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Dapsone

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
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
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   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 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 Advanced Quantitative Method(s)
      8.2.2 Tests 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 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      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 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, 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 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)


    PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Dapsone
     1.2 Group
       Dihydrofolate reductase inhibitor
     1.3 Synonyms
       Avlosulfon
       Avlosulphone
       Croysulfone
       DADPS
       DDS
       Diaphenylsulfone
       Diphenasone
       Diphone
       Disulone
       Dumitone
       Eporal
       Novophone
       Sulfona-Mae
       Sulphadione
       Udolac
     1.4 Identification numbers
       1.4.1 CAS number
             80-08-0
       1.4.2 Other numbers
             1358F 
             NCI-CO1718
             NSC 6091D
             RTECS: BY892500
             WR 488
     1.5 Brand names, Trade names
       Avlosulfon (ICI, Ayerst), DAPS (Sintyal), Dapsone USP (Jacobus 
       Pharmaceutical), Disulone 100 (Specia), Dubronax (Kela), 
       Maloprim (Burroughs Wellcome), Sulfona oral (Esteve), Udolac 
       (ICI).
     1.6 Manufacturers, Importers
       Disulone (Specia)
    2. SUMMARY
     2.1 Main risks and target organs
       Methaemoglobinaemia and haemolysis are the main risks of acute 
       intoxication. Haemolytic anaemia, agranulocytosis, aplastic 
       anaemia and other blood dyscrasias may occur in chronic 
       poisoning.
       
       Target organs are central and peripheral nervous systems, 
       blood, liver and skin.
     2.2 Summary of clinical effects
       Acute poisoning
       
       Methaemoglobinaemia is the principal and constant feature of 
       dapsone poisoning. Clinical features may include headache, 
       dizziness, agitation, restlessness, nausea, vomiting, 
       abdominal pain, bluish-grey cyanosis, tachycardia, 
       hyperventilation, stupor, convulsions, coma, jaundice, and 
       intravascular haemolysis.

         
       Chronic poisoning
       
       Haemolytic anaemia and agranulocytosis may occur with the 
       relatively low doses used for leprosy and malaria, whereas 
       peripheral neuropathy and hepatitis are only observed with the 
       higher doses used in the treatment of dermatitis herpetiformis 
       (Scholer et al., 1984). Deficiency of glucose-6-phosphate 
       dehydrogenase, and administration in combination with 
       primaquine are predisposing factors for the occurrence of 
       haemolytic anaemia.  Concurrent administration of primaquine 
       also predisposes to agranulocytosis (Chernof 1967; Hutchinson 
       et al., 1986).
     2.3 Diagnosis
       Nausea, vomiting, abdominal pain, features of 
       methaemoglobinaemia (cyanosis, headache, lethargy, syncope 
       etc), anaemia and jaundice are the features suggesting acute 
       dapsone poisoning when there is a history of exposure. In 
       severe cases there may be convulsions and coma.
       
       If methaemoglobinaemia is present the patient's blood will be 
       chocolate brown in colour. 
       
       Laboratory analysis of blood for methaemoglobin levels is 
       useful for the diagnosis. Methaemoglobin level correlates well 
       with symptoms. 
       
       Dapsone plasma concentrations are usually higher than 10 mg/l 
       in patients with methaemoglobinaemia.
       
       Other useful laboratory analyses include blood count, 
       reticulocytes, haptoglobin, bilirubin, plasma haemoglobin, 
       sulphaemoglobin, transaminases, arterial blood gases.
       
       Clinical features of chronic dapsone poisoning are haemolytic 
       anaemia, agranulocytosis, peripheral neuropathy and hepatitis. 
     2.4 First aid measures and management principles
       Patients with acute dapsone poisoning should be admitted to an 
       intensive care unit.
       
       Monitor respiration, blood pressure and urine output.
       
       Treatment may include:
         
       Gastric lavage or emesis
       
       Repeated oral activated charcoal
       
       Oxygen therapy and antidotes (methylene blue) for 
       methaemoglobinaemia.
       
       Haemodialysis in severe cases.
       
       Dapsone toxicity is due both to the parent drug and its 
       metabolites. Therefore aggressive therapy may be indicated to 
       enhance elimination of dapsone and its metabolites when 

       features of severe poisoning persist despite adequate 
       supportive, antidotal and charcoal therapy.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Synthetic
       
       Manufacturing : Reaction of excess sodium sulfide with 1-
       chloro-4-nitrobenzene followed by acetylation, oxidation with 
       hydrogen peroxide, reduction and acidic or basic hydrolysis; 
       amination of bis(4-chlorophenyl) sulfone.
     3.2 Chemical structure
       4,4'-Sulfonylbisbenzeneamine; 4,4'-sulfonyldianiline; bis(4-
       aminophenyl)sulfone; 4,4'-diaminodiphenyl sulfone.
       
       C12H12N2O2S
     3.3 Physical properties
       3.3.1 Properties of the substance
             Dapsone is a white or slightly yellowish-white, 
             odourless, crystalline powder with a slightly 
             bitter taste. Dapsone is practically insoluble 
             in water (1 in 7000 of water), soluble in 
             alcohol (1 in 30), methanol and freely soluble 
             in acetone.  Dapsone is also soluble in diluted 
             hydrochloric acid (Reynolds & Prasad, 1982). 
             
             Melting point: 175 - 176° C 
             also a higher melting form, m.p. 180.5°
       3.3.2 Properties of the locally available formulation
             To be completed 
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             To be completed 
       3.4.2 Shelf-life of the locally available formulation
             To be completed 
       3.4.3 Storage conditions
             Protect from light
       3.4.4 Bioavailability
             To be completed
       3.4.5 Specific properties and composition
             To be completed
    4. USES
     4.1 Indications
       Dapsone is the drug of choice for the treatment of 
       dermatitis herpetiformis.  It is an antibacterial drug used in 
       the treatment of leprosy.  Dapsone has also been used in malaria
       prophylaxis and in the treatment of relapsing polychondritis, 
       Pneumocystis carinii pneumonia, Kaposi's sarcoma and various other
       dermatoses.  It is also used in veterinary medicine. 
       
       Veterinary medicine: in streptococcal mastitis and coccidiosis of 
       cattle.  Topically in infectious keratitis of cattle and sheep and
       otitis externa of dogs.  Used experimentally to suppress 
       toxoplasmosis in swine.  
       
       Former use (non pharmaceutical) : hardening agent for epoxy resins.
     4.2 Therapeutic dosage

       4.2.1 Adults
             Leprosy: 50 to 100 mg per day (6 to 10 mg/kg per week). 
             Treatment may be continued for several years. 
             Dermatitis herpetiformis: 100 to 300 mg per day.
       4.2.2 Children
             Leprosy: 6 to 10 mg/kg per week
     4.3 Contraindications
       Hypersensitivity to dapsone.  Dapsone should be administered 
       with caution in patients with renal or hepatic failure and in 
       patients with glucose-6-phosphate dehydrogenase deficiency. 
       
       Dapsone levels are influenced by acetylation rates. Patients 
       with genetically determined slow acetylation rates, or who are 
       receiving treatment affecting acetylation, may require an 
       adjustment in dosage.
    5. ROUTES OF ENTRY
     5.1 Oral
       This is the only route of exposure.
     5.2 Inhalation
       No data available.
     5.3 Dermal
       No data available.
     5.4 Eye
       No data available.
     5.5 Parenteral
       No data available.
     5.6 Other
       No data available.
    6. KINETICS
     6.1 Absorption by route of exposure
       70 to 80% of a single oral dose of 100 mg is absorbed (Zuidema 
       et al., 1986) and most is recovered in the urine (Israili et 
       al., 1973).  The maximum plasma concentration is reached 
       within 3 - 6 hours.
     6.2 Distribution by route of exposure
       70 to 80% is bound to plasma proteins (Zuidema et al., 1986). 
       Dapsone is widely distributed with concentrations in most 
       organs similar to plasma concentrations.
       
       The apparent volume of distribution is 0.5 to 1 L/kg (Gelber 
       et al., 1971). Red cell concentrations are higher than those 
       in plasma (Scholer et al., 1984).  Dapsone crosses the 
       placenta (Zuidema et al., 1986).
     6.3 Biological half-life by route of exposure
       Plasma half-lives range between 21 and 30 hours (Gelber et al.,
        1971). Zuidema et al (1986) reported a mean elimination half-
       life of 30 hours (range: 14 to 83 hours) with a clearance of 
       about 0.038 L/kg/hr.
       
       
       The following half-lives of dapsone were reported after 
       overdose:
       
       Authors                 Dose ingested  Plasma
                                  (g)         half-life (h)
       ------------------------------------------------------

       Woodhouse et al., 1983      2.5          29.8
       Neuvonen et al., 1983       7           109
                                  70            88
                                   1            33
       Berlin et al., 1984        15            24
       ------------------------------------------------------
     6.4 Metabolism
       The principal metabolite in plasma is mono-N-acetyl dapsone, 
       which is 97 to 100% bound to plasma proteins and has an 
       elimination half-life of 30.5 hours. The proportion of this 
       metabolite in plasma is dependent on the acetylator phenotype. 
       The dapsone/mono-N-acetyl dapsone ratio is about 1 in slow 
       acetylators and about 0.2 in rapid acetylators (Gelber et al., 
       1971).
       
       Another metabolic pathway is the N-oxidation of dapsone to 4-
       amino-4'-hydroxamine-diphenylsulphone.  This metabolite may be 
       responsible for the haematological toxicity in overdose 
       (Zuidema et al., 1986).
       
       The kinetics of the main metabolite, mono-N-acetyl dapsone 
       (MADDS) after overdose have been reported: 
       
       Authors                Dapsone ingested    MADDS T1/2 (h)
       ---------------------------------------------------------
       Woodhouse et al., 1983         2.5           29.9
       Neuvonen et al., 1983          7             50.0
                                     10             70.0
                                      1             33.8
       ---------------------------------------------------------
     6.5 Elimination by route of exposure
       After oral exposure the drug is eliminated mainly by kidneys.
       
       Kidney:  Urinary excretion is the main route of elimination 
       and 20% of the drug is excreted unchanged and 80% as 
       derivatives, namely 20% glucuronide, 1.5% mono-N-acetyl, 1.5% 
       mono-acetyl glucuronide and 57% sulphamate derivatives 
       (Scholer et al., 1984).
       
       Faeces:  Only minor amounts of dapsone are excreted in faeces 
       (Zuidema et al., 1986).
       
       Bile:  10% of an oral dose was found in the bile (Lang,1979).
       
       Breast-milk:  Dapsone is excreted in breast milk (Sanders et 
       al., 1982; Zuidema et al., 1986).
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             Dapsone produces methaemoglobinaemia by oxidizing the 
             iron in haemoglobin from its ferrous to its ferric form. 
             This renders haemoglobin unable to carry oxygen to 
             tissues. Furthermore, haemolysis and changes in oxygen 
             affinity may occur, increasing the toxic symptoms more 
             than would be expected from the methaemoglobin 
             concentrations alone (Jaeger et al., 1987). The 

             hydroxylated metabolite of dapsone, T-amino-4'-
             hydroxamine-diphenylsulphone, is probably responsible 
             for methaemoglobinaemia and haemolysis (Israili et 1973; 
             Zuidema et al., 1986). 
             
             In vitro, this metabolite forms methaemoglobin (Kramer 
             et al., 1972) and induces haemolysis (Glader 1973). In 
             vitro, it generates hydrogen peroxide (Weetman et al,
             1980) and depletes cellular glutathione (Glader 1973; 
             Weetman et al., 1980). However, this metabolite has not 
             been detected in plasma of patients receiving dapsone.
       7.1.2 Pharmacodynamics
             The mechanism of the bacteriostatic action of dapsone is 
             probably similar to that of the sulphonamides as both 
             are inhibited by para-aminobenzoic acid (Lang, 1979). 
             Dapsone is bacteriostatic against Mycobacterium leprae. 
             It is also active against Plasmodium spp. In the mouse, 
             the minimum inhibitory concentration for M. leprae is 
             less than 10 mcg/l. In man, it has been estimated to be 
             up to 30 mcg/l. (Reynolds, 1989).
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     The toxic dose of dapsone is close to its 
                     therapeutic dose.  Severe poisonings have been 
                     observed after doses of 1 g in adults (Neuvonen 
                     et al., 1983). Recovery without sequelae has 
                     been reported in adults after ingestion of doses 
                     up to 15 g (Berlin et al., 1985).
             7.2.1.2 Children
                     The toxic dose of dapsone is close to its 
                     therapeutic dose.  Severe poisonings have been 
                     observed after doses of 100 mg in children 
                     (Reigart et al., 1982). Sturt (1967) reported a 
                     fatal poisoning in a 16-year-old boy who 
                     developed methaemoglobinaemia, jaundice, 
                     haematuria and coma after ingestion of 1.46 g.
       7.2.2 Relevant animal data
             Oral rat : LDLo: 1000 mg/kg
             Oral rat : TDLo: 20 mg/kg
             Oral mouse : LD50: 496 mg/kg  (NIOSH)
       7.2.3 Relevant in vitro data
             No data available.
     7.3 Carcinogenicity
       There are no case reports of carcinogenicity in humans. In 
       experimental animals dapsone has been shown to be carcinogenic 
       at doses much larger than those used therapeutically (Lang 
       1979).
     7.4 Teratogenicity
       No teratogenicity has been reported
     7.5 Mutagenicity
       No data available
     7.6 Interactions
       Probenecid increases serum dapsone levels by reducing the 
       renal elimination of dapsone and its metabolites (Goodwin and 
       Sparell 1969).

       
       Rifampicin lowers dapsone serum levels 7- to 10-fold by 
       accelerating plasma clearance.
       
       Folic acid antagonists such as pyrimethamine and primaquine 
       may increase the likelihood of haematologic reactions. 
     7.7 Main adverse effects
       The following adverse effects after therapeutic doses have 
       been reported: (Dukes 1976-1984, Drugdex 1990).
       
       Blood - agranulocytosis, haemolytic anaemia, 
       methaemoglobinaemia, pseudoleukaemia, aplastic anaemia, 
       mononucleosis with lymphadenopathy
       
       Nervous system -    psychosis, peripheral neuropathy
       
       Kidney - acute renal failure following intravascular 
       haemolysis, nephrotic syndrome, renal papillary necrosis
       
       Liver - hepatitis and jaundice with increased levels of 
       transaminases
       
       Skin - exfoliative dermatitis, toxic erythema, erythema 
       multiforme, urticaria, erythema nodosum
       
       Hypersensitivity reactions - leprotic reactions may occur in 
       leprosy if the low initial dose is increased too rapidly.
    8. TOXICOLOGICAL ANALYSES 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 Advanced Quantitative Method(s)
       8.2.2 Tests 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 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       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
             Symptoms may appear from a few minutes to 24 hours 
             following ingestion. Methaemoglobinaemia is the 
             principal feature of dapsone poisoning. Clinical 
             symptoms may include: headache, dizziness, agitation, 
             restlessness, nausea, vomiting, abdominal pain, bluish-
             grey cyanosis, tachycardia, hyperventilation, stupor, 
             convulsions, coma, jaundice, and intravascular 
             haemolysis.
       9.1.2 Inhalation
             No data available.
       9.1.3 Skin exposure
             No data available.
       9.1.4 Eye contact
             No data available.
       9.1.5 Parenteral exposure
             No data available.
       9.1.6 Other
             No data available.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Haemolytic anaemia and agranulocytosis may occur at the 
             relatively low doses used for leprosy and malaria, 
             whereas peripheral neuropathy and hepatitis are only 
             observed at the higher doses used in the treatment of 
             dermatitis herpetiformis (Scholer et al., 1984).  
             Deficiency in glucose-6-phosphate dehydrogenase, and 
             combination with primaquine are predisposing factors for 
             the occurrence of haemolytic anaemia, and concurrent 
             therapy with primaquine may be associated with 
             agranulocytosis (Chernof, 1967; Hutchinson et al., 
             1986).
       9.2.2 Inhalation
             No data available.
       9.2.3 Skin exposure
             No data available.
       9.2.4 Eye contact

             No data available.
       9.2.5 Parenteral exposure
             No data available.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       Methaemoglobinaemia may last for up to 10 days. Haemolysis is 
       usually delayed but it may persist for 14 days, returning to 
       normal within 3 to 4 weeks.
       
       With adequate treatment the prognosis is usually good, but a 
       death has been reported (Sturt 1967).
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Acute
             
             Tachycardia and hypotension may be observed and are 
             secondary to the hypoxaemia following 
             methaemoglobinaemia (Lambert et al., 1982; Berlin et al.,
              1985; Neuvonen et al., 1983).
             
             Chronic: No data available.
       9.4.2 Respiratory
             Acute
             
             Tachypnoea and hyperventilation may occur (Lambert et 
             al., 1982; Berlin et al., 1984).
             
             Cyanosis is due to methaemoglobinaemia
              
             Chronic: No data available.
       9.4.3 Neurological
             9.4.3.1 CNS
                     Headache, dizziness, restlessness, agitation and 
                     confusion are common in moderately severe acute 
                     poisonings.  In severe poisoning, uncoordinated 
                     movements, stupor, convulsions and coma have 
                     been reported (Schvartsman 1979;
                     Sturt 1967; Woodhouse et al., 1983).  Psychosis 
                     has been reported during therapeutic use (Lang 
                     1979).
             9.4.3.2 Peripheral nervous system
                     Sirsat et al (1987) reported three cases of 
                     motor neuropathy following acute ingestion.
                     
                     Peripheral motor neuropathy may develop in 
                     patients treated for several years at doses of 
                     300 mg/day or greater (Snavely and Hodges 1984). 
                     Slow acetylators are more likely to develop 
                     neuropathy.
             9.4.3.3 Autonomic nervous system
                     No data available
             9.4.3.4 Skeletal and smooth muscle
                     No data available
       9.4.4 Gastrointestinal
             Acute

             
             Nausea, vomiting and abdominal pain are usually the 
             first signs which appear.
             
             Chronic: No data available.
       9.4.5 Hepatic
             Acute
             
             Jaundice, elevated bilirubin and moderate increase of 
             transaminases have been reported (Berlin et al., 1984; 
             Sturt 1967).
             
             Chronic
             
             Jaundice and an increase of transaminases may occur 
             (Scholer 1984; Johnson et al., 1986).
       9.4.6 Urinary
             9.4.6.1 Renal
                     Acute: Haematuria has been reported (Sturt 
                     1967).
                     
                     Chronic
                     
                     Acute renal failure secondary to intravascular 
                     haemolysis has been reported after therapeutic 
                     doses in two patients (Chugh et al., 1977).  One 
                     case each of nephrotic syndrome (Hoffbrand 1978) 
                     and renal papillary necrosis have been reported 
                     (Belmont 1967).  
             9.4.6.2 Other
                     No data available.
       9.4.7 Endocrine and reproductive systems
             No data available
       9.4.8 Dermatological
             Acute
             
             Blue-grey cyanosis is due to methaemoglobinaemia
              
             Chronic
             
             Several dermatological reactions have been observed.  
             They were: exfoliative dermatitis, toxic erythema, 
             erythema multiforme, urticaria, and erythema nodosum.
       9.4.9 Eye, ear, nose, throat: local effects
             No data available.
       9.4.10 Haematological
              Acute
              
              Methaemoglobinaemia is the principal and consistent 
              feature of dapsone poisoning. Pronounced 
              methaemoglobinaemia exceeding 50 to 60% is associated 
              with serious clinical features (Schvartsman 1979); 
              haemolysis is usually severe in such cases. Cyanosis 
              and methaemoglobinaemia may persist for 8 to 10 days 
              following ingestion (Elonen et al., 1979; Lambert et 
              al., 1982; Neuvonen et al., 1983; Stanfield 1963).

              
              The following levels of methaemoglobin have been 
              reported:
              
              Authors             Dose ingested  Methaemoglobin (%)
                                      (g)
              
              Reigart et al., 1983      0.1                 27
              Lambert et al., 1983      3                   41.5
              Berlin et al., 1984      15                   48
              Neuvonen et al., 1983     7                   62
                                       10                   36
                                        1                   45
              Woodhouse et al., 1983    2.5                 22
              
              
              Methaemoglobin levels correlate well with symptoms in 
              most cases (Hall et al., 1986):
              
              15-20% clinical cyanosis, patient usually asymptomatic
              20-45% headache, lethargy, dizziness, syncope, dyspnoea
              45-55% increasing CNS depression
              55-70% coma, convulsions, shock
              > 70%  high mortality
              
              Haemolytic anaemia with Heinz bodies and  
              teticulocytosis is common in cases with severe 
              methaemoglobinaemia (Lambert et al., 1982; Berlin et 
              al., 1984; Neuvonen et al., 1983). Low haptoglobin and 
              elevated unconjugated bilirubin have been observed 
              (Lambert et al., 1982). Usually laboratory evidence 
              indicating haemolysis is apparent after 2 - 3 days and 
              reaches a maximum in 7 - 14 days after ingestion, the 
              evidence of haemolysis disappears within 3 - 4 weeks 
              (Neuvonen et al., 1983).
              
              Sulphaemoglobinaemia has been reported in a 22-year-old 
              man after an acute overdose with 3 g of dapsone. 
              Sulphaemoglobinaemia was maximal (9%) between days 4 
              and 8 (Lambert et al., 1982).
              
              Chronic
              
              Methaemoglobinaemia is also a frequent toxic side 
              effect during dapsone treatment and has been observed 
              in patients treated for malaria prophylaxis with 25 
              mg/day (Willerson et al., 1972). The incidence of 
              methaemoglobinaemia is even much higher when dapsone is 
              used in large doses in the treatment of leprosy or 
              dermatitis herpetiformis (Scholer et al., 1984).
              
              Haemolytic anaemia is dose related but may occur with 
              the relatively low doses used for leprosy and malaria 
              (Scholer et al., 1984).
              
              Agranulocytosis, neutropenia and thrombocytopenia have 

              also been reported (Leoung et al., 1986; Potter et al., 
              1989).
              
              Deficiency in glucose-6-phosphate dehydrogenase, and 
              combination with primaquine are predisposing factors 
              for the occurrence of haemolytic anaemia and concurrent 
              therapy with primaquine may cause agranulocytosis 
              (Chernof 1967; Hutchinson et al., 1986).
       9.4.11 Immunological
              Acute: No data available.
              
              Chronic
              
              Hypersensitivity reaction may be observed
              
              Sulfone syndrome : this is a hypersensitivity reaction 
              which includes fever, malaise, exfoliative dermatitis, 
              jaundice with liver necrosis, lymphadenopathy, 
              methaemoglobinaemia, and anaemia (Allday and Baines, 
              1951).
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       Acute
                       
                       Respiratory alkalosis or metabolic acidosis 
                       with impaired oxygenation has been reported 
                       (Berlin et al., 1984; Reigart et al., 1982).
              9.4.12.2 Fluid and electrolyte disturbances
                       No data available.
              9.4.12.3 Others
                       No data available.
       9.4.13 Allergic reactions
              Acute:  No data available.
              
              Chronic
              
              Hypersensitivity reactions may be observed. They 
              include: exfoliative dermatitis, toxic erythema, 
              erythema multiforme, urticaria, erythema nodosum.
       9.4.14 Other clinical effects
              No data available.
       9.4.15 Special risks
              Pregnancy:     Overdose of dapsone during pregnancy has 
              not been reported. The fetus may be at risk because of 
              the hypoxemia due to methaemoglobinaemia and 
              haemolysis.
               
              Breast feeding: Two cases of neonatal haemolytic 
              anaemia presumed to be due to dapsone in breast milk 
              have been reported (Zuidema et al., 1986).
              
              Enzyme deficiencies: Deficiency in glucose-6-phosphate 
              dehydrogenase is a predisposing factor for the 
              occurrence of haemolytic anaemia (Chernof, 1967).
     9.5 Other
       No data available.

     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Patients with acute dapsone poisoning should be admitted to 
         an intensive care unit.
         
         Monitor respiration, blood pressure and urine output.
         
         Treatment may include:
           
         Symptomatic measures, especially oxygen therapy
         Gastric lavage or emesis. Repeated oral activated charcoal
         Antidotes for methaemoglobinaemia: methylene blue
         
         Haemodialysis may be considered in severe cases.
         
         Given that dapsone toxicity is not only related to the 
         parent drug but also to its metabolites, aggressive therapy 
         in order to enhance elimination of dapsone and its 
         metabolites may be indicated when severe poisoning persists 
         despite adequate supportive, antidotal and charcoal therapy.
         
         Patients may require several days of observation.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                Collect blood and urine for analysis.
         10.2.2 Biomedical analysis
                The most relevant investigation in dapsone poisoning 
                is methaemoglobinaemia which correlates well with 
                symptoms.  The level of methaemoglobin should be 
                monitored.
                
                Other relevant laboratory analyses : blood count, 
                reticulocytes, haptoglobin, bilirubin, plasma 
                haemoglobin, sulphaemoglobin, transaminases, arterial 
                blood gases.
                 
                Urine analysis
         10.2.3 Toxicological analysis
                Dapsone plasma concentrations higher than 10 mg/l are 
                likely to be associated with features of 
                methaemoglobin-aemia. Therapeutic plasma levels are 1-
                3.5 mg/l. 
                     
                Monitoring of dapsone serum concentrations is not 
                necessary for treatment unless haemodialysis is 
                contemplated.
                               
                In acute poisoning, dapsone plasma concentrations of 
                10-150 mg/l have been reported (Berlin et al., 1985; 
                Elonen et al., 1979; Neuvonen et al., 1983; Woodhouse 
                et al., 1983).
                
                Table: plasma concentrations of dapsone following 
                acute overdose
                

                Authors               Age  Dose ingested  Dapsone 
                conc
                                            (year) (g)       (mg/ml)
                
                Berlin et al., 1984     2          15.0        80.0
                Neuvonen et al., 1983  27           7.0        28.0
                                       45          10.0        23.6
                                       21           1.0        17.5
                Endre et al., 1983                  4.0        22.3
                Elonen et al., 1979  child ?                  150.0
                                     child ?                   73.0
                Szajewski et al.,1979  18          10.0        12.0
                Linakis et al., 1989                3.5         3.9
                Woodhouse et al., 1983 57           2.5        18.8
         10.2.4 Other investigations
                No data available.
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         Monitor blood pressure, respiration and urine output.  
         Oxygen therapy is indicated if there are clinical signs of 
         methaemoglobinaemia. 
         
         Methylene blue is indicated when methaemoglobinaemia is 
         present. A dose of 1 to 2 mg/kg intravenously is 
         administered over a few minutes and may be repeated every 4 
         hours as needed. Because of the relapsing course of 
         methaemoglobinaemia due to the long half-life of dapsone, 
         repeated administration of methylene blue is sometimes 
         necessary (Berlin et al., 1984, Elonen et al., 1979, Lambert 
         et al., 1982). Berlin et al, (1984) recommended continuous 
         administration of methylene blue in order to avoid 
         overdosage. Monitoring of methaemoglobin is mandatory for 
         adjustment of the infusion rates: cyanosis is an unreliable 
         guide especially when anaemia is also present and methylene 
         blue may cause a bluish-grey discoloration of the skin 
         (Berlin et al., 1984). Methylene blue therapy should be 
         continued until the methaemoglobin level is below 10%.
         
         Supportive measures include treatment of respiratory failure,
          shock, acid-base disturbances, and convulsions.
      10.4 Decontamination
         Gastric lavage is indicated in recent ingestion, up to 6 
         hours.
         
         Repeated doses (20 g 4 times a day) of oral activated 
         charcoal are indicated because it enhances the total body 
         clearance and elimination of dapsone and its principal 
         metabolite, monoacetyldapsone. In patients receiving 
         therapeutic dosages of dapsone, the mean serum half-life was 
         decreased from 20.5 to 10.8 hours by charcoal (Neuvonen et 
         al., 1983). In three intoxicated patients, activated 
         charcoal decreased the mean dapsone and monoacetyldapsone 
         half-lives from 77 to 12.7 hours and from 51 to 13.3 hours,  
         respectively (Neuvonen et al., 1983). In these patients 
         charcoal did not prevent the primary absorption of dapsone, 
         but increased the elimination rates of dapsone and 

         monoacetyldapsone by adsorbing drugs secreted into the 
         gastrointestinal tract.
      10.5 Elimination
         Forced diuresis 
         
         No data indicating the benefit of forced diuresis are 
         available. However, in one case of poisoning with 15 g of 
         dapsone, 20% of the amount ingested was excreted in urine 
         (Berlin et al., 1984).
         
         Haemodialysis 
         
         Haemodialysis removes dapsone from the body. In one patient 
         who had ingested 7 g dapsone, haemodialysis decreased the 
         half-life of dapsone from 109 to 10.4 hours and the half-
         life of monoacetyldapsone from 50 to 10.9 hours (Neuvonen et 
         al., 1983). Szajewski et al, (1972) reported  a case of 
         severe dapsone poisoning in which haemodialysis was 
         successful with rapid correction of methaemoglobinaemia. In 
         these 2 patients a subsequent rebound of plasma dapsone 
         concentrations was observed.
         
         Haemoperfusion
         
         Endre et al (1983) reported a case of successful treatment 
         using charcoal haemoperfusion.
              
         Plasma exchange  
         
         Berlin et al (1984) treated a patient with plasma exchange. 
         Five plasma exchanges were performed on days 3 to 7 with a 
         total of 15.5 l. plasma exchanged. Only 2% of the amount 
         ingested was removed by plasma exchange. 
         
         Exchange transfusion
         
         Exchange transfusion has also been suggested (Schvartsman 
         1979; Stanfield 1963). Because of the low volume which can 
         be exchanged, this therapy is ineffective for drug removal. 
         However, it may be indicated when severe intravascular 
         haemolysis is associated with methaemoglobinaemia (Jaeger et 
         al., 1987).
      10.6 Antidote treatment
         10.6.1 Adults
                There is no specific antidote.
         10.6.2 Children
                There is no specific antidote.
      10.7 Management discussion
         Given that dapsone toxicity is not only related to the 
         parent drug but also to its metabolites, aggressive therapy 
         in order to enhance the elimination of dapsone and its 
         metabolites may be indicated when severe poisoning persists 
         despite adequate supportive, antidotal and charcoal therapy.
         
         After a bolus dose of methylene blue (1 to 2 mg/kg), a 
         continuous infusion at an initial rate of 0.1 to 0.5 mg/kg 

         has been recommended. The dose of methylene blue should be 
         titrated against the concentration of methaemoglobin (Dawson 
         and White, 1989)
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         Lambert et al (1979) reported a case of acute poisoning in a 
         22 year-old man who had ingested 3 g dapsone and developed 
         headache, dizziness, nausea, bluish-grey cyanosis and 
         methaemoglobinaemia (41.5%). Methaemoglobinaemia improved 
         with methylene blue. Subsequently, significant 
         sulphaemoglobinaemia (9% from day 4 to day 8) caused 
         prolonged cyanosis and mild haemolytic anaemia.
         
         An 18 month-old child developed methaemoglobinaemia (27%) 
         after ingestion of 100 mg dapsone. Activated charcoal was 
         administered orally (10 g every 6 hours). Treatment included 
         1 mg/kg methylene blue; the methaemoglobin level was 2.3%, 
         66 hours after ingestion (Reigart et al., 1982).
         
         A 57 year-old man was admitted 20 hours after ingestion of 
         2.5 g dapsone. Examination showed cyanosis with a 
         methaemoglobinaemia of 22% and an anaemia of 11.5 g/l 
         haemoglobin. The methaemoglobin level fell to 1% over 7 days 
         without specific treatment. The kinetics of dapsone and 
         monoacetyldapsone showed half-lives of 29.7 and 29.9 hours 
         respectively (Woodhouse et al., 1983).
         
         Neuvonen et al (1983) reported 3 cases of dapsone poisoning 
         in adults with doses of 7, 10 and 1 g, respectively, and 
         methaemoglobin concentrations of 36 - 62%. The elimination 
         half-lives were 109, 88 and 33 hours (mean 77) for dapsone 
         and 50, 70, and 33.8 hours (mean 51) for monoacetyldapsone. 
         With activated charcoal treatment, the plasma half-life was 
         12.7 hours for dapsone and 13.3 hours for monoacetyldapsone. 
         One patient underwent haemodialysis three times. During 
         haemodialysis, plasma half-lives of dapsone and 
         monoacetyldapsone decreased from 109 to 10.4 hours and from 
         50 to 10.9 hours, respectively.
         
         Berlin et al (1984) described a 28-year-old man who ingested 
         15 g dapsone and developed a methaemoglobin level of 50%. 
         The dapsone concentration rose to a peak of 80 mg/l on the 
         second day and then decreased with a half-life of 24 hours. 
         The patient was treated with activated charcoal, forced 
         diuresis and plasma exchange (5 exchanges on days 3 to 7 
         with a total of 15.5 l plasma exchanged. Of the amount 
         ingested, 25% was recovered in urine and only 2% was removed 
         by plasma exchange.
      11.2 Internally extracted data on cases
         To be added by the centre.
      11.3 Internal cases
         To be added by the centre.
    12. Additional information
      12.1 Availability of antidotes
         No antidote is available.
      12.2 Specific preventive measures

         No data available.
      12.3 Other
         No data available.
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    Zuidema J, Hilbers-Modderman ESM and Merkus FWHM (1986). Clinical 
    pharmacokinetics of dapsone. Clinical Pharmacokinetics 11:299-315.
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)
    Author:   J. Higa de Landoni
              Jefa Seccion Toxicologia
              Hospital de Clinicas "Jose de San Martin"
              Facultad de Medicina
              Universidad de Buenos Aires
              Cordoba 2351
              Buenos Aires
              Argentina
    
    Tel: 54-1-9621280
    Fax: 54-1-3318605
    
    Reviewed and rewritten: 
    
              Drs A. Jaeger, P. Sauder, J. Kopferschmitt, F. Flesch
              Service de Reanimation Medicale 
                et Centre Anti-poisons
              Hospice Civil de Strasbourg
              Pavillon Pasteur
              1 place de l'Hopital
              67091 Strasbourg Cedex
              France
    
    Tel: 33 88161144
    Fax: 33 88161330
    
    Date:          January 1991
    
    Peer Review: Newcastle-upon-Tyne, United Kingdom, January 1991
    
    Review:   IPCS, May 1993




See Also:
        Dapsone (IARC Summary & Evaluation, Supplement 7, 1987)
        Dapsone (IARC Summary & Evaluation, Volume 24, 1980)