Ethionamide
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Brand names, Trade names |
| 1.6 Manufacturers, Importers |
| 1.7 Presentation, Formulation |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First aid measures and management principles |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Properties of the substance |
| 3.3.1.1 Colour |
| 3.3.1.2 State/Form |
| 3.3.1.3 Description |
| 3.3.2 Properties of the locally available formulation(s) |
| 3.4 Other characteristics |
| 3.4.1 Shelf-life of the substance |
| 3.4.2 Shelf-life of the locally available formulation(s) |
| 3.4.3 Storage conditions |
| 3.4.4 Bioavailability |
| 3.4.5 Specific properties and composition |
| 4. USES |
| 4.1 Indications |
| 4.1.1 Indications |
| 4.1.2 Description |
| 4.2 Therapeutic dosage |
| 4.2.1 Adults |
| 4.2.2 Children |
| 4.3 Contraindications |
| 5. ROUTES OF ENTRY |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Other |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination by route of exposure |
| 7. PHARMACOLOGY AND TOXICOLOGY |
| 7.1 Mode of action |
| 7.1.1 Toxicodynamics |
| 7.1.2 Pharmacodynamics |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 7.7 Main adverse effects |
| 8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Toxicological analyses |
| 8.1.1.2 Biomedical analyses |
| 8.1.1.3 Arterial blood gas analysis |
| 8.1.1.4 Haematological analyses |
| 8.1.1.5 Other (unspecified) analyses |
| 8.1.2 Storage of laboratory samples and specimens |
| 8.1.2.1 Toxicological analyses |
| 8.1.2.2 Biomedical analyses |
| 8.1.2.3 Arterial blood gas analysis |
| 8.1.2.4 Haematological analyses |
| 8.1.2.5 Other (unspecified) analyses |
| 8.1.3 Transport of laboratory samples and specimens |
| 8.1.3.1 Toxicological analyses |
| 8.1.3.2 Biomedical analyses |
| 8.1.3.3 Arterial blood gas analysis |
| 8.1.3.4 Haematological analyses |
| 8.1.3.5 Other (unspecified) analyses |
| 8.2 Toxicological Analyses and Their Interpretation |
| 8.2.1 Tests on toxic ingredient(s) of material |
| 8.2.1.1 Simple qualitative test(s) |
| 8.2.1.2 Advanced qualitative confirmation test(s) |
| 8.2.1.3 Simple quantitative method(s) |
| 8.2.1.4 Advance quantitative method(s) |
| 8.2.2 Test for biological specimens |
| 8.2.2.1 Simple qualitative test(s) |
| 8.2.2.2 Advanced qualitative confirmation test(s) |
| 8.2.2.3 Simple quantitative method(s) |
| 8.2.2.4 Advance quantitative method(s) |
| 8.2.2.5 Other dedicated method(s) |
| 8.2.3 Interpretation of toxicological analyses |
| 8.3 Interpretation of toxicological analyses |
| 8.3.1 Biochemical analysis |
| 8.3.1.1 Blood, plasma or serum |
| 8.3.1.2 Urine |
| 8.3.1.3 Other fluids |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.3.4 Interpretation of biomedical investigations |
| 8.4 Other biomedical (diagnostic) investigations and their interpretation |
| 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations |
| 8.6 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin Exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 Central nervous system (CNS) |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Other |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ear, nose, and throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and Electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Others |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other investigations |
| 10.3 Life supportive procedures and symptomatic/specific treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases |
| 12. ADDITIONAL INFORMATION |
| 12.1 Availability of antidotes |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) |
1. NAME
1.1 Substance
Ethionamide (INN)
(WHO, 1992)
1.2 Group
ATC classification index
Antimycobacterials (J04)/Drugs for the treatment of
tuberculosis (J04A)/Thiocarbamide derivatives(J04AD).
(WHO, 1992)
1.3 Synonyms
Etionamide
1314-TH
Amidazine
Ethioniamide
(Budavari, 1989)
(To be completed by each Centre using local data)
1.4 Identification numbers
1.4.1 CAS number
536-33-4
1.4.2 Other numbers
RTECS
NS0350000
1.5 Brand names, Trade names
Ethatyl (SCS, S. Afr.)
Etiocidan (Cidan, Spain)
Panathide (Propan, S. Afr.)
Regenicide (Gedeon, Richter)
Thioniden (Kaken, Jpn)
Trecator (Belg., Theraplix, Fr)
Trecator-SC (Wyeth, USA)
Trescatyl (May & Baker, S. Afr; May & Baker, UK)
Tubenamide (Meiji. Jpn)
Resitran (Mla. Phil.)
(To be completed by each Centre using local data)
1.6 Manufacturers, Importers
To be completed by each Centre using local data
1.7 Presentation, Formulation
Tablets 250 mg, in packs of 100 (PDR, 1992)
(To be completed by each Centre using local data)
2. SUMMARY
2.1 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.
2.2 Summary of clinical effects
TOXIC REACTIONS FROM ETHIONAMIDE
SITE REACTIONS
Gastrointestinal Anorexia, vomiting, stomatitis, diarrhoea,
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, paraesthesias.
Eye Optic neuritis, optic atrophy, diplopia.
Nose Olefactory disturbances
Ear Deafness
Endocrine Hypothyroidism, gynaecomastia, impotence,
menorrhagia, hypoglycaemia
Integumentary Alopecia, acne, severe allergic rashes,
photodermatitis.
Haematology Thrombocytopenia
Skeletal system Rheumatic pains
Cardiovascular Postural hypotension
(Reynolds, 1989; Gilman et al., 1990)
2.3 Diagnosis
Clinical diagnosis is difficult to determine because of the
lack of history of toxic ingestions.
Quantitative Analysis
Confirmatory tests can be used to document poisoning using
High Pressure Liquid Chromatography on plasma, serum or urine
or a colour reaction on urine; detection limit 10 ng/mL.
Qualitative Analysis
Presence of sulphoxide derivative of ethionamide gives a
yellow colour in the acid extract.
2.4 First aid measures and management principles
Whether the presentation of the patient is an overdose or an
adverse drug event, the first principle is to evaluate the
vital functions and provide life-support measures to
stabilize the victim. Screening and confirmatory tests to
document poisoning in biological fluids should be done. (For
details, see 10.1)
Maintain patient airway, adequate breathing and circulation.
Decontaminate with activated charcoal and follow with
cathartic.
Although the drug is extensively metabolised by the liver in
toxic doses, excretion may be enhanced with diuretics.
There are no known antidotes for ethionamide overdose.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthesized from the interaction of 2-ethylisonicotinonitrile
and H2S in the presence of triethanolamine (Budavari, 1989).
3.2 Chemical structure
Structural formula
Molecular formula
C8H10N2S
Molecular weight
166.2
Structural Chemical names
2-Ethylpyridine-4-carbothioamide
2-ethyl-4-pyridinecarbothioamide
2-ethylththioisonicotinamide
3-ethylisothionicotinamide
2-ethylisothionicotinamide
2-ethyl-4-thiocarbamoylpyridine
alpha-ethylisonicotinoylthioamide
(Reynolds, 1993; Budavari, 1989)
3.3 Physical properties
3.3.1 Properties of the substance
3.3.1.1 Colour
Yellow (darkens on exposure to light)
3.3.1.2 State/Form
Crystal or crystalline powder
3.3.1.3 Description
Slight sulphide-like odour.
Melting range 158°C to 164°C.
pH 6.0 to 7.0 in a 1 in 100 slurry in
water.
Soluble in 1 in 30 of alcohol.
Very sparingly soluble in water.
Slightly soluble in chloroform (1 in 500)
Slightly soluble in ether (1 in 320).
Soluble in methyl alcohol.
Sparingly soluble in propylene glycol.
(Reynolds 1993, Budavari 1989, European
Pharmacopoeia, 1986)
3.3.2 Properties of the locally available formulation(s)
It is stable at all ordinary temperatures and levels of
humidity.
(To be completed by each Centre using local data).
3.4 Other characteristics
3.4.1 Shelf-life of the substance
No data available.
3.4.2 Shelf-life of the locally available formulation(s)
To be completed by each Centre using local data.
3.4.3 Storage conditions
Preserve in air-tight containers at less than 40°C,
preferably between 15 to 30°C.
3.4.4 Bioavailability
To be completed by each Centre using local data.
3.4.5 Specific properties and composition
To be completed by each Centre using local data
4. USES
4.1 Indications
4.1.1 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.
4.1.2 Description
Not applicable
4.2 Therapeutic dosage
4.2.1 Adults
Oral
Tuberculosis
0.5 to 1 g daily in divided doses (PDR, 1992)
15 to 20 mg/kg (given as a single daily dose, up to
maximum of 1 g (Reynolds, 1993).
Leprosy
250 to 375 mg daily (Reynolds, 1989; Gilman et al.,
1990)
5 mg/kg (as a single daily dose)(Reynolds, 1993)
4.2.2 Children
Oral
Tuberculosis
12 to 15 mg/kg body weight daily to a maximum of 750 mg
daily in divided doses.
Some children have received 20 mg/kg daily.
(Reynolds, 1989)
15 to 20 mg/kg (given as a single daily dose)
(Reynolds, 1993)
Note: Optimum dose for children has not been
established. A report showed the maximum daily dose as
750 mg (Shirkey, 1977).
4.3 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.
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.
5. ROUTES OF ENTRY
5.1 Oral
This is the usual route of administration for therapeutic
use.
5.2 Inhalation
Unknown.
5.3 Dermal
Unknown.
5.4 Eye
Unknown.
5.5 Parenteral
Ethionamide hydrochloride has been given intravenously, but
there is no commercial preparation.
5.6 Other
Ethionamide has been administered as rectal suppositories.
6. KINETICS
6.1 Absorption by route of exposure
Oral
Approximately 80% of a gastrointestinal oral dose of
ethionamide is rapidly absorbed from the gastrointestinal
tract. Following a single 1 g oral dose in adults, peak
plasma concentration of ethionamide averaging 20 ug/mL are
attained within 3 hours and less than 1 ug/mL at 24 hours.
Following a single 250 mg oral dose in adults, peak plasma
concentrations of ethionamide average 1-4 ug/ml (McEvoy,
1990).
After oral administration, the bioavailability is circa 100%.
(USPDI, 1993)
Rectal
Relative bioavailability after rectal administration was
57.3% of that following oral administration.
Parenteral
No data available.
6.2 Distribution by route of exposure
Oral
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.
(Reynolds, 1989; Gilman et al., 1990)
Protein binding is low (10%) (USPDI, 1993).
6.3 Biological half-life by route of exposure
Oral
Half-life is 2 to 3 hours (Reynolds, 1989).
6.4 Metabolism
Ethionamide is extensively metabolized, probably in the
liver, to ethionamide sulphoxide, 2-ethylisonicotinic acid
and 2-ethylisonicotinamide. The sulfoxide is the main active
metabolite (Moffat, 1986; McEvoy, 1993).
6.5 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.
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 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
(Manapat, 1992).
7.1.2 Pharmacodynamics
Ethionamide inhibits the synthesis of mycolic acids and
stimulates oxidation-reduction reactions. Treated cells
lose acid-fastness, thus the mechanism of action
appears to be similar to that of INH. Specific sites of
action may be different, since strains of
M.tuberculosis that are resistant to high
concentrations of INH are susceptible to ethionamide.
Both the drug and the sulphoxide 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. The average MIC (Minimum
Inhibitory Concentration) for Mycobacterium
tuberculosis is 0.6 - 2.5 mg/mL (Lorian, 1980). Most
susceptible organisms are inhibited by 10 ug/mL or
less.
It is bactericidal against M. leprae and a minimum
inhibiting concentration (MIC) of 0.05 ug/mL has been
reported in mice.
Resistance develops rapidly if used alone and there is
complete cross-resistance with prothionamide,
thiacetazone and thiambutosine. (Reynolds, 1989)
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
There is no experience with acute overdoses.
Some of the adverse effects are dose-dependent
and would be expected in an overdose situation.
The most serious effects are neuropsychiatric
symptoms and liver necrosis.
In clinical use, neuropsychiatric symptoms,
such as headache, sleeping, insomnia,
depression and paraesthesia may occur.
Elevation of liver transaminase enzymes has
been known to develop. (British Tuberculosis
Association, 1968).
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. (Dollery,
1991)
7.2.1.2 Children
No data available.
7.2.2 Relevant animal data
A rat study showed the sublethal neurotoxicity level of
ethionamide to be 1300 mg/kg. The principal signs were
paralysis, loss of screen grip and decreased motor
activity (Manapat et al., 1992).
7.2.3 Relevant in vitro data
No data available.
7.3 Carcinogenicity
No data available.
7.4 Teratogenicity
Teratogenic effects have been reported in rabbits, mice and
rats, in which high doses have led to abortions and some
malformations.
Conflicting reports exist in the literature concerning
congenital malformations in children when exposed to the drug
in utero. One observation attributes 7 malformations among 23
children exposed to ethionamide whereas in another study with
70 infants no such relationship to drug treatment during
pregnancy was found. (Dollery, 1991)
7.5 Mutagenicity
Ethionamide was not found to be mutagenic as shown by Ames
Salmonella and Micronuclei Assay Test (Peters, 1983).
7.6 Interactions
Ethionamide taken with pyrazinamide may lead to abnormalities
of liver function and the use of these two agents together
should be avoided (Reynolds, 1989).
The use of rifampicin with the thiomides (ethionamide or
prothionamide) as part of the regimens recommended by WHO for
the treatment of multibacillary leprosy has been associated
with an unexpectedly high incidence of hepatotoxicity (Pattyn
et al., 1984; Reynolds, 1989).
Adverse nervous system effects of ethionamide,
cylcoserine and isoniazid may be additive (McEvoy, 1990).
The side effects of other tuberculostatic agents may be
enhanced when ethionamide is administered concomitantly
(Griffin, 1988).
Alcohol may contribute to psychotropic reactions in an
ethionamide treated patient. More study is needed to clarify
the clinical significance of this interaction. (Griffin,
1988)
7.7 Main adverse effects
The most common adverse effects are dose-related, viz:
gastrointestinal disturbances, including anorexia, excessive
salivation, a metallic taste, nausea, vomiting, stomatitis,
diarrhoea 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,
gynaecomastia, 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 hypoglycaemia 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 (Reynolds, 1989).
Note: Many patients cannot tolerate therapeutic doses of
ethionamide and have to discontinue treatment.
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
Plasma, serum, or urine may be used; however,
blood is preferably collected on the third hour
post-ingestion.
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
The blood obtained should be frozen at -20 to
-40°.
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
The blood sample should be transported,
refrigerated and separated within 2 hours of
collection.
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple qualitative test(s)
Description
Yellow crystal or a yellow crystalline powder,
darkening on exposure to light, with a slight
sulphide-like odour.
Identity Tests
The assay exhibits an absorbence maximum at 290
+2 nm.
Dissolve 1 g of ethionamide tablets in 50 ml of
methanol and filter through a medium porosity
sintered-glass funnel. Evaporate the filtrate
on a steam bath and the obtained residue melts
between 155 and 164 (USP, 1985).
8.2.1.2 Advanced qualitative confirmation test(s)
8.2.1.3 Simple quantitative method(s)
8.2.1.4 Advance quantitative method(s)
8.2.2 Test for biological specimens
8.2.2.1 Simple qualitative test(s)
Qualitative analysis of urine based on a colour
reaction.
8.2.2.2 Advanced qualitative confirmation test(s)
8.2.2.3 Simple quantitative method(s)
8.2.2.4 Advance quantitative method(s)
Quantification analysis using High Pressure
Liquid Chromatography on plasma, serum, or
urine.
8.2.2.5 Other dedicated method(s)
8.2.3 Interpretation of toxicological analyses
Blood levels would peak by the third hour; levels at 6
to 20 ug/ml are considered therapeutic.
A yellow urine colour reaction detects the presence of
a sulfoxide derivative.
8.3 Interpretation of toxicological analyses
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
Liver function tests such as ALT, AST, Alkaline
Phosphatase, Direct and Indirect Bilirubin;
Prothrombin time; Blood Sugar; BUN, Creatinine
8.3.1.2 Urine
Urinalysis to detect glucose, protein, and
leucocytes; hourly urine output determination.
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
Not relevant.
8.3.3 Haematological analyses
In severe cases of jaundice or suspected
hepatotoxicity, a full blood count and prothrombin time
must be monitored for coagulopathy.
8.3.4 Interpretation of biomedical investigations
Transient increase 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.
Hepatotoxicity generally is reversible on
discontinuation of the drug.
8.4 Other biomedical (diagnostic) investigations and their
interpretation
T3, T4; urinary coproporphyrin, ophthalmoscopy.
8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations
8.6 References
United States Pharmacopeia, The National formulary (1985)
21st rev., 16th ed., Rockville MD, United States
Pharmacopeial Convention,, pp 413.
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
None reported.
9.1.2 Inhalation
None reported.
9.1.3 Skin exposure
Not relevant.
9.1.4 Eye contact
None reported.
9.1.5 Parenteral exposure
None reported.
9.1.6 Other
None reported.
9.2 Chronic poisoning
9.2.1 Ingestion
None reported.
9.2.2 Inhalation
None reported.
9.2.3 Skin Exposure
Not relevant.
9.2.4 Eye contact
None reported.
9.2.5 Parenteral exposure
None reported.
9.2.6 Other
9.3 Course, prognosis, cause of death
None reported.
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
None reported.
9.4.2 Respiratory
None reported.
9.4.3 Neurological
9.4.3.1 Central nervous system (CNS)
May cause encephalopathy with pellagra-like
symptoms; headaches; sleepiness, insomnia,
depression, tremors, convulsions (British
Tuberculosis Assn., 1968)
9.4.3.2 Peripheral nervous system
Peripheral nerve symptoms consisting of
paraesthesias, motor weakness or sensory
impairment have been observed, following
therapeutic doses (Snavely, 1984).
9.4.3.3 Autonomic nervous system
None reported.
9.4.3.4 Skeletal and smooth muscle
None reported.
9.4.4 Gastrointestinal
Dose-related
Anorexia, excessive salivation, metallic taste, nausea,
vomiting, stomatitis, and diarrhoea.
9.4.5 Hepatic
Although jaundice is rare, hepatitis may occur in about
5% of patients.
One study showed a 13% incidence of hepatitis when drug
is combined with rifampicin and dapsone. The
hepatocellular injury is non dose-related, especially
among diabetics.
9.4.6 Urinary
9.4.6.1 Renal
None reported.
9.4.6.2 Other
9.4.7 Endocrine and reproductive systems
Thyroid
May cause a disturbance in the synthesis of thyroid
hormone resulting in hypothyroidism.
Ethionamide inhibits the trapping of technetium and
organification of iodine at concentration seen
clinically (Drucker 1984).
Other
Gynaecomastia
Menorrhagia
Impotence
Hypoglycaemia
9.4.8 Dermatological
Dermatitis (photodermatitis)
Acne
Alopecia
9.4.9 Eye, ear, nose, and throat: local effects
Local effects
None reported.
Systemic effects
Optic neuritis, optic atrophy, degeneration of the
chiasma, deafness, olefactory disturbances (Holdiness,
1987).
9.4.10 Haematological
May cause acute porphyria because it has been shown to
be porphyrinogenic in animals.
Thrombocytopenia
9.4.11 Immunological
None reported.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
None reported.
9.4.12.2 Fluid and Electrolyte disturbances
None reported.
9.4.12.3 Others
Hypoglycaemia when given to diabetic
patients.
9.4.13 Allergic reactions
Hypersensitivity reactions may occur.
9.4.14 Other clinical effects
Rheumatic pains.
9.4.15 Special risks
Pregnancy
CNS malformations have been reported (Schardein,
1976).
Conflicting reports exist for congenital malformations
of children born to mothers receiving the drug during
pregnancy. Therefore, it is suggested that the drug be
avoided during pregnancy or in women of childbearing
potential unless the benefits outweigh its possible
hazard. (Dollery, 1991)
Breast-feeding
As far as can be determined there are no data
published indicating the secretion of ethionamide in
breast milk in measurable quantities (Dollery, 1991).
Enzyme deficiencies
None reported.
9.5 Others
No data available
9.6 Summary
Not applicable
10. MANAGEMENT
10.1 General principles
Whenever the presentation of the patient is an overdose or
adverse drug event, the first principle is to evaluate the
vital functions and provide life-support measures to
stabilize the victim.
Decontamination should be considered to reduce further
absorption, if patient seen early after poisoning.
There are no specific antidotes for ethionamide overdose;
however, high dose pyridoxine has been found to inhibit its
neurotoxic effects (Gennaro et al., 1985).
Pellagra-like symptoms can be reversed by niacin.
10.2 Relevant laboratory analyses
Bio-medical tests: (i.e., baseline liver function; platelet
count, blood sugar, prothrombin time).
10.2.1 Sample collection
Plasma, serum or urine may be used, however, blood
is preferably collected on the third hour post-
ingestion. Samples obtained should be frozen at
-20 to -40 °C and separated within 2 hours of
collection.
10.2.2 Biomedical analysis
Blood
Liver function tests such as ALT, AST, alkaline
phosphatase, Direct and Indirect Bilirubin;
Prothrombin time; Blood sugar; BUN, Creatinine.
Urine
Urinalysis to detect glucose, protein, and
leucocytes; hourly urine output determination.
10.2.3 Toxicological analysis
Blood levels taken on the third hour post-ingestion
whose values are beyond 20 ug/ml are considered
toxic.
10.2.4 Other investigations
Not relevant
10.3 Life supportive procedures and symptomatic/specific
treatment
Treatment is mainly supportive. If patient is in a
critical condition (i.e. cardiorespiratory distress)
maintain a clear airway, aspirate secretions if these are
present in the airway, administer oxygen, perform
endotracheal intubation if indicated, provide artificial
ventilation, if warranted. Maintain a patent intravenous
line to support circulation. Monitor vital signs
(sensorium, blood pressure, heart and respiratory rate)
regularly and correct hypotension with isotonic fluids or
inotropic agents. Monitor fluids and electrolyte balance
(i.e., input and urine output).
If there are cardiac dysrhythmias, antiarrhythmic agents
are best avoided, especially if the "torsades de pointes"
type of arrhythmia is present.
If bleeding ensues, correct by doing appropriate component
transfusion only if indicated.
Reevaluate other drugs which patient may be taking and
which may interact with ethionamide.
10.4 Decontamination
Methods to reduce gastrointestinal absorption consist of
inducing emesis or performing gastric lavage.
Perform gastric lavage if dose was high and ingestion was
recent. Protect airway if patient is unconscious.
Administer activated charcoal (1 mg/kg). (Note: The use of
cathartics is generally no longer recommended).
10.5 Elimination
No documented information available.
10.6 Antidote treatment
10.6.1 Adults
There are no specific antidotes for ethionamide
overdose. However, high dose pyridoxine may inhibit
its neurotoxic effects (Gennaro et al., 1985)
because of its similarity to isoniazid. This
possible antidotal effect has not been documented.
10.6.2 Children
There is no specific antidote. However, high dose
pyridoxine may prevent neurotoxicities.
10.7 Management discussion
Despite ethionamide's synthesis in 1956, there is still
paucity of both clinical and experimental data,
specifically in the management of acute poisoning overdose.
Drug induced hepatotoxicity was shown to be decreased by
pre-administration of methimazole (MMI)(Ruse, 1991).
High dose pyridoxine may prevent neurotoxicities.
Pellagra-like symptoms can be reversed by niacin.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Abnormalities of liver function (but no jaundice) occurred
in 12 of 80 patients treated with ethionamide as part of
their antituberculous chemotherapy. However, 10 of these
patients were also taking pyrazinamide. The use of these 2
agents together may increase the risk of hepatotoxicity and
should be avoided (Reynolds, 1989).
A girl developed acute hepatic necrosis and died after
treatment with ethionamide, isoniazid and aminosalicylic
acid. It was considered that ethionamide was the most
likely cause (Reynolds, 1989).
A report of encephalopathy with pellagra-like symptoms
occurring in association with ethionamide in 2 patients,
and with ethionamide and cycloserine in one patient.
Treatment was with nicotinamide and compound vitamin
preparations (Reynolds, 1989).
11.2 Internally extracted data on cases
No data available.
11.3 Internal cases
To be completed by each Centre using local data.
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes
To be completed by each Centre using local data.
12.2 Specific preventive measures
Caution is necessary in administration ethionamide to
patients with depression or other psychiatric illnesses,
chronic alcoholism, or epilepsy.
As there have been reports of goitre and hypothyroidism
associated with the use of ethionamide it should be
administered with care to patients requiring treatment for
hypothyroidism.
Difficulty may be experienced in controlling diabetes.
The side effects of other tuberculostatic agents may
be increased when ethionamide is used concurrently.
Ethionamide is contraindicated in pregnant and lactating
women, in patients with severe liver disease, and those
with severe hypersensitivity to the drug.
12.3 Other
No data available.
13. REFERENCES
British Tuberculosis Association (1968) Comparison of toxicity
of prothionamide and ethionamide: a report from the research
committee of the british tuberculosis association. Tubercule,
49(2): 125-135
Budavari S ed. (1989) The Merck Index, an encyclopedia of
chemicals, drugs, and biologicals, 11th ed. Rahway, New
Jersey, Merck and Co., Inc. p 590.
Dollery C ed. (1991) Therapeutic Drugs, Volume 1. Edinburgh,
Churchill & Livingstone.
Drucker D et al. (1984) Ethionamide-induced goitrous
hypothyroidism. Ann Intern Med, 100(6): 837-9
European Pharmacopoeia (1980-1986) 2nd. ed., Maison Neuve,
Council of Europe, p 142.
Gennaro AR ed. (1985) Remington's pharmaceutical sciences, 17th
ed. Easton, Pennsylvania, Mack Publishing Company, p 1216.
Gilman AG, Rall TW, Nies AS & Taylor P eds. (1990) Goodman and
Gilman's the pharmacological basis of therapeutics, 8th ed. New
York, Pergamon Press, pp 1154-1155
Griffin JP, O,Grady J, Well FO,& D'Arcy (1988) A manual of
adverse drug interactions, Butterworth and Co Ltd.
Holdiness MR (1984) Clinical pharmacokinetics of antituberculous
drugs. A review. Clin Pharmacokinetics, 9(6): 571-574
Lorian V ed. (1980) Antibiotics in laboratory medicine,
Baltimore Press, Williams and Wilkins Company, pp 160-165.
McEvoy GK ed. (1990) American hospital formulary service, drug
information, Bethesda, American Society of Hospital Pharmacists,
pp 343-344.
McEvoy GK ed. (1993) American hospital formulary service, drug
information, Bethesda, American Society of Hospital Pharmacists,
pp 343-344.
Manapat BD et al. (1992) The effectiveness of pyridoxine in
modifying the neurotoxidome of ethionamide overdose in sprague-
dawley rats. Manilla, Pharmacokinetic research paper, UP College
of Medicine-Department of Pharmacology.
Moffat AC ed. (1986) Clarke's isolation and identification of
drugs in pharmaceuticals, body fluids, and post-mortem material.
2nd ed. London, The Pharmaceutical Press, pp 597-598.
Reynolds JEF ed. (1989) Martindale, the extra pharmacopoeia,
29th ed. London, The Pharmaceutical Press, pp 562-563.
Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia,
30th ed. London, The Pharmaceutical Press, p 166.
Osol A et al. (1973) The united states dispensatory, 27th ed. ,
JB Lippincott Company, p 509.
Pattyn SR et al. (1984) Hepatotoxicity of the combination of
rifampicin-ethionamide. Int J Lepr and Other Mycobacterial
Diseases, 1: 1-6
Peters JH (1983) Mutagenic activity of antileprosy drugs and
their derivatives. Int J Lepr and Other Mycobacterial Diseases,
51(1): 45-53
Physician's Desk Reference (1992) 46th ed. Ordell NJ, Medical
Economics, p 2527.
Ruse MJ (1991) The effect of methimazole on thioamide
bioactivation and toxicity. Toxicol Lett, 58(1): 37-41
Schardein JL (1976) Drugs as teratogens. CRC Press, Inc,
p 202.
Shirkey HC (1984) Pediatric drug handbook , W B Saunders
Company.
Snavely SR et al. (1984) The neurotoxicity of antibacterial
agents. Ann Intern Med, 100(1): 92-104
USPDI (1983) Drug Information for the Health Care Professional.
Vol. 1, Rockville MD, United States Pharmacopeial Convention,
pp 396-397.
WHO (1992) Anatomical Therapeutic Chemical (ATC) classification
index. Oslo, WHO Collaborating Centre for Drug Statistics
Methodology, p 61.
WHO (1992) International nonproprietary names (INN) for
pharmaceutical substances. Geneva, World Health Organisation,
p 208.
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Author Dr Perlita Young, M.D.
National Poison Control and Information Service
University of the Philippines
College of Medicine
Philippine General Hospital
Ermita, Manila 1000
Philippines
Tel: 63-2-5218251
Fax: 63-2-501078
Date January 1992
Reviewer Dr M.C. Alonzo
CIAT 7- piso
Hospital de Clinicas
Av. Italia s/n
Montevideo
Uruguay
Tel: 598-2-804000
Fax: 598-2-470300
Peer Review Drs Maramba, Critchley, Caitens, Panganiban,
Ombega, Ten Ham & Ms Kaye. Newcastle-upon-Tyne,
United Kingdom, February 1992.