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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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