Registration Dossier

Toxicological information

Direct observations: clinical cases, poisoning incidents and other

Administrative data

direct observations: clinical cases, poisoning incidents and other
Adequacy of study:
other information

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: hematological side-effects

Test material


Results and discussion

Applicant's summary and conclusion

Executive summary:

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 methemoglobinemia of 15%, which is not clinically significant The hemotoxicity of dapsone is not caused by the drug itself, but by its hydroxylamine metabolites. 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.