Trecator (Page 2 of 3)

CONTRAINDICATIONS

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

WARNINGS

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 anti-tuberculosis 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 anti-tuberculous medication. Additional consultation from experts in the treatment of drug-resistant tuberculosis is recommended when patients develop drug-resistant organisms.

Severe Cutaneous Adverse Reactions

Cases of severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of combinations of anti-tuberculosis drugs that included ethionamide (see ADVERSE REACTIONS). If symptoms or signs of SCARs develop, discontinue suspect drug(s) immediately and institute appropriate therapy.

PRECAUTIONS

General

Prescribing Trecator in the absence of a proven or strongly suspected bacterial infection indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Ethionamide may potentiate the adverse effects of the other anti-tuberculous drugs administered concomitantly (see Drug Interactions). Ophthalmologic examinations (including ophthalmoscopy) should be performed before and periodically during therapy with Trecator.

Information For Patients

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.

Patients should be counseled that antibacterial drugs including Trecator should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Trecator is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Trecator or other antibacterial drugs in the future.

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 anti-tuberculosis drug or drugs may be discontinued temporarily until the laboratory abnormalities have resolved. Ethionamide and the companion anti-tuberculosis 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.

Drug Interactions

Trecator has been found to temporarily raise serum concentrations of isoniazid. Trecator may potentiate the adverse effects of other anti-tuberculous 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Teratogenic Effects

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.

ADVERSE REACTIONS

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.

Immune System Disorders: SCARs such as SJS, TEN, DRESS, and AGEP have been reported with the use of combinations of anti-tuberculosis drugs that included ethionamide (see WARNINGS).

OVERDOSAGE

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.

DOSAGE AND ADMINISTRATION

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.