Dapsone and analogues - Clinical Tree

General information

Dapsone is 4,4-diaminodiphenylsulfone (DDS, avlosulfone, disulfone) [ ]. It is a bacteriostatic antileprosy drug with a sulfonamide-like structure. The dosage should be 50–100 mg/day in adults [ ]. In children aged 3–5 years, the dosage should be reduced according to weight to, for example, 25 mg/day [ ].

Studies of patients with borderline leprosy have suggested that dapsone has mild immunosuppressive effects [ ]. Thus, it has been given with some success to patients with dermatitis herpetiformis, subcorneal pustular dermatosis, bullous dermatoses, relapsing polychondritis, thrombocytopenic purpura [ ], giant cell arteritis [ ], rheumatoid arthritis, and systemic lupus erythematosus [ ].

Dapsone is an alternative drug for Pneumocystis jirovecii pneumonia prophylaxis in individuals who cannot tolerate co-trimoxazole, and although this has become less of a problem since the advent of highly active antiretroviral drug therapy in countries able to afford these regimens, further data on the toxicity of dapsone in children are welcome. In a multicenter study from the USA daily and weekly dapsone regimens have been compared in 94 HIV-infected children, monitoring hematological and liver toxicity and the incidence of skin rashes, P. jirovecii pneumonia, or death [ ]. They concluded that the weekly regimen produced less hematological toxicity, but that this advantage was offset by a trend toward higher breakthrough rates of P. jirovecii pneumonia.

Dapsone analogues

The sulfone acedapsone (rINN) (4,4′-diacetyldiaminodiphenylsulfone, DADDS) is the diacetyl derivative of dapsone with a long half-life [ ]. However, its plasma concentrations are much lower than those of dapsone and it could enhance the emergence of resistant strains of Mycobacterium leprae . Its adverse effects are similar to those of dapsone, which it can replace if gastrointestinal symptoms become severe. It is available in an enteric-coated formulation, given in a dosage of 330 mg/day.

General adverse effects and adverse reactions

Adverse reactions to dapsone have been comprehensively reviewed [ ]. The most common untoward adverse effect is hemolysis of varying degree; it is usually mild, except in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Methemoglobinemia and Heinz body formation also occur and methemoglobinemia can be a problem at doses over 200 mg/day. Agranulocytosis is rare but potentially fatal. Mild gastrointestinal complaints and neurological effects of dapsone are not uncommon. Under 0.5% of the patients taking prolonged dapsone therapy develop the dapsone syndrome [ ]. Other rare adverse reactions include peripheral neuropathy, psychosis, hepatitis, nephritic syndrome, and renal papillary necrosis. Hypoalbuminemia has been seen after prolonged dapsone therapy of dermatitis herpetiformis [ ]. Erythema nodosum leprosum may be due to an immune complex mechanism; the antigen is provided by the bacteria and their degeneration products, possibly as a kind of Jarisch–Herxheimer reaction [ ]. Anaphylactic shock and tachycardia are rare. Rashes, serious cutaneous reactions, and erythema nodosum may have an immunological basis. Tumor-inducing effects have not been reported.

In France, dapsone is available in combination with ferrous oxalate as Disulone (Aventis), and in 1983–98, 249 adverse reactions were reported to French pharmacovigilance centers, mainly blood dyscrasias (often neutropenia and agranulocytosis, rarely hemolysis and anemia) [ ]. Five patients died; three of them had septicemia secondary to agranulocytosis. There were 29 cases of dapsone syndrome, 39 skin reactions, 27 cases of liver 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.

Organs and systems

Cardiovascular

Signs of heart failure with edema, ascites, and severe hypoalbuminemia have been described in the treatment of dermatitis herpetiformis with dapsone [ ].

Respiratory

Two cases of pulmonary eosinophilia attributed to dapsone were reported in 1998. Four cases had previously been reported, in which the fixed combination of dapsone and pyrimethamine (a malaria prophylactic) had been implicated, but only one previous report had implicated dapsone alone.

A French woman with chronic urticaria [ ] and an Indian man with lepromatous leprosy [ ] developed fever, wheezing, and breathlessness. Both had peripheral eosinophilia and chest X-rays showed infiltrates. The woman’s symptoms began 2 weeks after she started to take dapsone but recurred a few hours after a subsequent rechallenge. The man’s symptoms occurred a few hours after each daily dose. Symptoms in both cases resolved within a few days of stopping dapsone.

Nervous system

Dapsone-induced neuropathy is not common [ ], in spite of its widespread use in a variety of unrelated disorders. It has not been reported in patients with leprosy, but it would be easy to miss, since worsening neuropathy would readily be attributed to the underlying disease. Neuropathy has not been reported in patients with leprosy taking the usually recommended dosage of 100 mg/day. Isolated cases of dapsone-induced peripheral neuropathy, including motor and minor sensory defects, have been published [ , ]. The clinical characteristics include a motor neuropathy affecting the extremities with onset within 5 years after the start of dapsone therapy in doses of over 300 mg/day. Complete recovery from the neuropathy almost always occurs after the dose is reduced or the drug is withdrawn.

Infection with M. leprae affects the peripheral nerves and the dermis, causing an accumulation of macrophages and other immune cells at the infected site [ ].

Sensory systems

Ocular toxicity is rare with dapsone. Reduced visual acuity has been described after overdosage [ ].

Psychiatric

Dapsone-induced psychosis has rarely been reported [ ].

Hematologic

Hemolysis

The most common adverse effect of dapsone therapy is hemolysis [ ]. In varying degrees, it develops in nearly all patients who take dapsone in dosages of 200–300 mg/day. Even with the usual dose of 100 mg/day in normal persons and 50 mg/day in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, there can be some degree of hemolysis [ , ]. Red cell survival can be reduced by dapsone, depending on the dose of the sulfone and its oxidizing activity, but hemolytic anemia generally does not occur without a pre-existing disorder of the erythrocytes or bone marrow. The hemolysis can be so severe that manifestations of hypoxia become striking [ ].

The medical records of 12 patients with ocular cicatricial disease, of whom 11, mean age 72 (range 55–89) years, were treated with dapsone 50 mg bd as first line therapy for 19 (range 1–60) months, were reviewed [ ]. Six had reticulocytosis, including four with clinically significant hemolytic anemia. These patients were not checked for G6PD deficiency.

Mild hemolytic anemia occurred in a breast-fed infant and his mother, who had continuously been taking 100–150 mg/day; dapsone and its metabolite, monoacetyldapsone, were identified in the infant’s serum [ ].

Methemoglobinemia and sulfhemoglobinemia

Dapsone is an oxidant and can trigger methemoglobinemia and delayed sulfhemoglobinemia [ ]. Methemoglobinemia remains subclinical in most cases. However, it can be accurately inferred by a discrepancy between the oxygen saturation measured by pulse oximetry and the concentration of oxygen in the arterial blood [ ]. Methemoglobinemia at concentrations over 10% produces a visible lavender-colored cyanosis, and concentrations over 35% result in weakness and shortness of breath. Methemoglobinemia can be minimized by the administration of an antioxidant, such as vitamin C or vitamin E [ ]. Methemoglobinemia disappears after withdrawal of dapsone [ ].

A patient who had been taking dapsone inappropriately instead of an antispasmodic that had been prescribed for a spinal condition, because of incorrect labeling in a pharmacy, developed methemoglobinemia [ ]. Methylene blue was given intravenously and may have contributed to the severe hemolysis that followed.
An immunocompromised child with chronic immune thrombocytopenic purpura developed a fever, cough, perioral cyanosis, bilateral lower lobe coarse crackles, and a low O ₂ saturation by pulse oximetry (89%). His medications included prednisone and rituximab for chronic immune thrombocytopenic purpura, and dapsone for Pneumocystis jirovecii pneumonia prophylaxis. The methemoglobin concentration was 9.6%.

The frequency of methemoglobinemia and reduced cytochrome b5 reductase (Cb5r) activity have been studied in 15 children with acute lymphoblastic leukemia taking dapsone prophylaxis for Pneumocystis jirovecii and 10 taking co-trimoxazole [ ]. At a mean of 6.6 weeks, three children taking dapsone developed symptomatic methemoglobinemia, defined as increased concentrations of methemoglobin in association with hypoxemia (oxygen saturation <95%). The other 12 were all asymptomatic. All the controls had normal methemoglobin concentrations. Cb5 reductase activities in two of the three symptomatic children were below 50% of normal, suggesting heterozygosity, which was confirmed by assessment of their parent’s Cb5 reductase activities. Heterozygosity for Cb5 reductase deficiency can predispose to methemoglobinemia, and such patients tend to be symptomatic at low methemoglobin concentrations. Heterozygotes should therefore be monitored closely for the possibility of methemoglobinemia.

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