INTOX Home Page

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.
 
 
 
    13.  REFERENCES
 
        Budavari S ed. (1989) The Merck index, an encyclopedia of 
        chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey, 
        Merck and Co., Inc.  p 587.
        
        Collier J, Joekes AM, Philalithis PE, & Thompson FD (1976) Two cases 
        of ethambutol nephrotoxicity. Br Med J, 2:1105-6.
        
        Dictionnaire Vidal (1987) Vidal 1987. Editions du Vidal, Paris.
        
        Ducobu J, Dupont P, Laurent M, & Bruart J (1982) Acute 
        isoniazid/ethambutol/rifampicin overdosage (letter). Lancet, 
        1: 632.
        
        Dukes MNG ed. (1984) Meyler's Side Effects of Drugs, Volume 10. 
        Amsterdam, Elsevier.
        
        Dukes MNG ed. (1986) Meyler's Side Effects of Drugs Annual 10. 
        Amsterdam, Elsevier, p 270.
        
        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 1152-1153,1679.
        
 
        Gulliford M, Mackay AD, & Prowse K (1986) Cholestatic jaundice 
        caused by ethambutol. Br Med J, 292: 866.
        
        Jack et al (1978)  Fatal Rifampicin-ethambutol overdosage.  Lancet, 
        2: 1107-8.
        
        Jenkins PF, Williams TD, & Campbell IA (1980) Neutropenia with each 
        standard antituberculosis drug in the same patient. Brit Med J, 
        280: 1069-70.
        
        Karnik AM, Al Shamali MA, & Fenech FF (1985) A case of ocular 
        toxicity to ethambutol--an idiosyncratic reaction? Postgrad Med J, 
        61: 8ll-813.
        
        Mattila MJ, Linnoila M, Seppala T, & Koskinen R (1978) Effect of 
        aluminium hydroxide and glycopyrrhonium on the absorption of 
        ethambutol and alcohol in man.  Brit J Clin Pharmacol, 
        5: 161-166.
        
        Pegram PS Jr, Mountz JD, & O'Bar PR (1981) Ethambutol-induced toxic 
        epidermal necrolysis. Arch Intern Med, 141: 1677-8.
        
        Physician's Desk Reference (1989) 43rd ed. Ordell NJ, Medical 
        Economics, p 560.
        
        Postlethwaite AE, Bartel AG, & Kelley WN (1972) Hyperuricemia due to 
        ethambutol. New Engl J Med, 286: 761-762.
        
 
 
 
        Rabinovitz M, Pitlik SD, Halevy J, & Rosenfeld JB (1982) Ethambutol- 
        induced thrombocytopenia.  Chest, 81: 765-6.
        
        Reynolds JEF ed. (1982) Martindale, the extra pharmacopoeia, 28th 
        ed. London, The Pharmaceutical Press, pp 1569-1570.
        
        Reynolds JEF ed. (1989) Martindale, 29th ed. The Pharmaceutical 
        Press, pp 560-563.
        
        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 30th 
        ed. London, The Pharmaceutical Press. pp 164-165
        
        Self TH, Fountain FF, Taylor WJ, & Sutliff WD (1977) Acute gouty 
        arthritis associated with ethambutol. Chest, 71(4): 561-2.
        
        Spalding CT & Buss WC (1986) Toxic overdose of isoniazid, rifampicin 
        and ethambutol. Eur J Clin Pharmcol, 30: 381-382.
        
        Stone WJ, Waldron JA, Dixon JH, Primm RK, & Horn RG (1976) Acute 
        diffuse interstitial nephritis related to chemotherapy of 
        tuberculosis. Antimicrob Agents Chemother, 10(1): 164-172.
        
        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 
        207.
        
        Windholz M ed. (1983)  The Merck index, an encyclopedia of 
        chemicals, drugs, and biologicals, 10th ed. Rahway, New Jersey, 
        Merck and Co., Inc, p 539.
 
    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