Dapsone is an antibiotic used for treatment of and prophylaxis against various infections, including leprosy, malaria, and Pneumocystis pneumonia. The anti-inflammatory and immune-suppressant effects of dapsone make it valuable for the treatment of some rheumatologic and rare dermatologic disorders. Topical formulations of 5 and 7.5% are used for treatment of acne vulgaris.

Oxidation of dapsone by cytochrome P450 (CYP) produces toxic metabolites, which can lead to methemoglobinemia, sulfhemoglobinemia, and Heinz body hemolytic anemia, thereby decreasing the oxygen-carrying capacity of the blood.

1. Methemoglobinemia occurs when dapsone metabolites oxidize the ferrous (Fe²⁺) iron-hemoglobin complex to the ferric (Fe³⁺) state.
2. Sulfhemoglobinemia occurs when dapsone metabolites irreversibly sulfate the pyrrole hemoglobin ring.
3. Delayed hemolysis secondary to erythrocyte oxidative stress may be preceded by the appearance of Heinz body precipitates on the blood smear.
4. Pharmacokinetics. Absorption of dapsone after overdose is delayed; peak plasma levels occur between 4 and 8 hours after ingestion. Bioavailability ranges from 84% to 100%. The volume of distribution is 1.5 L/kg, and protein binding is 70-90%. Dapsone is metabolized by two primary routes: acetylation and CYP oxidation. Both dapsone and its acetylated metabolite undergo enterohepatic recirculation and oxidation. Currently, the isoenzymes thought to be primarily responsible for oxidation are CYP2C19 >> CYP2B6 > CYP2D6 > CYP3A4. The average elimination half-life is dose-dependent and variable: 10-50 hours with therapeutic doses and potentially more than 77 hours after an overdose. Dapsone concentrations persist in the liver and kidneys for up to 3 weeks after discontinuation of treatment.

Although the adult therapeutic dose ranges from 50 to 300 mg/d, dosing is limited by toxic effects. Chronic daily 100 mg dosing is associated with methemoglobin levels of 5-12%. Misuse of topical dapsone has caused clinically significant methemoglobinemia. Hemolysis has not been reported in adults with doses of less than 300 mg/d. Persons with glucose-6-phosphate dehydrogenase (G6PD) deficiency, congenital hemoglobin abnormalities, or underlying hypoxemia may experience greater toxicity at lower doses. Death has occurred after overdoses of 1.4 g and greater, although recovery from severe toxicity has been reported after ingestion of 7.5 g.

Manifestations of acute dapsone intoxication include vomiting, cyanosis, tachypnea, tachycardia, hypotension, altered or depressed mental status, and seizures. Methemoglobinemia and sulfhemoglobinemia usually are observed within a few hours of the overdose, but intravascular hemolysis is delayed. Dapsone poisoning usually lasts several days. Clinical manifestations are more severe in patients with underlying medical conditions that may contribute to hypoxemia.

1. Methemoglobinemia causes cyanosis and dyspnea. Blood may appear “chocolate” brown with methemoglobin levels greater than 15-20%. Because of the long half-life of dapsone and its metabolites, methemoglobinemia can persist for several days, requiring repeated antidotal treatment.
2. Sulfhemoglobinemia also decreases oxyhemoglobin saturation and is unresponsive to methylene blue. Sulfhemoglobinemia can produce a cyanotic appearance at a lower percentage of total hemoglobin compared with methemoglobin. The amount of sulfhemoglobin generated is rarely more than 5%.
3. Hemolysis may be delayed in onset, usually 2-3 days after acute overdose.
4. Chronic toxicity. Therapeutic doses may affect vision, peripheral motor neuronal, renal and hepatic functions. Dapsone hypersensitivity syndrome (fever, rash, and hepatitis) occurs in about 2% patients within 6 weeks of starting treatment. It is associated with HLA-B*13:01/15:02 and has a reported mortality rate of 11%.

Overdose should be suspected in cyanotic patients with elevated methemoglobin levels, especially if there is a history of dapsone use or a diagnosis that is likely to be treated with dapsone. Although there are many agents that can cause methemoglobinemia, there are very few that produce both detectable sulfhemoglobin and a prolonged, recurrent methemoglobinemia.

1. Specific levels. Dapsone levels are not routinely available. When plasma samples are analyzed by HPLC or LC-MS/MS (liquid chromatography—tandem mass spectrometry), both dapsone and monoacetyl dapsone can be measured.
   1. Methemoglobinemia is suspected when a cyanotic patient fails to respond to high-flow oxygen or cyanosis persists despite a normal arterial PO₂. Conventional two-wavelength pulse oximetry is not a reliable indicator of oxygen saturation in patients with methemoglobinemia. Specific methemoglobin concentrations can be measured by using a multiwave co-oximeter. Qualitatively, a drop of blood on white filter paper will appear brown (when directly compared with normal blood) if the methemoglobin level is greater than 15-20%.
   2. Note: Administration of the antidote methylene blue (see Item V.B.1 below) can cause transient false elevation of the measured methemoglobin level (up to 15%).
   3. Sulfhemoglobin is difficult to detect, in part because its spectrophotometric absorbance is similar to that of methemoglobin on the co-oximeter. A blood sample will turn red if a crystal of potassium cyanide is added but will not if significant sulfhemoglobin is present.
   4. The oxygen-carrying capacity of the blood is dependent not only on oxygen saturation but also on total hemoglobin concentration. Interpret methemoglobin and sulfhemoglobin levels in conjunction with the degree of anemia.
2. Other useful laboratory studies include CBC (with differential smear to look for reticulocytes and Heinz bodies), glucose, electrolytes, liver aminotransferases, bilirubin, renal function (BUN, creatinine), and venous or arterial blood gases. Consider testing for G6PD deficiency.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if needed. Administer supplemental oxygen.
   2. If hemolysis occurs, administer IV fluids, as for rhabdomyolysis, to mitigate risk for acute renal tubular necrosis. For severe hemolysis, blood transfusions may be required.
   3. Mild symptoms may resolve without intervention, but may take 2-3 days.
2. Specific drugs and antidotes
   1. Methylene blue is indicated in a symptomatic patient with a methemoglobin level greater than 20% or with lower levels if even minimal compromise of oxygen-carrying capacity is potentially harmful (eg, severe pneumonia, anemia, or myocardial ischemia). Intermittent administration of methylene blue every 6-8 hours as needed during prolonged dapsone poisoning can produce wide swings in methemoglobin levels over the course of treatment, aggravating erythrocyte oxidative stress and worsening hemolysis. Maintenance infusions have been reported to provide better and more even methemoglobin control.
      1. Loading dose: Give methylene blue, 1-2 mg/kg (0.1-0.2 mL/kg of 1% solution) IV over 5 minutes and repeat as necessary in 30-60 minutes with the goal of improved cyanosis and a methemoglobin level preferably under 10%. Then start the maintenance infusion.
      2. Maintenance infusion (dapsone intoxications only): 0.1-0.25 mg/kg/h, depending on the effective loading dose. After 48 hours, pause treatment to determine if significant methemoglobinemia returns over a 15-hour period. If it does, give another partial loading dose, titrating to effect, and restart another maintenance infusion. Treatment is usually required for at least 2-3 days.
      3. Methylene blue is ineffective for sulfhemoglobin and is contraindicated in patients with G6PD deficiency due to the risk of hemolysis. Methylene blue doses over 7 mg/kg may worsen methemoglobinemia.
   2. Cimetidine, an inhibitor of several CYP isoenzymes, can decrease the production of toxic metabolites.
      1. During chronic dapsone therapy, cimetidine improved patient tolerance and decreased methemoglobin levels at oral doses of 400 mg three times daily.
      2. To date, no evaluation of cimetidine in acute dapsone overdose has been performed. If considered after acute overdose, administration of activated charcoal would necessitate IV dosing.
   3. The efficacy of supplemental therapies, such as alpha-lipoic acid, ascorbic acid, and vitamin E, as antioxidants for dapsone toxicity is unproven.
3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Gastric lavage may be considered for a patient with a very large overdose (>75 mg/kg) presenting within 2-3 hours of ingestion but is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination
   1. Repeat-dose activated charcoal interrupts enterohepatic recirculation and can effectively reduce the dapsone half-life (from 77 to 13.5 hours in one report), but it should be used with caution in persons with severely altered mental status and discontinued if intestinal ileus occurs. Continue repeat-dose charcoal for 48-72 hours. Do not use preformulated charcoal and sorbitol combinations.
   2. Extracorporeal interventions may be considered in a severe intoxication unresponsive to conventional treatment. In one case report hemodialysis improved clinical symptoms though dapsone clearance rates were not reported. Continuous venovenous hemofiltration (CVVH) used alone for 72 hours reduced dapsone and metabolite half-life to 12.6 hours after overdose.