Ethionamide [Trecator 250mg]
(British Approved Name, US Adopted Name, rINN)
Drug Nomenclature
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Pharmacopoeias. In Europe, International, Japan, and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 ( Ethionamide). Small yellow crystals or a yellow crystalline powder. Practically insoluble in water; sparingly soluble in alcohol; soluble in methyl alcohol.
The United States Pharmacopeia 31, 2008 ( Ethionamide). A bright yellow powder having a faint to moderate sulfide-like odour. Slightly soluble in water, in chloroform, and in ether; sparingly soluble in alcohol and in propyleneglycol; soluble in methyl alcohol. pH of a 1% slurry in water is between 6.0 and 7.0. Store in airtight containers.
Uses
Tuberculosis
Active Tuberculosis
Ethionamide is used in conjunction with other antituberculosis agents in the treatment of clinical tuberculosis.
The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) currently recommend several possible multiple-drug regimens for the treatment of culture-positive pulmonary tuberculosis. These regimens have a minimum duration of 6 months (26 weeks), and consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months).
Ethionamide is considered a second-line antituberculosis agent for use in these regimens. The drug usually is used in the treatment of drug-resistant tuberculosis caused by Mycobacterium tuberculosis known or presumed to be susceptible to the drug, especially when isoniazid and/or rifampin cannot be used because of resistance and/or intolerance. If ethionamide is added as a new drug to a regimen in patients experiencing treatment failure who have proven or suspected drug-resistant tuberculosis, at least 2, preferably 3, new drugs known or expected to be active against the resistant strain should be added at the same time.
After results of in vitro susceptibility testing are available, the regimen can be adjusted accordingly. For information on general principles used in the treatment of tuberculosis, see the Antituberculosis Agents General Statement 8:16.04.
Other Mycobacterial Infections
Ethionamide has been used in conjunction with other antituberculosis or anti-infective agents in the treatment of Mycobacterium avium complex (MAC) infections. Some clinicians suggest that ethionamide be included in one alternative multiple-drug regimen for the treatment of MAC pulmonary infections in patients whose disease has failed to respond to therapy with a macrolide-containing regimen (e.g., clarithromycin or azithromycin, rifabutin or rifampin, and ethambutol). In such patients, subsequent therapy is complicated, may be associated with a high incidence of adverse effects, and should be undertaken only under the guidance of clinicians experienced in handling these patients.
Although ethionamide has been used in the treatment of multibacillary leprosy and previously was recommended as an alternative agent for use in multiple-drug regimens in patients who would not accept or could not tolerate clofazimine, the World Health Organization (WHO) no longer recommends use of ethionamide for the treatment of leprosy because severe hepatotoxicity has been associated with use of the drug.
The WHO and most clinicians currently recommend that multibacillary leprosy be treated with a multiple-drug regimen that includes rifampin, dapsone, and clofazimine, and that paucibacillary leprosy be treated with a multiple-drug regimen that includes rifampin and dapsone. If an alternative agent is needed for these regimens in patients who will not accept or cannot tolerate clofazimine or in patients who cannot receive rifampin because of adverse effects, intercurrent disease (e.g., chronic hepatitis), or infection with rifampin-resistant M. leprae, the WHO and other clinicians generally recommend use of ofloxacin and minocycline.
Administration
Ethionamide is administered orally.
If the drug is given as a single daily dose, the dose should be given at the time of day that the patient finds most suitable in order to avoid or minimize GI intolerance, which usually is at mealtimes.
Dosage
Active Tuberculosis
In the treatment of clinical tuberculosis, ethionamide should not be given alone. The drug is considered a second-line agent for use in daily multiple-drug regimens for the treatment of active tuberculosis. Data are not available to date regarding use of ethionamide in intermittent multiple-drug regimens used in the treatment of tuberculosis. Therapy for tuberculosis should be continued long enough to prevent relapse. The minimum duration of treatment currently recommended for patients with culture-positive pulmonary tuberculosis is 6 months (26 weeks), and recommended regimens consist of an initial intensive phase (2 months) and a continuation phase (usually either 4 or 7 months). However, completion of treatment is determined more accurately by the total number of doses and is not based solely on the duration of therapy.
Adult Dosage
The manufacturer states that the usual adult dosage of ethionamide for use in conjunction with other antituberculosis agents for the treatment of tuberculosis is 15-20 mg/kg (up to 1 g) daily. The drug may be administered once daily or, if GI intolerance occurs, in divided doses. The manufacturer states that initiation of therapy with a dosage of 250 mg daily, with gradual titration to optimal dosage as tolerated by the patient, also may be beneficial. A regimen consisting of ethionamide 250 mg daily for 1-2 days, followed by 250 mg twice daily for 1-2 days with a subsequent increase to 1 g daily in 3 or 4 divided doses, has been used.
The American Thoracic Society (ATS), US Centers for Disease Control (CDC), and Infectious Diseases Society of America (IDSA) state that the usual dosage of ethionamide for use in conjunction with other antituberculosis agents in adults and children 15 years of age or older is 15-20 mg/kg (up to 1 g) daily; a dosage of 500-750 mg daily usually is recommended given as a single daily dose or in 2 divided doses.
Pediatric Dosage
The manufacturer states that optimum dosage for children has not been established. However, the ATS, CDC, IDSA, and American Academy of Pediatrics (AAP) recommend a pediatric dosage of 15-20 mg/kg (up to 1 g) daily given in 2 or 3 divided doses. Limited evidence suggests that an ethionamide dosage of 20 mg/kg daily given as a single dose in children is more likely to produce CSF concentrations exceeding the minimum inhibitory concentration of 2.5 mcg/mL for Mycobacterium tuberculosis.
Cautions
GI Effects
GI disturbances are the most frequent adverse effects of ethionamide. Adverse GI effects of the drug include nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia, and weight loss. Adverse GI effects appear to be dose related, with approximately 50% of patients being unable to tolerate a single dose of 1 g. Adverse GI effects may be minimized by decreasing the dosage, changing the time of drug administration, or administering concomitant antiemetic therapy. Some patients tolerate ethionamide best when it is administered in a single dose at bedtime; others tolerate the drug best when it is administered in equally divided doses with meals. Nausea and vomiting may be severe enough to necessitate discontinuance of ethionamide.
Nervous System and Special Senses Effects
Psychotic disturbances, mental depression, restlessness, drowsiness, dizziness, headache, postural hypotension, and asthenia occur occasionally with ethionamide. Rarely, peripheral neuritis, paresthesia, seizures, tremors, a pellagra-like syndrome, hallucinations, diplopia, optic neuritis, blurred vision, and olfactory disturbances have been reported. Neurotoxic effects may be prevented or relieved by the concomitant administration of pyridoxine hydrochloride.
Hepatic Effects
Transient increases in serum bilirubin, AST (SGOT), and ALT (SGPT) concentrations have been reported in patients receiving ethionamide. Hepatitis (with or without jaundice) has also been reported, especially in patients with diabetes mellitus. Hepatotoxicity generally is reversible on discontinuance of the drug.
Other Adverse Effects
Hypersensitivity reactions including rash, photosensitivity, thrombocytopenia, and purpura have been reported rarely with ethionamide. Goiter, with and without hypothyroidism, has also been associated rarely with ethionamide therapy. Hypoglycemia, gynecomastia, impotence, menorrhagia, joint pain, acute rheumatic symptoms, and acne have also occurred. The management of patients with diabetes mellitus may become more difficult in those receiving ethionamide.
Precautions and Contraindications
Ethionamide is contraindicated in patients with severe hepatic impairment and in patients who are hypersensitive to the drug.
Serum AST (SGOT) and ALT (SGPT) concentrations should be determined prior to and every 4 weeks during ethionamide therapy. If serum aminotransferases (transaminases) become elevated during therapy with ethionamide, ethionamide and the concomitant antituberculosis drugs may be discontinued temporarily until the laboratory abnormalities resolve. Ethionamide and concomitant antituberculosis drugs should then be reintroduced sequentially to determine which drug(s) are responsible for the hepatotoxicity.
Ophthalmologic examinations (including ophthalmoscopy) should be performed prior to and periodically during therapy with ethionamide. Patients should be advised to consult their clinician if blurred vision or any loss of vision, with or without ocular pain, occurs during ethionamide therapy.
Blood glucose determinations should be performed prior to and periodically during therapy with ethionamide. In particular, diabetic patients should be alert for episodes of hypoglycemia.
Periodic monitoring of thyroid function tests is recommended as hypothyroidism, with or without goiter, has been reported during ethionamide therapy.
Pediatric Precautions
Limited information is available on the use of ethionamide in neonates, infants, and children. The manufacturer states that the drug should not be used in children younger than 12 years of age except when the infection being treated is definitely resistant to first-line therapy and systemic dissemination of the disease or other life-threatening complications of tuberculosis are judged to be imminent.
Pregnancy and Lactation
Safe use of ethionamide during pregnancy has not been established. The drug has caused teratogenic effects in rabbits and rats when administered in high doses. There are no adequate and controlled studies to date using ethionamide in pregnant women, and the manufacturer states that the drug should not be used in women who are or may become pregnant unless the clinicians considers the drug essential to treatment. The American Thoracic Society (ATS), US Centers for Disease Control and Prevention (CDC), and Infectious Diseases Society of America (IDSA) state that ethionamide should not be used during pregnancy since it crosses the placenta and is teratogenic in animals.
The effect of ethionamide on labor and delivery in pregnant women is unknown.
Because it is not known whether ethionamide is distributed into human milk, ethionamide should be administered to nursing mothers only if the benefits of therapy outweigh the potential risks to the infant. The manufacturer states that if ethionamide is administered during breastfeeding, the infant should be monitored for adverse effects.
Drug Interactions
Antituberculosis Agents
Serum concentrations of isoniazid reportedly may increase temporarily during concomitant ethionamide therapy. There is some evidence that adverse nervous system effects of ethionamide, cycloserine, and isoniazid may be additive; seizures have been reported in patients receiving concomitant therapy with ethionamide and cycloserine. Therefore, ethionamide should be used with caution in patients receiving cycloserine or isoniazid.
Excessive ingestion of alcoholic beverages should be avoided in patients taking ethionamide because of a reported psychotic reaction associated with this situation.
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.
Spectrum
Ethionamide is a highly specific agent and is active only against organisms of the genus Mycobacterium. Ethionamide is active in vitro and in vivo against M. tuberculosis, M. bovis, M. kansasii, and some strains of M. avium and M. intracellulare. The drug is also active against M. leprae in experimental leprosy in mice. In vitro, the minimum inhibitory concentration (MIC) of ethionamide for most susceptible mycobacteria is 0.6-10 mcg/mL.
Resistance
Natural and acquired resistance to ethionamide have been demonstrated in vitro and in vivo in strains of M. tuberculosis. Resistant strains of initially susceptible M. tuberculosis develop rapidly if ethionamide is used alone in the treatment of clinical tuberculosis. When ethionamide is combined with other antituberculosis agents in the treatment of the disease, emergence of resistant strains may be delayed or prevented. There is no evidence of cross-resistance between ethionamide and other antituberculosis agents currently available in the US.
Strains of M. leprae resistant to ethionamide have been reported rarely.
Pharmacokinetics
Absorption
Approximately 80% of an oral dose of ethionamide is rapidly absorbed from the GI tract. Following a single 1-g oral dose in adults, peak plasma concentrations of ethionamide averaging 20 mcg/mL are attained within 3 hours; plasma concentrations of the drug average 3 mcg/mL at 9 hours and less than 1 mcg/mL at 24 hours. Following a single 250-mg oral dose in healthy adults, peak plasma concentrations of ethionamide of about 2 mcg/mL generally were attained at 2 hours. Serum ethionamide concentrations 2 hours after doses of 250-500 mg of the drug generally average 1-5 mcg/mL.
Distribution
Ethionamide is widely distributed into body tissues and fluids; concentrations in plasma and various organs are approximately equal. The drug is about 30% bound to plasma proteins. The concentration of ethionamide in CSF is reported to be equal to concurrent plasma concentrations of the drug in patients with normal or inflamed meninges. In a study in children with tuberculous meningitis, peak concentrations of ethionamide in CSF generally occurred 1.5-2.5 hours after oral doses of 15 or 20 mg/kg but showed considerable interindividual and intraindividual variation. Ethionamide readily crosses the placenta. It is not known if ethionamide is distributed into milk.
Elimination
The plasma half-life of ethionamide is approximately 2-3 hours.
Ethionamide is extensively metabolized to active and inactive metabolites, probably in the liver. The major active metabolite is the sulfoxide, which may be converted back to ethionamide in vivo. Within 24 hours, 1-5% of an oral dose of ethionamide is excreted in urine as active drug and metabolites; the remainder is excreted in urine as inactive metabolites.
Chemistry and Stability
Chemistry
Ethionamide is a synthetic, isonicotinic acid-derivative antituberculosis agent. The drug occurs as a bright yellow, crystalline powder with a faint to moderate sulfide-like odor and is slightly soluble in water and sparingly soluble in alcohol.
Stability
Ethionamide tablets should be stored in well-closed containers at 20-25°C.
Preparations
Ethionamide
Oral Tablets 250 mg Trecator®-SC, (with povidone) Wyeth
Adverse Effects and Treatment
Many patients cannot tolerate therapeutic doses of ethionamide and have to stop treatment. The most common adverse effects are dose-related gastrointestinal disturbances, including nausea, vomiting, diarrhoea, anorexia, excessive salivation, a metallic taste, stomatitis, and abdominal pain. Tolerance may be improved by reducing the dose, adjusting the timing of dosage, or giving an antiemetic. Mental disturbances including depression, anxiety, and psychosis have been provoked. Dizziness, drowsiness, headache, postural hypotension, and asthenia may also occur occasionally. Peripheral and optic neuropathy, diplopia and blurred vision, and a pellagra-like syndrome have occurred. Pyridoxine or nicotinamide have been suggested for the treatment or prevention of neurotoxic effects. Hepatitis may occur occasionally, with or without jaundice. The incidence of hepatotoxicity is increased when ethionamide is given with rifampicin. Other adverse effects reported include hypersensitivity reactions, thrombocytopenia and purpura, alopecia, dermatitis (including photodermatitis), endocrine disturbances, hypoglycaemia, and hypothyroidism with or without goitre. Teratogenic effects have been reported in animals.
Effects on the liver
Use of ethionamide or protionamide with rifampicin for the treatment of multibacillary leprosy has been associated with a high incidence of hepatotoxicity. A hepatitis incidence of 4.5 to 5% has been reported for patients on ethionamide or protionamide, rifampicin, and either dapsone or clofaz-imine. In these studies, diagnosis of hepatitis was based on clinical assessment. When laboratory monitoring was used, an incidence of 13% was reported with a regimen of ethionamide or protionamide with rifampicin and dapsone. A regimen of protionamide, dapsone, rifampicin, and clofazimine has been associated with a 22% incidence based on laboratory monitoring Use of ethionamide with pyrazinamide has also resulted in a high incidence of abnormal liver function tests. In the above studies rifampicin was given daily during part or all of the regimens. The incidence of hepatotoxicity when ethionamide or protionamide is used with once-monthly rifampicin may be lower; hepatotoxicity was not reported in patients receiving monthly rifampicin and daily protionamide, isoniazid, and dapsone.
Precautions
Ethionamide should not be used in severe hepatic impairment. Liver function tests should be carried out before, and regularly during, treatment with ethionamide. Caution is necessary in patients with depression or other psychiatric illness. Difficulty may be experienced in the management of diabetes mellitus. Periodic monitoring of blood glucose, thyroid function, and visual function is desirable. Ethionamide is teratogenic in animals.
Porphyria
Ethionamide is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals or in-vitro systems.
Interactions
The adverse effects of other antimycobacterials may be increased when ethionamide is used (see Effects on the Liver, above, and under Cycloserine, Interactions).
Alcohol
A psychotic reaction has been reported in a patient receiving ethionamide after excessive intake of alcohol.
Antimicrobial Action
Ethionamide is active only against mycobacteria including Mycobacterium tuberculosis, M. kansasii, M. leprae, and some strains of M. avium complex. Resistance develops rapidly if used alone and there is complete cross-resistance between ethionamide and protionamide. Cross-resistance has been reported in vitro with isoniazid or with thioacetazone.
Pharmacokinetics
Ethionamide has been given as a sugar-coated tablet or more recently as a more stable film-coated tablet. Both formulations are readily absorbed from the gastrointestinal tract: after an oral dose of 250 mg, sugar-coated tablets produce a peak plasma concentration of about 1.5 micrograms/mL after 1.5 hours, while film-coated tablets give a peak plasma concentration of 2.16 micrograms/mL after about 1 hour. Distribution of ethionamide from the film-coated tablet into body tissues and fluids has not been studied, but is expected to be similar to that of the sugar-coated tablets. Ethionamide from sugar-coated tablets is widely distributed throughout body tissues and fluids. It crosses the placenta and penetrates the uninflamed meninges, appearing in the CSF in concentrations equivalent to those in serum. It is about 30% bound to plasma proteins. The half-life for the sugar-coated tablet is reported to be 2 to 3 hours and 1.92 hours for the film-coated tablet. Ethionamide is extensively metabolised, probably in the liver, to the active sulfoxide and other inactive metabolites and less than 1 % of a dose appears in the urine as unchanged drug.
Distribution
After single oral doses of ethionamide 15 or 20 mg/kg in children with tuberculous meningitis, the peak spinal fluid concentration was reached in 1 / to 2 / hours. A wide range of concentrations was reported but doses of 20 mg/kg were more likely to produce spinal fluid concentrations above 2.5 micrograms/mL, the concentration considered by the authors to be essential for therapeutic success.
Uses and Administration
Ethionamide is a thioamide derivative considered to be interchangeable with protionamide. It is used with other antitubercu-lous drugs for the treatment of tuberculosis when resistance to primary drugs has developed. It has also been used, as a substitute for clofazimine, in regimens for the treatment of leprosy but less toxic alternatives are now preferred. In the treatment of resistant tuberculosis, adults may be given 15 to 20 mg/kg daily (maximum 1 g daily) orally. Ethionamide may be given in divided doses with meals, or as a single daily dose after the evening meal, or at bedtime, to minimise gastrointestinal adverse effects. For details of doses in infants, children, and adolescents, see below. Similar doses were used for the treatment of leprosy. Ethionamide has also been used as rectal suppositories; the hydrochloride has been given intravenously.
Administration in children
For the treatment of drug-resistant tuberculosis in infants, children, and adolescents the American Academy of Pediatrics suggests an oral dose of ethionamide 15 to 20 mg/kg (to a maximum of 1 g) daily, given in 2 to 3 divided doses.
Preparations
The United States Pharmacopeia 31, 2008: Ethionamide Tablets.
Proprietary Preparations
Greece: Trecator; India: Ethide; Myobid; South Africa: Ethatyl; Thailand: Eton; Turkey: Etyomid; United States of America (US and USA): Trecator
Ethionamide: Side Effects
See also Antituberculosis drugs
Ethionamide is a synthetic derivative of thio-isonicotinamide. The initial oral dosage for adults is 250 mg/day, slowly increasing up to 15-20 mg/kg/day (maximum 1 g/day).
Protionamide is a pyridine derivative of ethionamide. The dosage is 250-300 mg/day.
Ethionamide and protionamide have often proved to be effective in non-tuberculous mycobacterial infections. Acute rheumatic symptoms and difficulty in the management of diabetes have been reported.
Organs and Systems
Nervous system
Mental depression, weakness, drowsiness, and hypotension are not rare in patients taking ethionamide or protionamide. Other neurological reactions include diplopia, olfactory disturbances, metallic taste, dizziness, paresthesia, headache, and tremor.
Psychological, psychiatric
Psychotic reactions have been described in patients taking ethionamide and may be exacerbated by alcohol.
Endocrine
Goitrous hypothyroidism has rarely been described in patients taking ethionamide , with recovery after withdrawal. Ethionamide inhibits both the uptake of iodine and its incorporation into trichloroacetic acid-precipitable protein.
Metabolism
Thionamides lower the blood glucose concentration and also suppress appetite, which influences carbohydrate intake.
Gastrointestinal
Nausea, vomiting, and anorexia reflect gastric intolerance, and ethionamide is best taken with meals. Protionamide has better gastric tolerance, but patients with a history of stomach ulcer are susceptible to gastric problems.
Skin
Severe allergic skin reactions, alopecia, acne, and purpura can occur in patients taking ethionamide. Other adverse effects include acneiform eruptions, photoderma-titis, and hair loss.
Sexual function
Gynecomastia, impotence, and menorrhagia have been observed in patients taking ethionamide.
Second-Generation Effects Teratogenicity
Ethionamide is teratogenic, and neither ethionamide nor protionamide should be administered during the first trimester of pregnancy.
Susceptibility Factors
Hepatic disease
Since hepatitis occurs in about 5% of patients treated with ethionamide or protionamide, frequent monitoring of liver function is compulsory.
Drug-Drug Interactions
Rifamycins
When thionamides are used in combination with rifampicin, hepatotoxicity is more common and severe. There was a 13% incidence of hepatotoxicity in patients with multibacillary leprosy treated with dapsone, rifampicin, and protionamide 10 mg/kg/day, and a 17% incidence in 110 patients treated with dapsone, rifampicin, and protionamide 5 mg/kg/day; however, although the lower dose of protionamide did not reduce the incidence of hepatotoxicity, it did reduce its severity. Protionamide does not affect the pharmacokinetics of rifampicin.
| Dosage forms of Ethionamide: | |
|---|---|
| Trecator-SC 250 mg tablet | Trecator 250 mg tablet |
Synonyms of Ethionamide:
ET, ETH, Ethinamide, Ethionamid Prothionamid, Ethionamidum [INN-Latin], Ethioniamide, Ethylisothiamide, Ethyonomide, Etionamid, Etionamida [INN-Spanish], Etionamide [DCIT], Etioniamid, ETP
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Therapeutic classes of Ethionamide:
Antitubercular Agents, Fatty Acid Synthesis Inhibitors, Leprostatic Agents
Delivery
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