Trecator® (ethionamide tablets, USP) is used in the treatment of tuberculosis. The chemical name for ethionamide is 2-ethylthioisonicotinamide with the following structural formula:

Ethionamide is a yellow crystalline, nonhygroscopic compound with a faint to moderate sulfide odor and a melting point of 162°C. It is practically insoluble in water and ether, but soluble in methanol and ethanol. It has a partition coefficient (octanol/water) Log P value of 0.3699. Trecator tablets contain 250 mg of ethionamide. The inactive ingredients present are croscarmellose sodium, FD&C Yellow #6, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, silicon dioxide, talc, and titanium dioxide.

Last updated on RxList: 6/15/2007

Trecator is primarily indicated for the treatment of active tuberculosis in patients with M. tuberculosis resistant to isoniazid or rifampin, or when there is intolerance on the part of the patient to other drugs. Its use alone in the treatment of tuberculosis results in the rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility tests. If the susceptibility tests indicate that the patient's organism is resistant to one of the first-line antituberculosis drugs (i.e., isoniazid or rifampin) yet susceptible to ethionamide, ethionamide should be accompanied by at least one drug to which the M tuberculosis isolate is known to be susceptible.³ If the tuberculosis is resistant to both isoniazid and rifampin, yet susceptible to ethionamide, ethionamide should be accompanied by at least two other drugs to which the M tuberculosis isolate is known to be susceptible.³

Patient nonadherence to prescribed treatment can result in treatment failure and in the development of drug-resistant tuberculosis, which can be life-threatening and lead to other serious health risks. It is, therefore, essential that patients adhere to the drug regimen for the full duration of treatment. Directly observed therapy is recommended for all patients receiving treatment for tuberculosis. Patients in whom drug-resistant M. tuberculosis organisms are isolated should be managed in consultation with an expert in the treatment of drug-resistant tuberculosis.

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.

REFERENCES

1. Feigin, R.D., and Cherry, J.D.: Textbook of Pediatric Infectious Diseases, 2nd Edition. Philadelphia, W.B. Saunders Co., 1987, pp. 1371-1372.
2. Nelson, W.E., Behrman, R.E., Vaughan, V.C. (eds.): Nelson Textbook of Pediatrics, 13th edition. Philadelphia, W.B. Saunders Co., 1987, p.636.
3. Treatment of Tuberculosis and Tuberculosis Infection in Adults and Children, Am J Respiratory and Critical Care Medicine, 149:1359-1374, 1994.
4. Peloquin, CA: Pharmacology of the Antimycobacterial Drugs, Med Clin North Am 77(6): 1230-1262, 1993.

American Thoracic Society. Am J Respir Crit Care Med 1997;156:S1-S25.

This product's label may have been updated. For current package insert and further product information, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556.

Manufactured for: Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101
By OSG Norwich Pharmaceuticals Inc., North Norwich, New York 13814
Rev 09/06., FDA rev date: 5/30/2007

Last updated on RxList: 6/15/2007

Gastrointestinal: The most common side effects of ethionamide are gastrointestinal disturbances including nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia and weight loss. Adverse gastrointestinal effects appear to be dose related, with approximately 50% of patients unable to tolerate 1 gm as a single dose. Gastrointestinal effects may be minimized by decreasing dosage, by changing the time of drug administration, or by the concurrent administration of an antiemetic agent.

Nervous System: Psychotic disturbances (including mental depression), drowsiness, dizziness, restlessness, headache, and postural hypotension have been reported with ethionamide. Rare reports of peripheral neuritis, optic neuritis, diplopia, blurred vision, and a pellagra-like syndrome also have been reported. Concurrent administration of pyridoxine has been recommended to prevent or relieve neurotoxic effects.

Hepatic: Transient increases in serum bilirubin, SGOT, SGPT; Hepatitis (with or without jaundice).

Other: Hypersensitivity reactions including rash, photosensitivity, thrombocytopenia and purpura have been reported rarely. Hypoglycemia, hypothyroidism, gynecomastia, impotence, and acne also have occurred. The management of patients with diabetes mellitus may become more difficult in those receiving ethionamide.

Trecator has been found to temporarily raise serum concentrations of isoniazid. Trecator may potentiate the adverse effects of other antituberculous drugs administered concomitantly. In particular, convulsions have been reported when ethionamide is administered with cycloserine and special care should be taken when the treatment regimen includes both of these drugs. Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported.

Last updated on RxList: 6/15/2007

The use of Trecator alone in the treatment of tuberculosis results in rapid development of resistance. It is essential, therefore, to give a suitable companion drug or drugs, the choice being based on the results of susceptibility testing. However, therapy may be initiated prior to receiving the results of susceptibility tests as deemed appropriate by the physician. 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). Drugs which have been used as companion agents are rifampin, ethambutol, pyrazinamide, cycloserine, kanamycin, streptomycin, and isoniazid. The usual warnings, precautions, and dosage regimens for these companion drugs should be observed.

Patient compliance is essential to the success of the antituberculosis therapy and to prevent the emergence of drug-resistant organisms. Therefore, patients should adhere to the drug regimen for the full duration of treatment. It is recommended that directly observed therapy be practiced when patients are receiving antituberculous medication. Additional consultation from experts in the treatment of drug-resistant tuberculosis is recommended when patients develop drug-resistant organisms.

General

Ethionamide may potentiate the adverse effects of the other antituberculous drugs administered concomitantly (see DRUG INTERACTIONS). Ophthalmologic examinations (including ophthalmoscopy) should be performed before and periodically during therapy with Trecator.

Laboratory Tests

Determination of serum transaminases (SGOT, SGPT) should be made prior to initiation of therapy and should be monitored monthly. If serum transaminases become elevated during therapy, ethionamide and the companion antituberculosis drug or drugs may be discontinued temporarily until the laboratory abnormalities have resolved. Ethionamide and the companion antituberculosis medication(s) then should be reintroduced sequentially to determine which drug (or drugs) is (are) responsible for the hepatotoxicity.

Blood glucose determinations should be made prior to and periodically throughout therapy with Trecator. Diabetic patients should be particularly alert for episodes of hypoglycemia.

Periodic monitoring of thyroid function tests is recommended as hypothyroidism, with or without goiter, has been reported with ethionamide therapy.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Teratogenic Effects: Pregnancy Category C

Animal studies conducted with Trecator indicate that the drug has teratogenic potential in rabbits and rats. The doses used in these studies on a mg/kg basis were considerably in excess of those recommended in humans. There are no adequate and well-controlled studies in pregnant women. Because of these animal studies, however, it must be recommended that Trecator be withheld from women who are pregnant, or who are likely to become pregnant while under therapy, unless the prescribing physician considers it to be an essential part of the treatment.

Labor and Delivery

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

Nursing Mothers

Because no information is available on the excretion of ethionamide in human milk, Trecator should be administered to nursing mothers only if the benefits outweigh the risks. Newborns who are breast-fed by mothers who are taking Trecator should be monitored for adverse effects.

Pediatric Use

Due to the fact that pulmonary tuberculosis resistant to primary therapy is rarely found in neonates, infants, and children, investigations have been limited in these age groups. At present, the drug should not be used in pediatric patients under 12 years of age except when the organisms are definitely resistant to primary therapy and systemic dissemination of the disease, or other life-threatening complications of tuberculosis, is judged to be imminent.

Last updated on RxList: 6/15/2007

No specific information is available on the treatment of overdosage with Trecator. If it should occur, standard procedures to evacuate gastric contents and to support vital functions should be employed.

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

Last updated on RxList: 6/15/2007

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.

Table 1: Mean (SD) Pharmacokinetic Parameters for Ethionamide Following Single-dose Administration of 250 mg Trecator Film-Coated Tablets to Healthy Adult Volunteers

	Cmax (• g/mL)	Tmax (hrs)	AUC (• g•hr/mL)
Film-Coated Tablet	2.16 (0.61)	1.02 (0.55)	7.67 (1.69)

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

In Vitro Activity

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.

In Vivo Activity

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.

SUSCEPTIBILITY TESTING

Ethionamide susceptibility testing should only be performed by qualified or reference laboratories.

Two standardized in vitro susceptibility methods are available for testing ethionamide against M. tuberculosis organisms. The modified proportion method (CDC or NCCLS M24-P) utilizes Middlebrook and Cohn 7H10 agar medium impregnated with ethionamide at a final concentration of 5.0 • g/mL. After 2 to 3 weeks of incubation, MIC₉₉ values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug, of at least 1% of the growth in the control culture, indicates resistance.

The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 5.0 • g/mL of ethionamide. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay.

Susceptibility test results obtained by these two different methods cannot be compared unless equivalent drug concentrations are evaluated.

The clinical relevance of in vitro susceptibility test results for mycobacterial species other than M. tuberculosis using either the radiometric or the proportion method has not been determined.

Last updated on RxList: 6/15/2007

Patients should be advised to consult their physician should blurred vision or any loss of vision, with or without eye pain, occur during treatment.

Excessive ethanol ingestion should be avoided because a psychotic reaction has been reported.

Last updated on RxList: 6/15/2007

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

ETHIONAMIDE - ORAL

(eth-eye-OH-nuh-mide)

COMMON BRAND NAME(S): Trecator

USES: This medication is used with other medications to treat active tuberculosis (TB) infection. Ethionamide belongs to a class of drugs known as antibiotics that are active against bacteria that cause TB.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used with other medications to help treat a serious, spreading infection (Mycobacterium avium complex-MAC) in those with advanced HIV infection.

HOW TO USE: Take this medication by mouth with or without food, usually once daily or as directed by your doctor. This medication is usually taken for 6-9 months for tuberculosis. To reduce the risk of side effects, your doctor may start you on a small dose and increase the dose every 1-2 days until you are taking the full dose. If severe stomach upset occurs, your doctor may divide the once-daily dose into smaller doses to be taken several times daily.

Dosage is based on your age, weight, medical condition, and response to therapy.

It is very important to continue taking this medication (and other TB medications) exactly as prescribed by your doctor.

This medication works best when the amount of drug in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals. To help you remember, take it the same time(s) each day.

Do not take more or less of this drug than prescribed or stop taking it (or other TB medicines) even for a short time unless directed to do so by your doctor. Skipping or changing your dose without approval from your doctor may cause the amount of TB bacteria to increase, make the infection more difficult to treat (resistant), or worsen side effects. If TB becomes resistant to this medication, it might also be resistant to other TB medications.

Your doctor may also direct you to take vitamin B6 (pyridoxine) to help prevent certain side effects (nerve problems) from ethionamide.

Inform your doctor if your condition persists or worsens.

SIDE EFFECTS: Nausea, vomiting, diarrhea, abdominal/stomach pain, increased saliva, strange metallic taste in the mouth, loss of appetite, weight loss, or sores in the mouth may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication may develop serious side effects, but with frequent visits to your doctor, this risk can be minimized.

Tell your doctor immediately if any of these unlikely but serious side effects occur: drowsiness, dizziness, persistent nausea/vomiting, weakness, tiredness, yellowing eyes/skin, brown urine, painful/swollen joints, mental/mood disorders (e.g., depression, strange/quickly changing behavior, restlessness), shakiness, headache, numbness/tingling of hands/feet, enlarged male breasts, decreased sexual interest/ability, acne.

Tell your doctor immediately if any of these rare but very serious side effects occur: vision changes in one or both eyes, fever, easy bleeding/bruising, bloody/pink urine.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking ethionamide, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: a certain eye problem (optic neuritis), severe liver problems.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: HIV infection, eye problems (e.g., cataracts, diabetic retinopathy), nerve problems in the hands/feet (peripheral neuropathy).

This drug may make you dizzy or drowsy. Use caution while driving, using machinery, or doing any activity that requires alertness. Avoid alcoholic beverages because they may increase your risk of dizziness and drowsiness.

Ethionamide may worsen liver problems you may already have. To reduce your risk of serious liver damage, avoid alcoholic beverages while taking this treatment.

If you have diabetes, this product may rarely decrease your blood sugar levels. Check your blood sugar levels regularly as directed by your doctor. Tell your doctor immediately if you have symptoms of low blood sugar, such as shakiness, inability to think, sleepiness, or unusual sweating. Your anti-diabetic medication or diet may need to be adjusted.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Therefore, consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: isoniazid, cycloserine, alcohol.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents should call the US National Poison Hotline at 1-800-222-1222. Canada residents should call a provincial poison control center.

NOTES: Do not share this medication with others.

Keep all medical and laboratory appointments.

Laboratory and/or medical tests (e.g., TB cultures, vision tests, liver function tests, blood cell counts, blood chemistries) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 68-77 degrees F (20-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.