Ethambutol
| 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 unknown |
| 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 ANALYSES AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Sample |
| 8.1.1 Collection |
| 8.1.2 Storage |
| 8.1.3 Transport |
| 8.2 Toxicological analytical methods |
| 8.2.1 Test for active ingredient |
| 8.2.2 Test for biological analyses |
| 8.3 Other laboratory analyses |
| 8.3.1 Haematological investigations |
| 8.3.2 Biochemical investigations |
| 8.3.2.1 Blood |
| 8.3.2.2 Urine |
| 8.3.3 Arterial blood gas analysis |
| 8.3.4 Other relevant biomedical analyses |
| 8.4 Interpretation |
| 8.5 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 systems |
| 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, throat: local effects |
| 9.4.10 Hematological |
| 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 Other |
| 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
Ethambutol (INN)
(WHO, 1992)
1.2 Group
ATC classification index
Antimycobacterials (J04)/
Drugs for treatment of tuberculosis (J04A)/
Other drugs for treatment of tuberculosis (J04AK)
(WHO, 1992)
1.3 Synonyms
CL-40881
(Reynolds, 1993)
(To be completed by each Centre using local data)
1.4 Identification numbers
1.4.1 CAS number
Ethambutol 74-55-5
Ethambutol hydrochloride 1070-11-7
1.4.2 Other numbers
RTECS EL3640000
1.5 Brand names, Trade names
Ethambutol (Argentina); Myambutol (Australia, Belgium,
Canada, Denmark, France, Germany, Netherlands, South Africa,
Spain, Sweden, Switzerland, UK, USA)
Mynah (UK)
Etibi (Canada)
Dexambutol (France)
EMS-Fasol (Germany)
Etambutyl, Etapiam, Miambutol, Mycobutol and Tibutolo (Italy)
Afimocil, Anvital, Cidanbutol, Etambin, Farmabutol, Fimbutol,
Inagen and Tisiobutol (Spain).
(To be completed by each Centre using local data)
1.6 Manufacturers, Importers
Northia (Argentina), Lederle (UK, both Myambutol and Mynah).
(To be completed by each Centre using local data)
1.7 Presentation, Formulation
Myambutol is available as powder (50 g per bottle) and
as tablets of 100 and 400 mg; Mynah is available as tablets
containing ethambutol and isoniazid. Mynah 200, Mynah 250,
Mynah 300 and Mynah 365 contain 200, 250, 300 and 365 mg of
ethambutol hydrochloride respectively, with 100 mg of
isoniazid.
(To be completed by each Centre using local data)
2. SUMMARY
2.1 Main risks and target organs
During chronic treatment ethambutol may produce visual
and neurological disturbances, allergic reactions,
gastrointestinal symptoms, psychiatric symptoms and transient
impairment of liver function. This last event has a very low
incidence.
Increased serum uric acid levels and acute gouty arthritis
have been reported.
2.2 Summary of clinical effects
Acute overdosage may cause gastrointestinal symptoms,
hallucinations and optic neuritis. Acute overdosage symptoms
include nausea, abdominal pain, fever, mental confusion,
visual hallucinations, and optic neuropathy (retrobulbar
neuritis) with doses over 10 g.
The effects of overdosage are not well established. During
chronic treatment the following have been reported:
Visual disturbances
Ethambutol may produce a reduction of visual acuity which
appear to be due to optic neuritis. Central scotoma and
green-red colour blindness may also occur.
Allergic reactions
Rash, anaphylactoid reactions, dermatitis, pruritus.
Gastrointestinal symptoms
Abdominal pain, anorexia, nausea, vomiting.
Neurological disturbances and psychiatric symptoms
Headache, peripheral neuritis, dizziness, mental confusion,
disorientation, hallucinations.
Other side-effects
Jaundice, transient impairment of liver function, fever,
increase of serum uric acid levels, joint pain, acute gouty
arthritis,malaise. Ethambutol may diffuse into milk.
2.3 Diagnosis
Clinical diagnosis is difficult, but the diagnosis of
poisoning with ethambutol should be considered as
differential in patients presenting with hallucinations,
visual disturbances and gastrointestinal symptoms.
The following laboratory tests may be performed to detect
side effects:
Serum uric acid levels;
Liver and renal function tests; and
Haematological examinations (neutropenia has been reported in
patients treated with rifampicin, isoniazid and
ethambutol).
2.4 First aid measures and management principles
In cases of overdosage with ethambutol gastric lavage or
inducing emesis should be considered, if seen 1 to 2 hours
after ingestion. Activated charcoal may be reasonably left in
the stomach after gastric lavage.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Ethambutol is a synthetic oral antibiotic derivative of
ethylenediamine which contains two imine radicals and two
butanol radicals.
3.2 Chemical structure
CH3CH2CH(CH2OH)NHCH2CH2NHCH(CH2OH)CH2CH3
Molecular formula
Ethambutol base C10H24N2O2
Ethambutol hydrochloride C10H24N2O2,2HCl
Molecular weight
Ethambutol base 204.3
Ethambutol hydrochloride 277.2
Chemical names
(S,S)-N,N'-Ethylenebis(2-aminobutan-1-ol)dihydrochloride
2,2'-(1,2-ethanediyldiimino)bis-l-butanol
(+)- (R,R)-NN'-Ethylenebis(2-aminobutan-1-ol)dihydrochloride
(+)-2,2'-(ethylenediimino)di-1-butanol
d-N,N'-bis(1-hydroxymethylpropyl)ethylenediamine
(Reynolds, 1982,1993; Budavari, 1989)
3.3 Physical properties
3.3.1 Properties of the substance
3.3.1.1 Colour
White
3.3.1.2 State/Form
Crystalline hygroscopic powder
3.3.1.3 Description
Odourless or almost odourless
Bitter taste
Melting point 199 °C to 204 °C
Soluble 1 in 1 of water, 1 in 4 of alcohol, 1
in 850 of chloroform, and 1 in 9 of methyl
alcohol; very slightly soluble in ether.
A solution in water is dextrorotatory.
Solutions are stable when heated at 121 °C for
10 minutes.
(Reynolds, 1993; Windholz, 1983)
3.3.2 Properties of the locally available formulation(s)
(To be completed by each Centre using local data)
3.4 Other characteristics
3.4.1 Shelf-life of the substance unknown
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
Store in airtight containers 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
4.1.2 Description
For the treatment of tuberculosis in conjunction
with at least one other antituberculous drug.
4.2 Therapeutic dosage
4.2.1 Adults
Treatment (oral)
Initial phase (8 weeks) 25 mg/kg per day as a single
dose in continuous regimens; or 30 to 40 mg/kg three
times weekly in intermittent regimens.
Continuation phase: 15 mg/kg daily
Prophylaxis (oral)
15 mg/kg per day
Note:
The dose of ethambutol should be reduced or dosage
interval should be adjusted in patients with impaired
renal function.
A dose supplement should be given to patients
undergoing haemodialysis or peritoneal dialysis.
Ethambutol is usually given with isoniazid, rifampicin
and pyrazinamide in the initial 8 week phase
(Reynolds,1993)
4.2.2 Children
Ethambutol is not recommended for use in
children under thirteen years of age since safe
conditions for use have not been established (PDR,
1989). However, children over the age of 6 years have
been given doses similar to those used for adults
(Reynolds, 1989).
4.3 Contraindications
Ethambutol hydrochloride is contraindicated in patients
who are known to be hypersensitive to this drug. Renal
impairment, old age and optic neuritis are relative
contraindications (PDR, 1989).
5. ROUTES OF ENTRY
5.1 Oral
Ethambutol is only available for oral use. Data about
other routes of entry are not available.
5.2 Inhalation
Not relevant
5.3 Dermal
Not relevant
5.4 Eye
Not relevant
5.5 Parenteral
Not relevant
5.6 Other
Not relevant
6. KINETICS
6.1 Absorption by route of exposure
Ethambutol hydrochloride, following a single oral dose
of 25 mg/kg of body weight, attains a peak of up to 5 œg/mL
in serum within 4 hours after administration and is less than
1 ug/ml by 24 hours. When the drug is administered daily for
longer periods of time at this dose, serum levels are
similar.
About 80% of an oral dose of ethambutol is absorbed from the
gastro-intestinal tract, and the remainder appears in the
faeces unchanged. Absorption is not significantly impaired by
food.
(Reynolds, 1993)
6.2 Distribution by route of exposure
Ethambutol diffuses readily into red blood cells and
into the cerebrospinal fluid when the meninges are inflamed.
The concentration in erythrocytes at steady state is
approximately twice the plasma concentration.
Protein binding is less than 5%; the volume of distribution
is 1.6 L/kg (Gilman et al., 1990)
It has been reported to cross the placenta and is excreted in
breast milk (Reynolds, 1989). The concentration of
ethambutol in one sample of breast milk collected during a 2
hour period after a dose of 15 mg per kg body-weight was 1.4
mcg/mL. Another woman had simultaneous concentrations of 4.62
and 4.60 œg/mL in plasma and milk respectively, but no dose
had been specified (Reynolds, 1989).
6.3 Biological half-life by route of exposure
The serum half-life in therapeutic doses is 3 hours,
increasing in renal failure, as 80% is excreted renally
(Gilman et al., 1990).
In 6 healthy subjects given a single dose of ethambutol 15
mg/kg bodyweight as an aqueous solution and as a commercial
tablet preparation the apparent mean elimination half-life
was 4.78 and 4.06 hours respectively, for plasma
concentration measured up to 12 hours after administration.
It was increased to about 10 hours for 24 to 72 hour
samplings. The serum levels of ethambutol falls to
undetectable levels by 24 hours after the last dose, except
in some patients with abnormal renal function.
6.4 Metabolism
The main path of metabolism appears to be an initial
oxidation of the alcohol to an aldehydic intermediate,
followed by conversion to a dicarboxylic acid (PDR,
1989).
6.5 Elimination by route of exposure
During the 24-hour period following oral administration
of ethambutol, approximately 50% of the initial dose is
excreted unchanged in the urine, while an additional 8% to
15% appears in the form of metabolites. From 20 to 22% of
the initial dose is excreted in the faeces as unchanged drug
(PDR, 1989).
No drug accumulation has been reported with consecutive
single daily doses of 25 mg/kg in patients with normal kidney
function, although marked accumulation has been demonstrated
in patients with renal insufficiency (PDR, 1989).
The intrinsic total body clearance is 9 mL/min/kg (Gilman et
al., 1990).
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
The underlying cause of visual alterations
appears to be a disturbance of metabolism due to
depletion of copper and zinc which serve as prosthetic
groups for many enzymes. The eye normally contains a
considerable store of zinc, amounting to 0.5% of the
weight of the eyeball. Much of the zinc is in the
pigmented cells of the outer zone of the retina, where
it serves as a metal prosthetic group for retinol
(alcohol) dehydrogenase.
7.1.2 Pharmacodynamics
Ethambutol is an oral chemotherapeutic agent
which is specifically effective against actively
growing microorganisms of the genus Mycobacterium,
including M. tuberculosis (PDR,1989). Ethambutol is
bacteriostatic and appears to inhibit the synthesis of
one or more metabolites, thus causing impairment of
cell metabolism, arrest of multiplication, and cell
death. No cross resistance with other available
antimycobacterial agents has been demonstrated.
Ethambutol has been shown to be effective against
strains of mycobacterium tuberculosis but does not seem
to be active against fungi, viruses, or other bacteria.
Ethambutol is also active against some atypical
mycobacteria including M. kansasii. Primary resistance
to ethambutol is uncommon in developed countries but
resistant strains of M. tuberculosis are readily
produced if the drug is used alone.
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Adverse effects to ethambutol appear
to be uncommon with doses of 15 mg/kg body-
weight (Reynolds, 1989). Optic neuropathy is
virtually unknown when ethambutol is given in
doses of up to 15 mg/kg body-weight and is rare
at doses of up to 25 mg/kg. However, a patient
developed rapid progressive deterioration of
vision only 3 days after beginning therapy with
ethambutol 800 mg daily by mouth (about 15
mg/kg body-weight) and this patient remained
blind over one year after the initial reaction
(Karnik et al., 1985).
Subclinical impairment of colour discrimination
was reported to be relatively common in 54
patients receiving about 15 mg/kg body-weight
of ethambutol daily as part of antituberculous
chemotherapy when compared with 50 patients
receiving other antituberculous agents
(Reynolds, 1989).
Peripheral neuropathy has been reported in 3
tubercular patients who had received ethambutol
13 to 50 mg/kg body-weight, among other drugs.
It has been reported that a patient who took
ethambutol 20 g, rifampicin 9 g and isoniazid
6 g made an uneventful recovery after
haemodialysis and treatment with pyridoxine
(Reynolds, 1989).
7.2.1.2 Children
No available data.
7.2.2 Relevant animal data
Toxicological studies in dogs on high prolonged
doses, produced evidence of myocardial damage and
failure, and depigmentation of the tapetum lucidum of
the eyes, the significance of which is not known.
Degenerative changes in the central nervous system,
apparently not dose-related, have also been noted in
dogs receiving ethambutol hydrochloride over a
prolonged period (PDR, 1989).
In the rhesus monkey, neurological signs appeared after
treatment with high doses given daily over a period of
several months. These correlated with specific serum
levels of ethambutol hydrochloride and with definite
neuro-anatomical changes in the central nervous system.
Focal interstitial carditis was also noted in monkeys
which received ethambutol hydrochloride in high doses
for a prolonged period (PDR, 1989).
7.2.3 Relevant in vitro data
Information about in vitro toxicological tests
is not available.
7.3 Carcinogenicity
No available data. Tumour inducing effects are not known.
7.4 Teratogenicity
Although ethambutol may be teratogenic in animals, there
is no evidence of teratogencity in man (Reynolds,
1989).
7.5 Mutagenicity
No available data
7.6 Interactions
Results of a crossover study involving 13 tuberculous
patients suggest that concomitant administration of aluminium
hydroxide may delay and reduce absorption of ethambutol in
some patients (Mattila et al., 1978).
Untoward effects may be enhanced when ethambutol is combined
with isoniazid or rifampicin (Dukes, 1984).
7.7 Main adverse effects
Ethambutol may produce decreased visual acuity which
appear to be due to optic neuritis and to be related to dose
and duration of treatment. The effects are generally
reversible when administration of the drug is discontinued
promptly (PDR, 1989).
Ethambutol may produce constriction of visual field, central
and peripheral scotoma, and green-red colour blindness which
may be associated with retrobulbar neuritis (Dukes, 1984;
Reynolds, 1989).
Renal clearance of urate may be reduced in about 50% of
patients receiving ethambutol and acute gout has been
precipitated in patients with gout or impaired renal function
(Reynolds, 1989).
Cholestatic jaundice has been reported (Gulliford et al., 1986).
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Sample
8.1.1 Collection
8.1.2 Storage
8.1.3 Transport
8.2 Toxicological analytical methods
An agar diffusion microbiological assay, based upon
inhibition of Mycobacterium smegmatis (ATCC 607) may be used to
determine concentrations of ethambutol hydrochloride in serum
and urine. This technique has not been published.
8.2.1 Test for active ingredient
8.2.2 Test for biological analyses
8.3 Other laboratory analyses
8.3.1 Haematological investigations
Full blood count might be convenient to detect
adverse effects. Leucopenia with neutropenia and
thrombocytopenia have been reported in patients treated
with ethambutol, isoniazid and rifampicin.
8.3.2 Biochemical investigations
8.3.2.1 Blood
The following laboratory test may be
performed to detect side-effects: serum uric
acid levels; liver function tests; serum urea
and creatinine concentrations.
8.3.2.2 Urine
8.3.3 Arterial blood gas analysis
8.3.4 Other relevant biomedical analyses
8.4 Interpretation
Ethambutol may increase uric acid levels by reducing renal
clearance of urate. Rarely, it might induce liver or renal
disfunction.
8.5 References
See Section 13
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
The acute overdosage symptoms include nausea,
abdominal pain, fever, mental confusion, visual
hallucinations and optical neuropathy with doses above
10 g.
According to scarce available information about
ethambutol overdosage in humans, no deaths due to
ethambutol alone have been reported. One fatal case of
overdose with rifampicin and ethambutol has been
reported (Jack et al., 1978).
Ethambutol may induce many other side-effects which
were mentioned as "Main adverse effects" in the item
7.7. Possible presentation of these signs and symptoms
in an acute overdose with ethambutol is
unknown.
9.1.2 Inhalation
Not relevant.
9.1.3 Skin exposure
Not relevant.
9.1.4 Eye contact
Not relevant.
9.1.5 Parenteral exposure
Not relevant.
9.1.6 Other
Not relevant.
9.2 Chronic poisoning
9.2.1 Ingestion
Signs and symptoms reported in long-term
treatments with ethambutol have been presented in item
7.7. Other data are not available in our
centre.
9.2.2 Inhalation
Not relevant.
9.2.3 Skin exposure
Not relevant.
9.2.4 Eye contact
Not relevant.
9.2.5 Parenteral exposure
Not relevant.
9.2.6 Other
Not relevant.
9.3 Course, prognosis, cause of death
As it has been mentioned, no deaths due to ethambutol
have been reported. Decrease in visual acuity induced by
ethambutol was reversible when administration of the drug was
discontinued. In rare cases, recovery may be delayed for up
to one year or more and the effects may possibly be
irreversible in these cases. Patients should be advised to
report promptly to their physician any change in visual
acuity (PDR,1989). If careful evaluation confirms the
magnitude of visual change and fails to reveal another cause,
ethambutol therapy should be discontinued and the patient
reevaluated at frequent intervals. Patients developing
visual abnormality during ethambutol therapy may show
subjective visual symptoms before, or simultaneously with,
the demonstration of decreases in visual acuity, and all
patients receiving ethambutol should be questioned
periodically about blurred vision and other subjective eye
symptoms (PDR, 1989). Recovery of visual acuity generally
occurs over a period of weeks or months after the drug has
been discontinued. Patients have then received ethambutol
again without recurrence of loss of visual acuity (PDR,
1989).
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)
Confusion, disorientation,
hallucinations, headache, dizziness,
retrobulbar neuritis with a reduction in visual
acuity, constriction of visual field, central
or peripheral scotoma and green-red colour
blindness have been reported as adverse-effects
of ethambutol therapy. Retinal haemorrhage has
occurred rarely (Reynolds, 1989).
Mental confusion, visual hallucination and
optical neuropathy have been reported in cases
of acute overdosage. The incidence and severity
of ocular damage appears to be dose-dependent.
In severe cases even blue- yellow defects
occurred which may result in achromatopsia
(Dukes, 1986). Visual-evoked potential testing
is reported to be the most reliable method for
early detection of ocular
abnormalities.
9.4.3.2 Peripheral nervous systems
Peripheral neuritis may precede or
accompany ocular damage. Changes are more
severe in the sensory than in the motor nervous
system.
9.4.3.3 Autonomic nervous system
Unknown
9.4.3.4 Skeletal and smooth muscle
Joint pains can occur with ethambutol
therapy.
9.4.4 Gastrointestinal
Digestive disturbances may be present both in
acute poisoning or in long-term therapy. Metallic
taste, nausea, vomiting, anorexia, and abdominal pain
have been reported as adverse-effects to ethambutol
treatment.
9.4.5 Hepatic
Jaundice and transient liver dysfunction are not
unusual findings during ethambutol treatment.
9.4.6 Urinary
9.4.6.1 Renal
Renal clearance of urate may be
reduced in about 50% of patients receiving
ethambutol. There are scarce reports about
renal failure and acute diffuse interstitial
nephritis related with ethambutol
therapy.
9.4.6.2 Other
None reported.
9.4.7 Endocrine and reproductive systems
Unknown
9.4.8 Dermatological
Skin rashes and pruritus may occur.
9.4.9 Eye, ear, nose, throat: local effects
Ocular disturbances as described in
9.4.3.1.
9.4.10 Hematological
Leucopenia is an unusual finding.
9.4.11 Immunological
Acute thrombocytopenia, probably due to an
immunological mechanism, has been described in a single
patient (Dukes, 1984). Various exanthemas, Stevens-
Johnson syndrome, "toxic" epidermal necrolysis,
purpura-like vasculitis, acute thrombopenic purpura,
joint pain, drug fever, and leukopenia have been
attributed to hypersensitivity. These reactions may
arise during combined treatment with other
tuberculostatics and it is therefore difficult to
determine which drug is responsible.
9.4.12 Metabolic
Elevation of serum uric acid levels may occur
during ethambutol treatment (Dukes, 1986) and
precipitation of acute gout has been reported (PDR,
1989).
9.4.12.1 Acid-base disturbances
Unknown
9.4.12.2 Fluid and electrolyte disturbances
No data available
9.4.12.3 Others
No data available
9.4.13 Allergic reactions
Anaphylactoid reactions
9.4.14 Other clinical effects
Fever has been reported as an adverse-effect.
It has been attributed to hypersensitivity.
9.4.15 Special risks
Pregnancy
The effects of combination of ethambutol with other
antituberculous drugs on the foetus is not known.
While administration of this drug to pregnant human
patients has produced no detectable effect upon the
foetus, the possible teratogenic potential in women
capable of bearing children should be weighed carefully
against the benefits of therapy. There are published
reports of five women who received the drug during
pregnancy without apparent adverse effect upon the
foetus (PDR,1989).
Breastfeeding
Ethambutol may diffuse into milk.
Enzyme deficiencies
No data available.
Alcohol
In alcoholics with liver damage, in patients with
intercurrent or previous hepatitis or in diabetics with
retinopathy, monthly controls of the pathological state
are necessary (Dukes, 1984).
9.5 Other
No data available
9.6 Summary
Not relevant
10. MANAGEMENT
10.1 General principles
Consider prevention of absorption by enemas or gastric
lavage, if patient seen within 1 to 2 hours after ingestion.
Otherwise treatment is supportive.
10.2 Relevant laboratory analyses
10.2.1 Sample collection
10.2.2 Biomedical analysis
As with any potent drug, assessment of organ
system functions, including renal, hepatic, and
haematopoietic, should be made.
10.2.3 Toxicological analysis
Ethambutol concentrations may be evaluated both
in blood and urine.
10.2.4 Other investigations
No data available.
10.3 Life supportive procedures and symptomatic/specific
treatment
Usual life-supportive and/or symptomatic measures,
depending on clinical presentation of the patient.
10.4 Decontamination
In case of overdosage, the common methods employed to
limit the absorption of the drug from the gastrointestinal
tract may be utilized. Activated charcoal suspension may be
left in the stomach after gastric lavage.
10.5 Elimination
Based on the low protein binding (<5%) and volume of
distribution (1.6 L/kg) haemodialysis may theoretically
remove significant amounts of ethambutol. However, the high
intrinsic clearance (9 mL/min/kg) and short half-life (3
hours) indicate that this procedure may only be considered if
renal failure develops. (Jacobsen, personal
communication).
10.6 Antidote treatment
10.6.1 Adults
Antidotes are not available
10.6.2 Children
Antidotes are not available
10.7 Management discussion
There are no data about the efficacy of treatment in
cases of ethambutol overdosage.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Neutropenia in a 75-year-old man treated with isoniazid,
ethambutol, and rifampicin. Neutropenia was induced, on
challenge, by each of the 3 agents (Jenkins et al., 1980). A
patient who took ethambutol 20 g, rifampicin 9 g, and isoniazid
6 g made an uneventful recovery after haemodialysis and
treatment with pyridoxine (Ducobu et al., 1982).
Substitution of ethambutol by isoniazid was considered to be
responsible for thrombocytopenia in a 71 year-old woman who had
been receiving isoniazid and rifampicin for tuberculosis
(Rabinovitz et al., 1982).
A patient developed rapid progressive deterioration of vision
only 3 days after beginning therapy with ethambutol 800 mg
daily by mouth (about 15 mg/kg body-weight) as part of
combination chemotherapy for pulmonary tuberculosis. The
patient remained blind over one year after the initial reaction
(Karnik et al., 1985).
Ethambutol might have caused renal failure in 2 patients
(Collier et al., 1976).
A report of acute diffuse interstitial nephritis in 3 patients
attributed to antituberculous therapy and especially isoniazid
and/or ethambutol (Stone et al., 1976).
Ethambutol was considered to be the cause of jaundice which
developed in a patient also receiving isoniazid and
streptomycin. Rechallenge was positive for ethambutol or
ethambutol and streptomycin (Gulliford et al., 1986).
A report of toxic epidermal necrolysis associated with the use
of ethambutol in one patient (Pegram et al., 1981).
Hyperuricaemia has been found in up to 66% of patients
receiving ethambutol (Postlethwaite et al, 1972) and there have
been reports of acute gouty arthritis precipitated by
ethambutol in some patients (Self et al., 1977).
An acute overdose of isoniazid (7.l g), rifampicin (15 g) and
ethambutol(20 g) produced seizures with loss of consciousness
and full extension of all four extremities in a 21-year-old
female who had ingested the medication 3.5 hours earlier.
Neurological examination revealed no focal or lateralizing
defects. Convulsions resisted conventional treatment with
diazepam and phenytoin, but did not recur following
approximately 8.0 g pyridoxine and haemodialysis for 4 hours.
Pancuronium (2 mg intravenously) was also administered under
intubation of the patient. A severe metabolic acidosis,
typical of acute overdosage with isoniazid was treated with
sodium bicarbonate infusion. The patient's SGOT and SGPT
peaked on day 3 and declined rapidly thereafter. She was
released on day 9 with no significant complications. (Spalding
& Buss, 1986).
A fatal case of overdose with both rifampicin and ethambutol
has been reported. A man was found lying in the street and was
dead on admission to hospital. He had been receiving
rifampicin and ethambutol. At necropsy, a pink discoloration of
the skin and internal organs was noted. The dead man's urine
was bright red. Blood and urine concentrations of rifampcin
and ethambutol were respectively 182 œg/ml and 3.3 mg/ml and 84
œg/ml and 6.8 œg/ml. These levels may correlate with acute
overdosage with both drugs. Alcohol concentrations were very
low. Discolouration of skin, mucous membranes, and urine is
typical of rifampicin treatment, since the drug and its
metabolites are deep-red (Jack et al., 1978).
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
Antidotes are not available.
12.2 Specific preventive measures
Ethambutol should be given in reduced dosage to patients
with impaired kidney function; it should be used with great
care in patients with visual defects, the elderly, and in
children in whom evaluation of changes in visual acuity may be
difficult; it should not be used in children under at least 6
years and some consider it should not be used in patients with
visual defects; ocular examinations are recommended before
treatment with ethambutol and some consider that regular
examinations are necessary during treatment especially in
children; patients should be advised to report visual
disturbances immediately and ethambutol should be withdrawn if
vision deteriorates; desensitization may be attempted following
hypersensitivity reactions if the use of ethambutol is
considered essential for provision of adequate
chemotherapy.
12.3 Other
No data available.
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14. AUTHOR(S), REVIEWER(S), DATE(S), (INCLUDING UPDATES), COMPLETE
ADDRESS(ES)
Co-authors Dr Julia Higa de Londoni
Professor and Chief
Toxicology Section
Department of Internal Medicine
Hospital de Clínicas José de San Martín
Av Córdoba 2351
1120 Buenos Aires
Argentina
Dr Roberto Juan Gabach
Toxicology Section
Department of Internal Medicine
Hospital de Clínicas José de San Martín
Av Córdoba 2351
1120 Buenos Aires
Argentina
Date January 1990
Reviewer Dr R. Ferner Newcastle-upon-Tyne
Peer Review Strasbourg, France, April 1990