What is the relationship between methemoglobinemia and Dapsone (diaminodiphenylsulfone)?

From the Guidelines

Dapsone is a well-known cause of methemoglobinemia, and patients taking this medication should be closely monitored for signs and symptoms of this condition. Methemoglobinemia occurs when dapsone or its metabolites oxidize the iron in hemoglobin from the ferrous (Fe2+) to the ferric (Fe3+) state, creating methemoglobin which cannot effectively carry oxygen 1. This reaction typically develops within the first few days to weeks of dapsone therapy and is dose-dependent, with higher doses carrying greater risk. Some key points to consider when prescribing dapsone include:

• Patients may present with cyanosis, headache, fatigue, dizziness, and shortness of breath when methemoglobin levels exceed 10-15% 1
• Severe cases can cause altered mental status, metabolic acidosis, cardiac arrhythmias, seizures, and even death
• Certain individuals are more susceptible, including those with G6PD deficiency, anemia, or taking other oxidizing medications
• Management includes discontinuing dapsone, providing oxygen, and administering methylene blue for symptomatic patients or those with levels above 20% Key substances and factors that may increase methemoglobin levels include:
• Drugs such as phenacetin, phenazopyridine, dapsone, chloroquine, primaquine, trimethoprim, sulfonamides, and rasburicase 1
• Foods and drinks that contain nitrates or other oxidizing agents
• Clinical conditions such as infections, which can increase methemoglobin levels 1

From the FDA Drug Label

ADVERSE REACTIONS In addition to the warnings listed above, the following syndromes and serious reactions have been reported in patients on Dapsone. Hematologic Effects: Dose-related hemolysis is the most common adverse effect and is seen in patients with or without G6PD deficiency Almost all patients demonstrate the inter-related changes of a loss of 1-2g of hemoglobin, an increase in the reticulocytes (2-12%), a shortened red cell life span and a rise in methemoglobin. PRECAUTIONS General: Hemolysis and Heinz body formation may be exaggerated in individuals with a glucose-6-phosphate dehydrogenase (G6PD) deficiency, or methemoglobin reductase deficiency, or hemoglobin M.

The relationship between methemoglobinemia and Dapsone (diaminodiphenylsulfone) is that Dapsone can cause a rise in methemoglobin. This is a dose-related effect and is more pronounced in patients with G6PD deficiency or methemoglobin reductase deficiency. Key points include:

• Methemoglobinemia is a known adverse effect of Dapsone therapy
• G6PD deficient patients are at higher risk of developing methemoglobinemia
• Dose-related hemolysis is the most common adverse effect of Dapsone, and is associated with a rise in methemoglobin 2, 2

From the Research

Relationship between Methemoglobinemia and Dapsone

• Methemoglobinemia is a known adverse effect associated with dapsone use, as reported in several studies 3, 4, 5, 6, 7.
• The majority of publications describing methemoglobinemia associated with dapsone use reported this adverse effect at therapeutic doses, with symptoms ranging from cyanosis to dyspnea 3.
• Comorbid conditions, such as anemia or pneumonia, may contribute to the onset of symptomatic methemoglobinemia in patients taking dapsone 3, 5.
• Management of dapsone-induced methemoglobinemia typically consists of administration of methylene blue, with most reports describing a successful outcome and no mortality resulting from methemoglobinemia associated with therapeutic use 3, 4, 6, 7.
• However, some cases of refractory methemoglobinemia have been reported, requiring additional doses of methylene blue and other treatments 6.
• The clinical course of dapsone-induced methemoglobinemia can be worse than that of other toxic-agent-induced methemoglobinemia, despite no significant difference in initial clinical presentation 4.
• Clinicians should be aware of the adverse effects associated with dapsone therapy and evaluate patients with dyspnea and hypoxemia of unclear etiology for methemoglobinemia 3, 4, 5, 6, 7.

Factors Influencing Methemoglobinemia

• Comorbid conditions, such as anemia or pneumonia, may exacerbate methemoglobinemia in patients taking dapsone 3, 5.
• The presence of underlying risk factors, such as G6PD deficiency, may increase the risk of methemoglobinemia in patients taking dapsone, although this is not always the case 6.
• The dose and duration of dapsone therapy may also influence the risk of methemoglobinemia, with higher doses and longer durations of therapy potentially increasing the risk 3, 4, 7.

Treatment and Management

• Methylene blue is the primary treatment for dapsone-induced methemoglobinemia, with most reports describing a successful outcome with this treatment 3, 4, 6, 7.
• Additional treatments, such as ascorbic acid and cimetidine, may be necessary in some cases of refractory methemoglobinemia 6.
• Continuous monitoring of serum methemoglobin levels is necessary for patients with dapsone-induced methemoglobinemia, as the condition can be unpredictable and require ongoing treatment 4, 6.