Agranulocytosis dapsone

Maloprim, the fixed dose combination of pyrimethamine with dapsone, is not recommended for routine prophylaxis because of the potential for fatal agranulocytosis. 

Although dapsone (Avlosulfon) was once used in the treatment and prophylaxis of chloroquine-resistant P. falciparum malaria, the toxicities associated with its administration (e.g., agranulocytosis, methemoglobinemia, hemolytic anemia) have severely reduced its use. 

Dapsone is oxidized by CYP2E1 with high affinity both in vitro and in vivo, and also by CYP3A4 (Scheme 11.20). The major side effects of dapsone (methemoglobinemia, agranulocytosis) are linked to its N-oxidation (25, 26). 

In France, dapsone is available in combination with ferrous oxalate as Disulone (Aventis), and in 1983-98, 249 adverse reactions were reported to French pharma-covigilance centers, mainly blood dyscrasias (often neutropenia and agranulocytosis, rarely hemolysis and anemia) (11). Five patients died three of them had septicemia secondary to agranulocytosis. There were 29 cases of dapsone syndrome, 39 skin reactions, 27 cases of hver damage, and 27 cases of neurological and psychiatric adverse effects. Patients taking dapsone need to be under close medical supervision for early recognition of adverse reactions. 

The combination of pyrimethamine plus dapsone causes a higher incidence of blood dyscrasias than pyrimethamine alone in particular, the occurrence of agranulocytosis increases and even deaths have been reported (SEDA-13, 812) (SEDA-18, 287). 

Sulfonamides or sulfones usually account for most toxicity associated with coadministration of these antifolate drugs (see Chapter 43). The combination of pyrimethamine (25 mg) and sulfa-doxine (500 mg) (fansidar) causes severe and even fatal cutaneous reactions in up to 1 in 5000 people. This combination also has been associated with serum sickness-type reactions, urticaria, exfoliative dermatitis, and hepatitis. Pyrimethamine-sulfadoxine is contraindicated in individuals with previous reactions to sulfonamides, lactating mothers, and infants <2 months of age. Administration of pyrimethamine with dapsone (MALOPRIM, unavailable in the U.S.), occasionally has been associated with agranulocytosis. Higher doses pyrimethamine (75 mg daily) used along... 

The most common hematological adverse effects of dapsone are hemolytic anemia and methemoglobinemia. Agranulocytosis [45, 46 ] can also occur, as can rarely sulfhemo-globinemia [47", 48 ], aplastic anemia [49 ], and pure red cell aplasia [5(1 ]. 

Agranulocytosis due to dapsone occurs particularly in the first 3 months of therapy, and the risk is increased in patients with dermatitis herpetiformis [52 ]. The mechanism is not known, but it has been proposed that selective preservation of basophils, as found in a patient with severe dapsone-induced agranulocytosis, could be relevant [53 ]. 

Ranawaka RR, Mendis S, Weerakoon HS. Dapsone-induced haemolytic anaemia, hepatitis and agranulocytosis in a leprosy patient with normal glucose-6-phosphate-dehydrogenase activity. Lepr Rev 2008 79 (4) 436 0. 

Coleman MD. Dapsone-mediated agranulocytosis risks, possible mechanisms and prevention. Toxicology 2001 162(1) 53-60. 

Besser M, Vera J, Clark J, Chitnavis D, Beatty C, Vassiliou G. Preservation of basophils in dapsone-induced agranulocytosis suggests a possible pathogenetic role tor leukocyte peroxidases. Int J Lab Hematol 2009 31(2) 245-7. 

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