Tuberculosis, drug resistant (alternative agent): Note: Expert consultation for optimal regimen and duration of treatment is advised; coadministration of pyridoxine is recommended for prevention of neurotoxic effects.
Oral: 15 to 20 mg/kg/day in 1 or 2 divided doses (usually 250 or 500 mg once or twice daily) in combination with additional appropriate antituberculosis agents. Some experts recommend starting with 250 mg once daily and gradually increasing over 1 week; few patients tolerate 500 mg twice daily (maximum daily dose: 1 g/day) (ATS/CDC/ERS/IDSA [Nahid 2019]).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in manufacturer's labeling; however, the following adjustments have been reported in the literature (ATS/CDC/IDSA [Nahid 2016]):
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute: 250 to 500 mg/day.
End-stage renal disease (ESRD) on hemodialysis: 250 to 500 mg/day.
Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution (ATS/CDC/IDSA [Blumberg 2003]).
Severe impairment: Use is contraindicated.
(For additional information see "Ethionamide: Pediatric drug information")
Active TB infection (excluding meningitis), treatment (second-line therapy):
Note: Recommendations often change due to epidemiology (resistance) and emerging information; consult CDC and WHO for detailed information. Always use as part of a multidrug regimen (ATS/CDC/IDSA [Nahid 2016]). Coadministration of pyridoxine is recommended for prevention of neurotoxic effects.
Infants, Children, and Adolescents: Oral: 15 to 20 mg/kg/day in divided doses once or twice daily (in HIV-exposed/-infected, divided doses three times daily have also been recommended); usual adult dose range: 250 to 500 mg/dose; maximum daily dose: 1,000 mg/day. Note: Ethionamide causes nausea and patients are often unable to tolerate the maximum dose divided twice daily (eg, in adults, 500 mg twice daily); therefore, experts suggest beginning with a low once daily dose and gradually increasing as tolerated; may consider therapeutic drug monitoring to aid in determining appropriate dose (ATS/CDC/IDSA [Nahid 2016]; HHS [OI pediatric 2020]; Seddon 2012).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in manufacturer labeling nor recommendations specific for pediatric patients; experience in adult patients suggests that dosage adjustment may be necessary.
Mild or moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution (Blumberg 2003).
Severe impairment: Use is contraindicated.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Trecator: 250 mg [contains fd&c yellow #6 (sunset yellow)]
No
Oral: Directly observed therapy is recommended. Administer with or without meals. GI adverse effects may be decreased by administration at meals or bedtime, decreased dose, or giving with antiemetics.
Oral: Administer with meals or at bedtime to decrease GI distress (nausea)
Tuberculosis: Treatment of active tuberculosis, in combination with other antituberculosis agents, in patients with Mycobacterium tuberculosis resistant to isoniazid or rifampin, or when there is intolerance to other drugs.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Frequency not defined:
Cardiovascular: Orthostatic hypotension
Dermatologic: Acne vulgaris, skin photosensitivity, skin rash
Endocrine & metabolic: Goiter, gynecomastia, hypoglycemia, hypothyroidism, pellagra (pellagra-like syndrome), weight loss
Gastrointestinal: Abdominal pain, anorexia, diarrhea, nausea, sialorrhea, stomatitis, vomiting
Genitourinary: Impotence
Hematologic & oncologic: Purpuric disease, thrombocytopenia
Hepatic: Hepatitis, increased serum alanine aminotransferase, increased aspartate aminotransferase, increased serum bilirubin, jaundice
Hypersensitivity: Hypersensitivity reaction
Nervous system: Depression, dizziness, drowsiness, headache, metallic taste, peripheral neuritis, psychiatric disturbance, restlessness
Ophthalmic: Blurred vision, diplopia, optic neuritis
Hypersensitivity to ethionamide or any component of the formulation; severe hepatic impairment
Concerns related to adverse effects:
• Dermatologic reactions: Cases of severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms syndrome have been reported. Discontinue treatment immediately and institute appropriate therapy if signs or symptoms of SCAR develop.
Disease-related concerns:
• Diabetes: Use with caution in patients with diabetes mellitus; may cause hypoglycemia.
• Hepatotoxicity: May cause hepatotoxicity; monitor liver function tests at baseline and monthly.
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction; hypothyroidism (reversible; with and without goiter) has been reported.
Other warnings/precautions:
• Appropriate use: Drug-resistant tuberculosis develops rapidly if ethionamide is used alone; must administer with other antituberculosis agents. Directly observed therapy (DOT) is recommended.
• Ethanol use: Avoid excessive ethanol intake; psychotic reaction may occur.
• Eye exams: Eye exams are recommended at baseline and periodically during therapy.
None known.
Alcohol (Ethyl): May enhance the adverse/toxic effect of Ethionamide. Specifically, there may be a risk for a psychotic episode/reaction. Risk C: Monitor therapy
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy
Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination
CycloSERINE: Ethionamide may enhance the adverse/toxic effect of CycloSERINE. Risk C: Monitor therapy
Immune Checkpoint Inhibitors: Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors. Risk C: Monitor therapy
Isoniazid: Ethionamide may increase the serum concentration of Isoniazid. Risk C: Monitor therapy
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy
Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modification
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification
Evaluate pregnancy status prior to treatment of multidrug resistant tuberculosis in females of reproductive potential. Females of reproductive potential should use effective contraception during treatment for multidrug resistant tuberculosis (Esmail 2018).
Based on data from animal reproduction studies and limited human data, in utero exposure to ethionamide may cause fetal harm (HHS [OI 2020]). In addition, ethionamide may increase the risk of nausea and vomiting in pregnant patients (Esmail 2018).
Active tuberculosis infection is associated with adverse fetal outcomes including intrauterine growth restriction, low birth weight, preterm birth, and perinatal death (Esmail 2018; Miele 2020) as well as adverse maternal outcomes, including increased risks for anemia and cesarean delivery. Placental transmission may rarely occur with active maternal disease (Miele 2020).
Data are limited for use of second line drugs during pregnancy (ie, ethionamide) (ATS/CDC/ERS/IDSA [Nahid 2019]). The treatment of multidrug resistant tuberculosis in pregnant patients should be individualized; evidence to support a specific regimen is not available (ATS/CDC/ERS/IDSA [Nahid 2019]; WHO 2020). Use of ethionamide should be avoided when possible (HHS [OI 2020]).
It is not known if ethionamide is present in breast milk.
If ethionamide is used while breastfeeding, monitor the infant for adverse effects. Patients with multidrug resistant tuberculosis and a sputum smear-positive test should avoid breastfeeding when possible (Esmail 2018).
Healthcare provider may recommend an increase in dietary intake of pyridoxine to prevent neurotoxic effects of ethionamide. Avoid alcohol.
Baseline and monthly serum ALT and AST; baseline and periodic ophthalmic exams; periodic blood glucose and TSH; signs and symptoms of severe cutaneous adverse reactions; ethionamide serum concentrations (when clinically indicated).
Note: Obtain samples at 2 and 6 hours post dose to detect delayed absorption or malabsorption (Peloquin 2002).
Therapeutic peak levels: 1 to 5 mcg/mL after a 250 to 500 mg dose (Peloquin 2002).
Inhibits peptide synthesis; bacteriostatic
Absorption: Essentially complete absorption
Distribution: Vd: 93.5 L; widely distributed into body tissues and fluids including CSF
Protein binding: ~30%
Metabolism: Prodrug; extensively hepatic to active and inactive metabolites
Half-life elimination: ~2 hours
Time to peak, serum: ~1 hour
Excretion: Urine (<1% as unchanged drug; as active and inactive metabolites)
Tablets (Trecator Oral)
250 mg (per each): $6.73
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