CHAPTER 2-57: DAPSONE

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

The toxic effects are caused by oxidized cytochrome P450 (CYP) dapsone metabolites, which can lead to methemoglobinemia, sulfhemoglobinemia, and Heinz body hemolytic anemia, decreasing the oxygen-carrying capacity of the blood.

1. Methemoglobinemia occurs when dapsone metabolites oxidize the ferrous iron–hemoglobin complex to the ferric 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 (see also Table II–66). 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 and patient tolerance are limited by toxic effects. Chronic daily dosing of 100 mg can cause methemoglobin levels of 5–12%. 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, altered or depressed mental status, and seizures. Methemoglobinemia and sulfhemoglobinemia usually are observed within a few hours of the overdose, but intravascular hemolysis may be delayed. The illness 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. Drawn blood may appear "chocolate" brown when the methemoglobin level is greater than 15–20%. Because of the long half-life of dapsone and its metabolites, methemoglobinemia may 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, but 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, 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. Dapsone was the leading cause of methemoglobinemia in one retrospective review of patients in an American hospital.

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 cooximeter. 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 cooximeter. 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 with reference to 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 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 and consider alkalinizing the urine, 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 this 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). Conventionally, methylene blue has been given intermittently every 6–8 hours as needed during prolonged dapsone intoxications. However, intermittent administration can produce wide swings in methemoglobin levels over the course of treatment, which can aggravate erythrocyte oxidative stress and worsen 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. Conditions allowing, administer in 1-mg/kg increments, allowing 30 minutes for response. The goal is 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. Supplemental therapies, such as alpha-lipoic acid, ascorbic acid, and vitamin E, have been proposed as antioxidants for dapsone toxicity, but their efficacy is unproven.

3. Decontamination. Administer activated charcoal orally if conditions are appropriate (see Table I–38). 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. Hemodialysis clears very little dapsone and metabolites because of high protein binding, but in one recent case report symptomatic improvement was observed. Charcoal hemoperfusion efficiently clears dapsone and reduces the plasma dapsone half-life to 1.5 hours in overdose. Continuous venovenous hemofiltration (CVVH) with regional citrate anticoagulation for 72 hours effectively reduced dapsone and metabolite half-life to 12.6 hours after overdose.