism is known to be susceptible (see INDICATIONS AND USAGE).

Trecator is administered orally. The usual adult dose is 15 to 20 mg/kg/day, administered once daily or, if patient exhibits poor gastrointestinal tolerance, in divided doses, with a maximum daily dosage of 1 gram.

Trecator tablets have been reformulated from a sugar-coated tablet to a film-coated tablet. Patients should be monitored and have their dosage retitrated when switching from the sugar-coated tablet to the film-coated tablet (see CLINICAL PHARMACOLOGY).

Therapy should be initiated at a dose of 250 mg daily, with gradual titration to optimal doses as tolerated by the patient. A regimen of 250 mg daily for 1 or 2 days, followed by 250 mg twice daily for 1 or 2 days with a subsequent increase to 1 gm in 3 or 4 divided doses has been reported.4,5 Thus far, there is insufficient evidence to indicate the lowest effective dosage levels. Therefore, in order to minimize the risk of resistance developing to the drug or to the companion drug, the principle of giving the highest tolerated dose (based on gastrointestinal intolerance) has been followed. In the adult this would seem to be between 0.5 and 1.0 gm daily, with an average of 0.75 gm daily.

The optimum dosage for pediatric patients has not been established. However, pediatric dosages of 10 to 20 mg/kg p.o. daily in 2 or 3 divided doses given after meals or 15 mg/kg/24 hrs as a single daily dose have been recommended.1,2 As with adults, ethionamide may be administered to pediatric patients once daily. It should be noted that in patients with concomitant tuberculosis and HIV infection, malabsorption syndrome may be present. Drug malabsorption should be suspected in patients who adhere to therapy, but who fail to respond appropriately. In such cases, consideration should be given to therapeutic drug monitoring (see CLINICAL PHARMACOLOGY).

The best times of administration are those which the individual patient finds most suitable in order to avoid or minimize gastrointestinal intolerance, which is usually at mealtimes. Every effort should be made to encourage patients to persevere with treatment when gastrointestinal side effects appear, since they may diminish in severity as treatment proceeds.

Concomitant administration of pyridoxine is recommended.

Duration of treatment should be based on individual clinical response. In general, continue therapy until bacteriological conversion has become permanent and maximal clinical improvement has occurred.

Trecator® (ethionamide tablets, USP) are supplied in bottles of 100 tablets as follows:

250 mg, orange film-coated tablet marked "W" on one side and "4117" on reverse side, NDC 0008-4117-01.

Store at controlled room temperature 20° to 25°C (68° to 77°F). Dispense in a tight container.