Trecator-SC

Other Agents for Tuberculosis

 
Directly observed therapy (DOT) is recommended. [34361] [34362] [61094]
Concomitant pyridoxine is recommended.

Administer at bedtime or with meals to minimize gastrointestinal intolerance.

optic neuritis / Delayed / 0-1.0
visual impairment / Early / 0-1.0
toxic epidermal necrolysis / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known

blurred vision / Early / 0-1.0
neuritis / Delayed / 0-1.0
peripheral neuropathy / Delayed / 0-1.0
thrombocytopenia / Delayed / 0-1.0
stomatitis / Delayed / 10.0
depression / Delayed / Incidence not known
hepatitis / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known
jaundice / Delayed / Incidence not known
orthostatic hypotension / Delayed / Incidence not known
hypoglycemia / Early / Incidence not known
impotence (erectile dysfunction) / Delayed / Incidence not known
goiter / Delayed / Incidence not known
hypothyroidism / Delayed / Incidence not known

diplopia / Early / 0-1.0
purpura / Delayed / 0-1.0
photosensitivity / Delayed / 0-1.0
rash / Early / 0-1.0
weight loss / Delayed / 10.0
anorexia / Delayed / 10.0
vomiting / Early / 10.0
nausea / Early / 10.0
abdominal pain / Early / 10.0
hypersalivation / Early / 10.0
metallic taste / Early / 10.0
diarrhea / Early / 10.0
dizziness / Early / Incidence not known
drowsiness / Early / Incidence not known
headache / Early / Incidence not known
restlessness / Early / Incidence not known
acneiform rash / Delayed / Incidence not known
gynecomastia / Delayed / Incidence not known
vitamin B6 deficiency / Delayed / Incidence not known

Trecator

Rx

Second-line agent for tuberculosis; for disease resistant to rifampin and/or isoniazid, or for patients who are intolerant of rifampin and isoniazid; used in combination with at least one other antitubercular drug; only film-coated tablets (Trecator®) available.

15 to 20 mg/kg/day (Max: 1 g/day) or 5 days/week PO divided once or twice daily. Start with an initial dose of 250 mg PO once daily and gradually increase as tolerated. Usual dose: 250 to 500 mg PO once or twice daily.[31321] [34362] [61094] Ethionamide is generally recommended as second-line therapy; duration is dependent on the site of involvement.[61094]

15 to 20 mg/kg/day (Max: 1 g/day) or 5 days/week PO divided 1 to 3 times daily. The FDA-approved dosage is 10 to 20 mg/kg/day (Max: 1 g/day).

15 to 20 mg/kg/day (Max: 1 g/day) PO divided once or twice daily. Start with an initial dose of 250 mg PO once daily and gradually increase as tolerated. Usual dose: 250 to 500 mg PO once or twice daily.

15 to 20 mg/kg/day (Max: 1 g/day) PO divided 1 to 3 times daily. The FDA-approved dosage is 10 to 20 mg/kg/day (Max: 1 g/day).

Ethionamide is contraindicated in patients with severe hepatic impairment.[31321]

Adult†
CrCl 30 mL/minute or more: No dosage adjustment necessary.
CrCl less than 10 to 30 mL/minute: 250 to 500 mg PO once daily or decrease dose by 50%. No dosage adjustment may be necessary.
 
Intermittent hemodialysis†
250 to 500 mg PO once daily. No dosage adjustment may be necessary.
 
Peritoneal dialysis†
No dosage is adjustment necessary.
 
Continuous renal replacement therapy (CRRT)†
NOTE: Various CRRT modalities include continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), continuous venovenous high-flux hemodialysis (CVVHFD), continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), and continuous arteriovenous hemodiafiltration (CAVHDF). Dosing should take into consideration patient-specific factors (e.g., intrinsic renal function), type of infection, the duration of renal replacement therapy, the effluent flow rate, and the replacement solution administered.
 
No dosage is adjustment necessary.

Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and aminosalicylate sodium, aminosalicylic acid. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Bacillus Calmette-Guerin Vaccine, BCG: (Major) Urinary concentrations of ethionamide could interfere with the therapeutic effectiveness of BCG. Postpone instillation of BCG if the patient is receiving antibiotics.
Capreomycin: (Moderate) Adverse hepatic effects have been associated with capreomycin, especially with concurrent use of other antituberculosis drugs known to alter hepatic function. Theoretically, coadministration of capreomycin and ethionamide could increase the risk of hepatotoxicity. Monitor patients for changes in liver function if these drugs are coadministered.
Cycloserine: (Moderate) Cycloserine interacts with ethionamide, possibly increasing the risk of developing CNS effects, especially seizures.
Ethambutol: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking ethionamide. A psychotic reaction has been reported with excessive alcohol ingestion. (Moderate) A psychotic reaction has been reported in patients receiving ethionamide and consuming excessive amounts of alcohol. Also, ethionamide appears to be metabolized by the liver. Chronic alcohol ingestion may increase enzymatic activity of the liver whereas acute alcohol ingestion can inhibit liver enzymatic activity.
Isoniazid, INH: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Also, concomitant administration of isoniazid, INH and ethionamide may cause a temporary increase in serum concentrations of isoniazid. Carefully monitor patients for adverse effects of isoniazid. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Also, concomitant administration of isoniazid, INH and ethionamide may cause a temporary increase in serum concentrations of isoniazid. Carefully monitor patients for adverse effects of isoniazid. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Isoniazid, INH; Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Also, concomitant administration of isoniazid, INH and ethionamide may cause a temporary increase in serum concentrations of isoniazid. Carefully monitor patients for adverse effects of isoniazid. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Pyrazinamide, PZA: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Rifabutin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and ethionamide. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.

Trecator-SC Oral Tab: 250mg

1 g/day PO.

1 g/day PO.

20 mg/kg/day (Max: 1 g/day) PO.

20 mg/kg/day (Max: 1 g/day) PO.

20 mg/kg/day PO.

Safety and efficacy have not been established.

Ethionamide's exact mechanism of action is not known. Similar to isoniazid, ethionamide appears to work by inhibiting mycolic acid synthesis, which disrupts the formation of the mycobacterial cell wall. Susceptible strains of Mycobacterium convert ethionamide to an ethionamide S-oxide metabolite by S-oxidation. Studies have demonstrated that conversion to this active metabolite by susceptible organisms and within the liver is responsible for ethionamide's activity. Ethionamide exhibits bacteriostatic or bactericidal action depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. Cross-resistance between ethionamide and the antitubercular agent isoniazid has been demonstrated in multi-drug resistant strains of M. tuberculosis; however, most M. tuberculosis isolates that are resistant to one are usually susceptible to the other drug. Limited data shows that cross-resistance may exist between ethionamide and thiacetazone. There is no evidence of cross-resistance between ethionamide and para-aminosalicylic acid, streptomycin, or cycloserine.

Ethionamide is administered orally.
 
Ethionamide does not undergo any significant first pass metabolism. Ethionamide is approximately 30% protein bound. Ethionamide crosses the placenta, but it is unknown whether it distributes into breast milk. Distribution of ethionamide into tissues and fluids, including cerebrospinal fluid (CSF), 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. After administration of the sugar-coated tablet, ethionamide is rapidly and widely distributed into all body tissues and fluids. Plasma and tissue concentrations are approximately equal. Ethionamide CSF concentrations exceeding the in vitro minimum inhibitory concentration for Mycobacterium tuberculosis (2.5 mcg/mL) were obtained in most patients after a single oral dose of 20 mg/kg/day. Of 18 children (median age 26.5 months) with tuberculous meningitis, an ethionamide spinal fluid concentration of at least 2.5 mcg/mL was reached on 11 of 13 occasions after 20 mg/kg/day but on only 7 of 26 occasions after 15 mg/kg/day.
 
Ethionamide is extensively metabolized presumably in the liver to active and inactive metabolites. The sulphoxide metabolite has demonstrated antimicrobial activity against Mycobacterium tuberculosis. The mean (SD) plasma half-life observed in 40 healthy volunteers following a single 250 mg oral dose of the film-coated tablet was 1.92 (0.27) hours. Less than 1% of the oral dose is excreted as unchanged drug in the urine.

Ethionamide is rapidly and essentially completely absorbed from the gastrointestinal tract. Peak serum concentrations are obtained within 1—2 hours. The mean (SD) ethionamide systemic exposure after a single 250 mg film-coated tablet in 40 healthy, fasting adults was 7.67 (1.69) mcg x hr/mL. The mean systemic exposure is not significantly different from the old sugar-coated tablet. However, the maximum concentration for the film-coated tablets (2.16 mcg/mL) is significantly higher that of the sugar-coated tablets (1.48 mcg/mL).

There are no adequate and well-controlled studies with ethionamide in human pregnancy. Based on animal data, withhold ethionamide from women who are pregnant, or who are likely to become pregnant while receiving therapy, unless the prescriber considers it to be an essential part of the treatment. Animal studies conducted with ethionamide indicate that the drug has teratogenic potential in rabbits and rats. The doses used in these studies on a mg/kg basis were considerably more than those recommended in humans.[31321] Guidelines suggest avoiding ethionamide during pregnancy if alternative agents can be used for effective treatment.[65465] The effect of ethionamide on labor and delivery in pregnant women is unknown.[31321]

Because no information is available on the excretion of ethionamide in human milk, use ethionamide in breast-feeding mothers only if the benefits outweigh the risks. Monitor newborns who are breast-fed by mothers who are taking ethionamide for adverse effects.[31321] Ethionamide use as part of multidrug regimens to treat 2 pregnant women with multidrug-resistant tuberculosis, 1 throughout pregnancy and postpartum and the other postpartum only, has been reported. The infants were breast-fed and developing normally except for a mild speech delay in 1 infant and hyperactivity in the other.[48384]