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Health surveillance data

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Administrative data

health surveillance data
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The publication is a comprehensive review of dermal health effects of dapsone published before 2003 and includes > 300 reports from peer reviewed journals.

Data source

Reference Type:
Ronni Wolf, Hagit Matz, Edith Orion, Binnur Tuzun, Yalcin Tuzun
Bibliographic source:
Dermatololgy Online Journal 8(1): 2

Materials and methods

Endpoint addressed:
other: side-effects of dapsone therapy in humans
Principles of method if other than guideline:
Literature Review on side-effects of dapsone therapy in humans

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:

Results and discussion

Applicant's summary and conclusion

The risk of dapsone therapy is acceptable. The main side-effects during therapy with 100 mg/day is methemoglobinemia.
Executive summary:

Dapsone therapy may cause a variety of adverse effects, which may be categorized as pharmacologic, dose-dependent, and allergic, or idiosyncratic reactions.

The most frequent and well-documented pharmacologic reactions are the hematological side-effects, such as methemoglobinemia, hemolysis and anemia.

Effective clinical use of dapsone is limited because of dose-dependent adverse hematological reactions, even at the low daily dosages of 100 mg used in the chemotherapy of leprosy and dermatological conditions. Patients with a genetic deficiency of certain enzymes (i.e., glucose-6-phosphate dehydrogenase or glutathione reductase) are more susceptible to the hematological effects.

Long-term administration of dapsone at standard doses (100 mg/d) in normal patients usually results in methemogloginemia of 15%, which is not clinically significant The hemotoxicity of dapsone is not caused by the drug itself, but by its hydroxylamine metabolites. The formation of hydroxylamine is catalyzed either by hepatic enzymes such as cytochrome P450, flavin monooxygenase and others, or by myeloperoxidase found in peripheral polymorphonuclear leukocytes. Dapsone hydroxylamine reacts with oxyhemoglobin (Fe2+) to form methemoglobin (Fe3+) and nitrosoarene, which, in turn, is reduced to hydroxylamine by either NADPH methemoglobin reductase or glutathione. The hydroxylamine then reacts with another molecule of oxyhemoglobin, thus continuing the redox cycle. Each hydroxylamine molecule is capable of oxidizing up to five oxyhemoglobin molecules, and the cycle only ceases when the erythrocyte is almost totally depleted of glutathione. Methemoglobinemia occurs to some extent in all patients receiving dapsone and becomes less pronounced as treatment is continued due to an adaptive increase in the activity of NADH-dependent reductase in the erythrocytes. Methemoglobin levels of under 20% are not usually associated with symptoms. Dyspnea, nausea and tachycardia usually occur at levels of 30% or above, while lethargy, stupor and deteriorating consciousness occur as methemoglobin levels approach 55%. Levels of 70% are usually fatal.

Agranulocytosis is another hematologic adverse effect of dapsone. Unlike methemoglobinemia, this severe adverse effect is due to an unpredictable idiosyncratic reaction. For unknown reasons, the risk of agranulocytosis in patients with dermatitis herpetiformis is more than 25-fold compared with other patients. Agranulocytosis was estimated to develop in 1 of 240 - 425 patients with dermatitis herpetiformis receiving dapsone therapy, whereas this side effect in patients with leprosy is almost unknown.Factors such as drug dosage, immune status, degree of malnutrition, and ethnic origin are probably important determinants of the risk of developing agranulocytosis.

Another serious idiosyncratic adverse effect is the dapsone hypersensitivity syndrome. Drug hypersensitivity syndrome is a severe idiosyncratic reaction to a drug defined by the clinical triad of fever, rash, and internal organ involvement (most commonly the liver and the hematologic system). It occurs in a relatively small proportion of patients but is associated with considerable morbidity and mortality. The unpredictability and potential severity of this reaction make it a major concern in clinical practice and drug development.

Although this reaction to dapsone is rare considering the widespread use of the drug (particularly in patients receiving multidrug therapy for leprosy), it ranks high among drugs that cause this syndrome. Dapsone-induced hypersensitivity syndrome usually appears four or more weeks after initiation of therapy. Symptoms include a mononucleosis-like rash with fever and lymphadenopathy. Involvement of other organs varies and includes the liver (hepatomegaly, icterus, hepatitis and hepatic encephalopathy), lymphadenopathy, eosinophilia, and others. The course of the disease is also variable, but it may last four weeks or more and fatalities have been reported. Exanthematous skin eruptions usually resolve within two weeks of stopping dapsone, although patients in whom Stevens-Johnson syndrome or toxic epidermal necrolysis develops have increased morbidity and mortality.

There is a low and insignificant risk of congenital malformations in patients receiving dapsone during prengnancy. In lactating mothers, since dapsone diffuses into breast milk and there are reports of hemolytic anemia induced by this drug transmitted through breast milk, we recommend that if dapsone is required, breast feeding should be discontinued.As for treatment of pregnant patients, it is now generally considered that the benefits of dapsone in the treatment of leprosy and other infectious and non-infectious diseases outweigh any potential risk.