Ethionamide

166.24

166.24

208-628-9

OAY8ORS3CQ

757028|255115

DTXSID0020577

C47522

Yellow crystals from ethanol

J - Antiinfectives for systemic use

2933399090

71

1.1

Ethionamide appears as yellow crystals or canary yellow powder with a faint to moderate sulfide odor. (NTP, 1992)

1.17 g/cm3

163 °C

167 °C / 1mmHg

>110°(230°F)

1.599

soluble in DMSO. Sparingly soluble in water

2-8°C

1.3X10-4 mm Hg at 25 deg C (est)

LD50 oral in rat: 1320mg/kg

Faint to moderate sulfide odor

Henry's Law constant = 7.5X10-10 atm-cu m/mol at 25 °C (est)

pKa = 4.49 (pyridyl nitrogen) (est)

135.8 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Hydroxyl radical reaction rate constant = 7.5X10-10 cu cm/molecule-sec at 25 °C (est)

Insoluble in water.

Amines, Phosphines, and Pyridines

A thiocarbamate/amine. Thiocarbamates slowly decompose in aqueous solution to form carbon disulfide and methylamine or other amines. Such decompositions are accelerated by acids. Flammable gases are generated by the combination of thiocarbamates and dithiocarbamates with aldehydes, nitrides, and hydrides. Thiocarbamates and dithiocarbamates are incompatible with acids, peroxides, and acid halides.

NONH for all modes of transport

3

22-63

36/37

NS0350000

Xn

P281

H302-H361

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl ethionamide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Flash point data for this chemical are not available. It is probably combustible. (NTP, 1992)

|Warning|H302 (95.65%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P312, P308+P313, P330, P405, and P501|Aggregated GHS information provided by 46 companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Fires involving this compound can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. (NTP, 1992)

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with 60-70% ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 60-70% ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. STORAGE PRECAUTIONS: You should store this material in a refrigerator. (NTP, 1992)

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Symptoms of overdose include convulsions, nausea, and vomiting.|IDENTIFICATION: Ethionamide is a drug for the treatment of tuberculosis. Ethionamide is a yellow crystalline powder. Soluble in 1 in 30 of alcohol. Very sparingly soluble in water. Slightly soluble in chloroform. Slightly soluble in ether. Soluble in methyl alcohol. Sparingly soluble in propylene glycol. Indications: For the treatment of pulmonary and extrapulmonary tuberculosis in conjunction with other antituberculous agents (when resistance to primary agents has developed). For the treatment of leprosy, as part of multi-drug regimens. In the treatment of pulmonary disease in Mycobacterium kansasii and other atypical mycobacteria. HUMAN EXPOSURE: Main risks and target organs: Most common adverse reactions are gastrointestinal disturbances including anorexia, nausea, vomiting, excessive salivation, a metallic taste, stomatitis and diarrhoea and hepatitis. Central nervous system effects include dizziness, drowsiness, headaches, convulsions, peripheral neuropathy, tremors and paraesthesias. There is no experience in acute overdose of ethionamide. One of the metabolites resembles isoniazid and one should watch for similar symptoms. Summary of clinical effects: Gastrointestinal: Anorexia, vomiting, stomatitis, diarrhea, System: excessive salivation, metallic taste, hepatotoxicity. Central Nervous: Mental depression, anxiety or psychosis, System: encephalopathy with pellagra-like symptoms, dizziness, drowsiness, headache, convulsion, peripheral neuropathy, tremors, paresthesias. Eye: Optic neuritis, optic atrophy, diplopia. Nose: olfactory disturbances Ear: Deafness Endocrine: Hypothyroidism, gynecomastia, impotence, menorrhagia, hypoglycemia. Integumentary: Alopecia, acne, severe allergic rashes, photodermatitis. Hematology: Thrombocytopenia Skeletal system: Rheumatic pains Cardiovascular: Postural hypotension Contraindications: Ethionamide should not be given to pregnant women unless the benefits outweigh its possible risk. To be used with caution in women of child-bearing age. Individuals with severe liver disease. Severe hypersensitivity. Note: Caution is necessary in administering ethionamide to patients with depression or other psychiatric diseases, chronic alcoholism, epilepsy, hypothyroidism or diabetes mellitus. Routes of entry: Oral: This is the usual route of administration for therapeutic use. Parenteral: Ethionamide hydrochloride has been given intravenously, but there is no commercial preparation. Other: Ethionamide has been administered as rectal suppositories. Absorption by route of exposure: Approximately 80% of a gastrointestinal oral dose of ethionamide is rapidly absorbed from the gastrointestinal tract. After oral administration, the bioavailability is about 100%. Relative bioavailability after rectal administration was 57.3% of that following oral administration. Distribution by route of exposure: It is widely distributed throughout body tissues and fluids. It crosses the placenta and penetrates the meninges, appearing in the CSF in concentrations equivalent to those in the serum. Protein binding is low (10%). Biological half-life by route of exposure: Half-life is 2 to 3 hours. Ethionamide is extensively metabolized, probably in the liver, to ethionamide sulfoxide, 2-ethylisonicotinic acid and 2-ethylisonicotinamide. The sulfoxide is the main active metabolite. Elimination by route of exposure: Less than 1% of a dose appears in the urine as unchanged drug, the remainder is excreted in the urine as inactive metabolites. Mode of action: Toxicodynamics: In view of the structural similarity of the metabolite 2-methylisonicotinic acid to isoniazid, it has been suggested that toxicity is due to pyridoxine deficiency. Pharmacodynamics: Ethionamide inhibits the synthesis of mycolic acids and stimulates oxidation reduction reactions. Treated cells lose acid fastness. Both the drug and the sulfoxide metabolite are active against M.tuberculosis. 2-ethylisonicotinic acid and 2-ethylisonicotinamide are not active metabolites. It is bacteriostatic against M. tuberculosis at therapeutic concentrations, but may be bactericidal at higher concentrations. It is bactericidal against M. lepra. Resistance develops rapidly if used alone and there is complete cross-resistance with prothionamide, thiacetazone and thiambutosine. Toxicity: Adults: In clinical use, neuropsychiatric symptoms, such as headache, sleeping, insomnia, depression and paresthesia may occur. Elevation of liver transaminase enzymes has been known to develop. No special precautions are required due to age, as doses are adjusted according to patient response. However, dose should be modified depending on liver and renal status. Interactions: Ethionamide taken with pyrazinamide may lead to abnormalities of liver function and the use of these two agents together should be avoided. The use of rifampicin with the thioamides (ethionamide or prothionamide) as part of the treatment of multibacillary leprosy has been associated with an unexpectedly high incidence of hepatotoxicity. Adverse nervous system effects of ethionamide, cylcoserine and isoniazid may be additive. The side effects of other tuberculostatic agents may be enhanced when ethionamide is administered concomitantly. Alcohol may contribute to psychotropic reactions in an ethionamide treated patient. More study is needed to clarify the clinical significance of this interaction. Main adverse effects: The most common adverse effects are dose-related, viz: gastrointestinal disturbances, including anorexia, excessive salivation, a metallic taste, nausea, vomiting, stomatitis, diarrhea and hepatitis. Dizziness, drowsiness, headache, postural hypotension and asthenia may also occur occasionally. Other side effects reported include acne, allergic reactions alopecia, convulsions, deafness, dermatitis (including photodermatitis), visual disturbances, tremors, gynecomastia, impotence, menstrual disturbances, olfactory disorders, peripheral and optic neuropathy, thrombocytopenia and rheumatic pains. Mental disturbances, including depression, anxiety and psychosis have been provoked. A pellagra-like syndrome with encephalopathy has been reported rarely. A tendency towards hypoglycemia may occur and could be of significance in patients with diabetes mellitus. Hypothyroidism has also occurred. Racial differences in tolerance may occur, e.g. Chinese and Africans are often more tolerant of ethionamide than are Europeans. ANIMAL/PLANT STUDIES: A rat study showed the sublethal neurotoxicity which included paralysis, loss of screen grip and decreased motor activity. Teratogenicity: Teratogenic effects have been reported in rabbits, mice and rats, in which high doses have led to abortions and some malformations. Mutagenicity: Ethionamide was not found to be mutagenic as shown by Ames Salmonella and micronuclei assay test.

Ethionamide therapy has been linked to elevations in serum aminotransferase levels in a proportion of patients, but these elevations are typically self-limited and asymptomatic. More importantly, ethionamide has been linked to many instances of clinical apparent acute liver injury that arise in up to 5% of patients and can be severe and even fatal. The time to onset and clinical features of hepatic injury due to ethionamide resemble those of isoniazid, the latency ranging from 2 weeks to more than 6 months after starting (most arise within 1 to 3 months), and the pattern of enzyme elevations typically being hepatocellular and resembling acute viral hepatitis. Features of hypersensitivity (rash, fever and eosinophilia) are uncommon. Like isoniazid, ethionamide therapy may be associated with development of autoantibodies (typically ANA), but titers are generally low and rarely accompanied by autoimmune conditions. Cases of severe hypersensitivity reaction including Stevens Johnson Syndrome and DRESS which can be accompanied by liver injury have been described with ethionamide.

Patients receiving ethionamide should avoid excessive ingestion of alcohol because a psychotic reaction has been reported in this situation.|Serum concentrations of isoniazid may increase temporarily during concomitant ethionamide therapy.|Ethionamide may potentiate the adverse effects of other antituberculosis agents included in the treatment regimen. There is some evidence that adverse nervous system effects of ethionamide, cycloserine, and isoniazide may be additive. Seizures have been reported in patients receiving regimens that included both ethionamide and cycloserine and caution is advised if these drugs are used concomitantly.|Concurrent administration of ethionamide with other neurotoxic medications may increase the potential for neurotoxicity, such as optic and peripheral neuritis.|Concurrent use /of cycloserine/ may result in increased incidence of central nervous system [CNS] effects, especially seizures; dosage adjustments may be necessary and patients should be monitored closely for signs of CNS toxicity.

Approximately 30% bound to proteins.

It is not known whether ethionamide is distributed into breast milk.

For use in the treatment of pulmonary and extrapulmonary tuberculosis when other antitubercular drugs have failed.|FDA Label

Ethionamide is a second line drug in the therapy of tuberculosis used only in combination with other agents and for drug-resistant tuberculosis. Ethionamide has been linked to transient, asymptomatic elevations in serum aminotransferase levels and in uncommon instances of acute liver injury, which can be severe.

Antituberculosis Agents

Antibacterial (tuberculostatic)|Ethionamide is indicated in combination with other antituberculosis medications in the treatment of tuberculosis, including tuberculous meningitis, after failure with the primary medications (streptomycin, isoniazid, rifampin, and ethambutol) or when these cannot be used because of toxicity or development of resistant tubercle bacilli. Ethionamide is effective only against mycobacteria. /Included in US product label/|Ethionamide is used in combination with other antileprosy agents in the treatment of Hansen's disease. /Not included in US product label/|Ethionamide is used in the treatment of atypical mycobacterial infections, such as Mycobacterium avium complex (MAC). /Not included in US product label/|Ethionamide and prothionamide are thioamides used as second-line antituberculosis drugs for treatment of multi-drug resistant tuberculosis.

Adverse GI effects, including nausea, vomiting, diarrhea, abdominal pain, excessive salivation, metallic taste, stomatitis, anorexia, and weight loss, are the most common adverse effects reported with ethionamide. Nausea and vomiting may be severe enough to necessitate discontinuance of ethionamide. GI effects appear to be dose related, and approximately 50% of patients are unable to tolerate a single 1-g dose of the drug.|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.|The manufacturer of ethionamide recommends concomitant use of pyridoxine to prevent or relieve neurotoxic effects during ethionamide treatment.|Transient increases in serum bilirubin, AST (SGOT), and ALT (SGPT) concentrations have been reported in patients receiving ethionamide. Hepatitis (with or without jaundice) also has been reported. Hepatotoxicity generally is reversible following discontinuance of the drug.|For more Drug Warnings (Complete) data for ETHIONAMIDE (22 total), please visit the HSDB record page.

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, but emergence of resistant strains may be delayed or prevented when ethionamide is used in conjunction with other antituberculosis agents.|Although most M. tuberculosis isolates resistant to ethionamide or isoniazid usually are susceptible to the other drug, multi-drug resistant M. tuberculosis (MDMT) may have acquired resistance to both isoniazid and ethionamide. Limited data suggest that cross-resistance also may occur between ethionamide and thiosemicarbazones such as thiacetazone (drugs not commercially available in the US). There is no evidence to date of cross-resistance between ethionamide and cycloserine, aminosalicylic acid, or streptomycin.|Strains of M. leprae resistant to ethionamide have been reported rarely.

Ethinamate is bacteriostatic against M. tuberculosis. In a study examining ethionamide resistance, 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.

Drugs used in the treatment of tuberculosis. They are divided into two main classes: "first-line" agents, those with the greatest efficacy and acceptable degrees of toxicity used successfully in the great majority of cases; and "second-line" drugs used in drug-resistant cases or those in which some other patient-related condition has compromised the effectiveness of primary therapy. (See all compounds classified as Antitubercular Agents.)|Compounds that interfere with FATTY ACID SYNTHASE resulting in a reduction of FATTY ACIDS. This is a target mechanism in humans of some ANTINEOPLASTIC AGENTS and ANTI-OBESITY AGENTS and of some ANTI-INFECTIVE AGENTS which interfere with CELL WALL and CELL MEMBRANE formation. (See all compounds classified as Fatty Acid Synthesis Inhibitors.)

Essentially completely absorbed following oral administration and not subjected to any appreciable first pass metabolism. Bioavailability approximately 100%.|Less than 1% of the oral dose is excreted as ethionamide in urine. Ethionamide is extensively metabolized to active and inactive metabolites.|93.5 L [healthy volunteers]|Rapidly absorbed from the gastrointestinal tract following oral administration. Bioavailability approximately 100%.|Ethionamide is essentially completely absorbed following oral administration and does not undergo any appreciable first-pass metabolism.|Following a single 250-mg oral dose of ethionamide given as film-coated tablets in fasting adults, peak plasma concentrations of ethionamide average 2.16 mcg/mL and are attained within 1 hour. When a single 250-mg oral dose of ethionamide is given as sugar-coated tablets (Trecator-SC; no longer commercially available in the US) in healthy adults, peak plasma concentrations average 1.48 mcg/mL and are attained within 1.5 hours.|Time to peak concentration: Approximately 1.8 hours; Peak serum concentration: Approximately 2.2 mcg/mL after a single oral 500-mg dose.|For more Absorption, Distribution and Excretion (Complete) data for ETHIONAMIDE (11 total), please visit the HSDB record page.

Hepatic and extensive. Metabolized to the active metabolite sulfoxide, and several inactive metabolites. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis.|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 .

2 to 3 hours|The plasma half-life of ethionamide following a 250-mg oral dose given as film-coated tablets is 1.92 hours.|Half-life: Approximately 2 to 3 hours.

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. Ethionamide, like prothionamide and pyrazinamide, is a nicotinic acid derivative related to isoniazid. It is thought that ethionamide undergoes intracellular modification and acts in a similar fashion to isoniazid. Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. Specifically isoniazid inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis, by forming a covalent adduct with the NAD cofactor. It is the INH-NAD adduct that acts as a slow, tight-binding competitive inhibitor of InhA.|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.

SYMPTOMS: Symptoms of exposure to this compound may include toxic hepatitis, elevated levels of liver enzymes in the plasma; anorexia, nausea, vomiting, severe postural hypotension, mental depression, drowsiness, asthenia, convulsions, peripheral neuropathy, olfactory disturbances, blurred vision, diplopia, dizziness, paresthesias, headache, restlessness, tremors, severe allergic skin rashes; purpura, stomatitis, gynecomastia, impotence, menorrhagia, acne, alopecia, jaundice, gall bladder changes and acute rheumatic symptoms. ACUTE/CHRONIC HAZARDS: This compound may cause severe skin irritation on contact. When heated to decomposition it emits very toxic fumes. (NTP, 1992)

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. SKIN: IMMEDIATELY flood affected skin with water while removing and isolating all contaminated clothing. Gently wash all affected skin areas thoroughly with soap and water. If symptoms such as redness or irritation develop, IMMEDIATELY call a physician and be prepared to transport the victim to a hospital for treatment. INHALATION: IMMEDIATELY leave the contaminated area; take deep breaths of fresh air. If symptoms (such as wheezing, coughing, shortness of breath, or burning in the mouth, throat, or chest) develop, call a physician and be prepared to transport the victim to a hospital. Provide proper respiratory protection to rescuers entering an unknown atmosphere. Whenever possible, Self-Contained Breathing Apparatus (SCBA) should be used; if not available, use a level of protection greater than or equal to that advised under Protective Clothing. INGESTION: DO NOT INDUCE VOMITING. If the victim is conscious and not convulsing, give 1 or 2 glasses of water to dilute the chemical and IMMEDIATELY call a hospital or poison control center. Be prepared to transport the victim to a hospital if advised by a physician. If the victim is convulsing or unconscious, do not give anything by mouth, ensure that the victim's airway is open and lay the victim on his/her side with the head lower than the body. DO NOT INDUCE VOMITING. IMMEDIATELY transport the victim to a hospital. (NTP, 1992)

Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/CASE REPORTS/ A 42-year-old woman developed goitrous hypothyroidism while receiving ethionamide for treatment of an atypical mycobacterial infection. Five weeks after discontinuation of ethionamide therapy, thyroid function had returned to normal. The goitrogenic effect was studied in vitro by incubating ethionamide in various concentrations (1.0 X 10-3 to 1.0 X 10-7 mol/L) with ovine thyroid cells in tissue cultures. Ethionamide inhibited the trapping of technetium and organification of iodine at concentrations seen clinically (1.0X 10-5 mol/L). Ethionamide appears to be a potential goitrogen in susceptible persons.

Amidazine

Oral tablets film-coated, 250 mg, Trecator ( with povidone), Wyeth

Analyte: ethionamide; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: ethionamide; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards|Analyte: ethionamide; matrix: chemical purity; procedure: ultraviolet absorption spectrophotometry at 290 nm with comparison to standards|Analyte: ethionamide; matrix: pharmaceutical preparation (tablet); procedure: ultraviolet absorption spectrophotometry at 290 nm with comparison to standards (chemical identification and chemical purity)|For more Analytic Laboratory Methods (Complete) data for ETHIONAMIDE (7 total), please visit the HSDB record page.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients