Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) Bis(p-Aminophenyl) Sulfone
2) Bis(4-Aminophenyl) Sulfone
3) DADPS
4) Dapson
5) Dapsonum
6) DDS
7) Dwuaminodwufenylosulfonem
8) Diamino-4,4'-diphenyl Sulfone
9) p,p'-Diaminodiphenyl Sulfone
10) 4,4'-Diaminodiphenyl Sulfone
11) Di(p-Aminophenyl) Sulfone
12) Di(4-Aminophenyl) Sulfone
13) Diaphenylsulfon
14) Diaphenylsulfone
15) Diphenasone
16) Diamine-diphenylsulphone
17) 1358F
18) F 1358
19) NCI-c 01718
20) NSC 6091
21) NSC 6091D
22) 4,4'-Sulfonylbisbenzamine
23) 1,1'-Sulfonylbis(4-aminobenzene)
24) 4,4'-Sulfonylbisaniline
25) p,p'-Sulfonylbisbenzamine
26) p,p'-Sulfonyldianiline
27) 4,4'-Sulfonyldianiline
28) Sulphadione
29) Sulphon-Mere
30) WR 488
31) 1358F (DAPSONE)
32) DAPSONIUM
33) F 1358 (DAPSONE)
34) WR, 488 (DAPSONE)
35) CAS 80-08-0

1.2.1) MOLECULAR FORMULA
1) C12H12N2O2S

Available Forms Sources

A)

1) Dapsone is available in the US as 25 mg and 100 mg tablets, and as a 5% and 7.5% topical gel (Prod Info ACZONE(R) topical gel, 2016; Prod Info ACZONE(R) topical gel, 2015; Prod Info DAPSONE oral tablets, 2009).

B)

1) Dapsone is approved for the treatment of Dermatitis herpetiformis, leprosy, and acne vulgaris (Prod Info ACZONE(R) topical gel, 2016; Prod Info DAPSONE oral tablets, 2009).
2) Dapsone is not FDA-approved, but widely used as an alternative agent, for the treatment and prophylaxis of Pneumocystis pneumonia and prophylaxis of toxoplasmosis in HIV patients (Centers for Disease Control and Prevention et al, 2009; Centers for Disease Control and Prevention et al, 2009a).
3) ADULTERANT: Dapsone was the only agent detected in an aphrodisiac used by a young adult man who developed methemoglobinemia (Lee et al, 1999).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Dapsone is an sulfone antimicrobial that is used as a topical gel for acne and as an oral tablet for leprosy, dermatitis herpetiformis, and Pneumocystis carinii pneumonia.
B) PHARMACOLOGY: It is a competitive antagonist of para-aminobenzoic acid (PABA), and thus inhibits normal bacterial utilization of PABA for folic acid synthesis.
C) TOXICOLOGY: the primary toxic effects are due to its P-450 metabolites. Dapsone metabolites oxidize the ferrous iron hemoglobin complex to the ferric state, resulting in methemoglobinemia. These metabolites can sulfate the pyrrole hemoglobin ring in an irreversible reaction, resulting in sulfhemoglobinemia. Finally, oxidative stress with depletion of glutathione may contribute to hemolysis.
D) EPIDEMIOLOGY: Dapsone is not widely used in the United States, and thus significant exposures are rare.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: ORAL: Adverse reactions from oral formulations include: hematologic abnormalities, seen in greater than 10% of patients and include hemolysis (usually dose related and may occur in patients with and without G6PD deficiency), decreases in hemoglobin (1 to 2 g/dL [observed in most patients]), reticulocyte increases from 2% to 12%, methemoglobinemia, and a shortened red blood cell life span. Other potential adverse reactions from oral formulations may include: tachycardia, fever, headache, insomnia, psychosis, vertigo, dermatologic effects (eg, bullous or exfoliative dermatitis, erythema nodosum, morbilliform or scarlatiniform reactions, phototoxicity, Stevens-Johnson syndrome, toxic epidural necrolysis and urticaria), hypoalbuminemia without proteinuria, abdominal pain, nausea, vomiting, pancreatitis, agranulocytosis, anemia, leucopenia, cholestatic jaundice, hepatitis, drug-induced lupus erythematosus, lower motor neuron toxicity (prolonged drug therapy), peripheral neuropathy (rare), blurred vision, tinnitus, albuminuria, nephritic syndrome, renal papillary necrosis, interstitial pneumonitis, pulmonary eosinophilia, and an infectious mononucleosis-like syndrome (ie, rash, fever, lymphadenopathy, and hepatic dysfunction). TOPICAL: Reported adverse reactions from topical formulations include: facial edema, depression, psychosis, suicide attempt, tonic clonic movements, methemoglobinemia, abdominal pain, pancreatitis, vomiting, and sinusitis.

F) WITH POISONING/EXPOSURE

1) MILD TO SEVERE TOXICITY: Hemotoxicity (eg, hemolytic anemia, methemoglobinemia, sulfhemoglobinemia), tachycardia, hypertension, agitation, hallucinations, confusion, nausea, vomiting, diarrhea, hepatotoxicity, hematuria, peripheral neuropathy, cold perspiration and blue-gray cyanosis may develop following overdose. Cases of dapsone toxicity have all occurred following oral exposure; significant toxicity is very unlikely from dermal exposure.

0.2.3)

A) WITH THERAPEUTIC USE

1) Fever has been reported following therapeutic use of dapsone.

0.2.20)

A) Generally, dapsone is contraindicated in pregnancy due to its ability to produce anemia or methemoglobinemia. Dapsone is considered Pregnancy Category C by the manufacturer.

0.2.21)

A) At the time of this review, the manufacturer does not report any carcinogenic potential.

Laboratory Monitoring

A)

B)

C)

D)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Treatment is largely supportive, intravenous fluids and antiemetics may be necessary for patients with persistent vomiting. Symptomatic methemoglobinemia should be treated with methylene blue.

B) MANAGEMENT OF SEVERE TOXICITY

1) Treatment is primarily supportive. In general, patients with methemoglobinemia usually respond to 2 doses of methylene blue> If no clinical improvement, consider G6PD deficiency or methemoglobin reductase deficiency. However, dapsone may cause prolonged oxidative stress, which may require repeat dosing of methylene blue every 6 to 8 hours for 2 to 3 days. A methylene blue infusion may also be considered. For life-threatening overdoses, consider using multiple-dose activated charcoal, hemoperfusion, hemodialysis, and exchange transfusion.

C) DECONTAMINATION

1) PREHOSPITAL: Ipecac-induced vomiting is not recommended. Administer activated charcoal if the patient is alert and is able to protect their airway. For dermal or eye exposures, immediate decontamination of the skin or rinsing of the eyes is recommended.
2) HOSPITAL: Activated charcoal should be considered in asymptomatic or minimally symptomatic patients with large ingestions who present within a few hours of ingestion, or in symptomatic patients who have a secure airway. Gastric lavage is generally not warranted.

D) ANTIDOTE

1) There is no specific antidote.

E) METHEMOGLOBINEMIA

1) Treat symptomatic patients (generally methemoglobin concentrations of 30% or more) with methylene blue. Initial dose is 1 to 2 mg/kg IV over 5 minutes. Because dapsone has a long half-life, rebound methemoglobinemia is common. Additional methylene blue doses may be needed every 6 to 8 hours. Alternatively, a methylene blue IV infusion may be initiated (0.1 to 0.15 mg/kg/hour) immediately after the initial bolus in patients with significant methemoglobinemia. Exchange transfusion has been used in a small number of patients with severe methemoglobinemia that did not respond to methylene blue. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials.

F) ENHANCED ELIMINATION

1) There have been case reports of the use of hemoperfusion, hemodialysis, exchange transfusion and multiple-dose activated charcoal in patients with dapsone toxicity. Though these modalities have been shown to increase the clearance of dapsone, they may not affect outcome. These modalities should be considered in patients with severe toxicity that do not respond to supportive care.

G) PATIENT DISPOSITION

1) HOME CRITERIA: In general, children with inadvertent ingestions should be evaluated, as methemoglobinemia has developed after 100 mg ingestions in toddlers. Patients with uncertain exposures and who are asymptomatic may be monitored at home, but all others should be evaluated at a health care facility.
2) OBSERVATION CRITERIA: Any patient who is experiencing symptoms or who had a self-harm attempt should be sent to a health care facility for observation. Observe asymptomatic patients for 4 to 6 hours. Admit patients with severe symptoms, those who develop methemoglobinemia requiring treatment, or patients who are still symptomatic at the end of observation.
3) ADMISSION CRITERIA: Patients exhibiting significant symptoms should be admitted, potentially to an ICU depending on symptoms, until symptoms resolve.
4) CONSULT CRITERIA: For the acutely ill patient, the following may need to be consulted: an intensivists (to assess for possible mechanical ventilation), a hematologist (to rule out other causes of anemia), and a nephrologist (to assess for potential dialysis). If available, a toxicologist can help guide therapy, and poison centers should be notified of all exposures.

H) PREDISPOSING CONDITIONS

1) Patients with a G6PD deficiency, hemoglobin M deficiency, or a methemoglobin reductase deficiency are at increased risk for methemoglobinemia and hemolysis. Patients with anemia or underlying pulmonary or cardiac disease are less tolerant of methemoglobinemia. Although dapsone has not been shown to increase congenital anomalies when given during pregnancy (all trimesters), case reports have described adverse effects in neonates after in utero exposure to dapsone, including neonatal hemolytic disease, methemoglobinemia, and hyperbilirubinemia. Dapsone is excreted in breast milk.

I) PITFALLS

1) Methemoglobinemia may be prolonged (eg, days after exposure). Rebound methemoglobinemia may occur. Dapsone levels may rebound after hemodialysis.

J) PHARMACOKINETICS

1) Dapsone is well absorbed orally. The parent drug is 70% to 90% protein bound and its acetylated metabolite is about 99% protein bound. Little systemic absorption occurs after dermal application. It has a volume of distribution between 1 and 2 L/kg. It is metabolized hepatically via acetylation and P-450 oxidation and it has multiple metabolites that are then excreted mostly through urine (approximately 85%). Approximately, 20% of an oral dose of dapsone is eliminated unchanged renally. It has a half-life of elimination from 30 to 50 hours. Peak plasma levels occur between 4 to 8 hours after ingestion. Both dapsone and its acetylated metabolite undergo enterohepatic circulation. Of note, N-acetylation of dapsone is subject to genetic polymorphism, with about 40% of the general population being rapid acetylators, 50% being slow acetylators, and the remaining 10% with intermediate rate of acetylation.

K) TOXICOKINETICS

1) Half-life has been described as long as 77 hours after an overdose.

L) DIFFERENTIAL DIAGNOSIS

1) The differential diagnosis includes other drugs or substances that can cause methemoglobinemia (eg, nitrites, nitrates, local anesthetics, sulfonamides, and aniline dyes).

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) ADVERSE EFFECTS: ORAL: Adverse reactions from oral formulations include: hematologic abnormalities, seen in greater than 10% of patients and include hemolysis (usually dose related and may occur in patients with and without G6PD deficiency), decreases in hemoglobin (1 to 2 g/dL [observed in most patients]), reticulocyte increases from 2% to 12%, methemoglobinemia, and a shortened red blood cell life span. Other potential adverse reactions from oral formulations may include: tachycardia, fever, headache, insomnia, psychosis, vertigo, dermatologic effects (eg, bullous or exfoliative dermatitis, erythema nodosum, morbilliform or scarlatiniform reactions, phototoxicity, Stevens-Johnson syndrome, toxic epidural necrolysis and urticaria), hypoalbuminemia without proteinuria, abdominal pain, nausea, vomiting, pancreatitis, agranulocytosis, anemia, leucopenia, cholestatic jaundice, hepatitis, drug-induced lupus erythematosus, lower motor neuron toxicity (prolonged drug therapy), peripheral neuropathy (rare), blurred vision, tinnitus, albuminuria, nephritic syndrome, renal papillary necrosis, interstitial pneumonitis, pulmonary eosinophilia, and an infectious mononucleosis-like syndrome (ie, rash, fever, lymphadenopathy, and hepatic dysfunction). TOPICAL: Reported adverse reactions from topical formulations include: facial edema, depression, psychosis, suicide attempt, tonic clonic movements, methemoglobinemia, abdominal pain, pancreatitis, vomiting, and sinusitis.

F)

1) MILD TO SEVERE TOXICITY: Hemotoxicity (eg, hemolytic anemia, methemoglobinemia, sulfhemoglobinemia), tachycardia, hypertension, agitation, hallucinations, confusion, nausea, vomiting, diarrhea, hepatotoxicity, hematuria, peripheral neuropathy, cold perspiration and blue-gray cyanosis may develop following overdose. Cases of dapsone toxicity have all occurred following oral exposure; significant toxicity is very unlikely from dermal exposure.

Vital Signs

3.3.1)

A) WITH THERAPEUTIC USE

1) Fever has been reported following therapeutic use of dapsone.

3.3.3)

A) WITH THERAPEUTIC USE

1) Fever has been reported following therapeutic use of dapsone (Mok et al, 1998).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) SUMMARY: Clinical effects following exposure can include: photosensitivity, blurred vision, and permanent eye damage following acute or subacute dapsone poisoning (JEF Reynolds , 1999; Ellenhorn et al, 1997).
2) CASE REPORT: Decreased visual acuity with permanent retinal damage was reported in an adult with massive hemolysis following an intentional ingestion of 10 g of dapsone (Seo et al, 1997). The authors suggested that a combination of severe peripheral hypoxemia and the vascular obstructive effect of red cell fragments caused the retinal damage.
3) RETINAL ISCHEMIA/CASE REPORT: A 30-year-old woman with linear bullous immunoglobulin A dermatosis treated with dapsone 50 mg daily, but suspected of taking larger daily doses for several weeks, presented with decreased visual acuity. An ophthalmologic fundus examination revealed ischemic retinal edema of both eyes with retinal hemorrhages and cotton wool spots in the mid-periphery and posterior pole. Her visual acuity had decreased from 20/20 in both eyes (in 2010) to 20/200 of the right eye and 20/400 of the left eye. Liquid chromatography revealed serum dapsone and N-acetyl dapsone (metabolite) concentrations of 20,044 mcg/mL (therapeutic range 1 to 3.5 +/-0.5 mcg/mL) and 16,095 mcg/mL, respectively. With supportive therapy, including co-administration of methylene blue (1 mg/kg IV, repeated twice during the first day) and vitamin C (500 mg IV three times daily), and an exchange transfusion, the patient's macular ischemic lesions disappeared and there was improvement in her visual acuity, with 20/100 of the right eye and 20/125 of the left eye at the 6-month follow-up (Hanuschk et al, 2015).

Cardiovascular

3.5.2)

A) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Tachycardia and hypotension may be seen (Park et al, 2014; Lambert et al, 1982; Berlin et al, 1985; Neuvonen et al, 1983).

Respiratory

3.6.2)

A) DYSPNEA

1) WITH POISONING/EXPOSURE

a) Exertional dyspnea has been reported following overdose (Lambert et al, 1982).
b) A retrospective review was conducted of patients who presented to the ED of a Korean tertiary care hospital from 2006 to 2014 with acute dapsone poisoning. A total of 43 patients were identified with a median dapsone dose ingested of 600 mg (doses ranging from 400 to 1000 mg). The most common signs and symptoms reported at initial presentation included cyanosis (30 patients; 69.8%), dyspnea (25 patients; 58.1%), decreased mental status (13 patients; 30.2%), and headache (5 patients; 11.6%). Other symptoms observed included nausea, vomiting, dizziness, general weakness, and seizures. Pneumonia was the most common complication following dapsone poisoning (22 patients; 51.2%), with death occurring in 10 patients as a result of pneumonia and multi-organ failure (Cha et al, 2016).

B) TACHYPNEA

1) WITH POISONING/EXPOSURE

a) Tachypnea and moderate impairment of oxygenation have been reported in patients with significant methemoglobinemia following acute dapsone overdose (Park et al, 2014; Masurkar et al, 2011; Berlin et al, 1985).
b) CASE REPORT: A 15-year-old-girl presented to the emergency department with altered mental status and methemoglobinemia after intentionally ingesting 7.2 g of dapsone. Upon presentation she was tachypneic, tachycardic, agitated, cyanotic, confused, and had an O2 saturation of 89% on 15 L/min via a nonrebreather mask. She was intubated and ventilated for 5 days. Other therapy included gastric lavage, IV methylene blue, and multiple dose activated charcoal. However, after initially dropping to 9.9%, methemoglobin levels rebounded to 18.7% (within 10 hours of presentation). Continuous veno-venous hemofiltration was initiated and maintained for 75 hours effectively lowering dapsone to subtherapeutic levels. She was extubated on day 5 and discharged home on day 11 with no sequelae (Masurkar et al, 2011).

C) ALLERGIC PNEUMONIA

1) WITH THERAPEUTIC USE

a) Eosinophilic pneumonia has been reported in an adult following therapeutic use of dapsone; upon accidental rechallenge symptoms of dyspnea, cough, and fever occurred within several hours of ingestion (Jaffuel et al, 1998).

1) The authors suggested that previous reports of eosinophilic pneumonia induced by combinations of pyrimethamine and dapsone may be more attributable to dapsone ingestion than the former.

D) PNEUMONIA

1) WITH POISONING/EXPOSURE

a) A retrospective review was conducted of patients who presented to the ED of a Korean tertiary care hospital from 2006 to 2014 with acute dapsone poisoning. A total of 43 patients were identified with a median dapsone dose ingested of 600 mg (doses ranging from 400 to 1000 mg). The most common signs and symptoms reported at initial presentation included cyanosis (30 patients; 69.8%), dyspnea (25 patients; 58.1%), decreased mental status (13 patients; 30.2%), and headache (5 patients; 11.6%). Other symptoms observed included nausea, vomiting, dizziness, general weakness, and seizures. Pneumonia was the most common complication following dapsone poisoning (22 patients; 51.2%), with death occurring in 10 patients as a result of pneumonia and multi-organ failure (Cha et al, 2016).

Neurologic

3.7.2)

A) CENTRAL STIMULANT ADVERSE REACTION

1) WITH POISONING/EXPOSURE

a) Signs of CNS stimulation following overdose include: giddiness, dizziness, confusion, restlessness, excitement, aggressive behavior, agitation, and hallucinations (Rajagopalan & Rao, 1967; Elonen et al, 1979; Lambert et al, 1982; Woodhouse et al, 1983; Ferguson & Lavery, 1997).
b) CASE REPORT: A 15-year-old girl developed methemoglobinemia and became agitated and confused after intentionally ingesting 7.2 g of dapsone. Upon presentation to the emergency department she was cyanotic, tachycardic, tachypneic, and had an O2 saturation of 89% on 15 L/min via a nonrebreather mask. She was intubated and ventilated for 5 days. Other therapy included gastric lavage, IV methylene blue, and multiple dose activated charcoal. Initially, methemoglobin levels dropped to 9.9% (46.8% at admission). However, within 10 hours of initial presentation, levels rebounded to 18.7%. Continuous veno-venous hemofiltration was initiated and maintained for 75 hours. She was discharged to home on day 11 with no sequelae (Masurkar et al, 2011).
c) A retrospective review was conducted of patients who presented to the ED of a Korean tertiary care hospital from 2006 to 2014 with acute dapsone poisoning. A total of 43 patients were identified with a median dapsone dose ingested of 600 mg (doses ranging from 400 to 1000 mg). The most common signs and symptoms reported at initial presentation included cyanosis (30 patients; 69.8%), dyspnea (25 patients; 58.1%), decreased mental status (13 patients; 30.2%), and headache (5 patients; 11.6%). Other symptoms observed included nausea, vomiting, dizziness, general weakness, and seizures. Pneumonia was the most common complication following dapsone poisoning (22 patients; 51.2%), with death occurring in 10 patients as a result of pneumonia and multi-organ failure (Cha et al, 2016).

B) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache is a common complaint following overdose (Lambert et al, 1982; Neuvonen et al, 1983).
b) A retrospective review was conducted of patients who presented to the ED of a Korean tertiary care hospital from 2006 to 2014 with acute dapsone poisoning. A total of 43 patients were identified with a median dapsone dose ingested of 600 mg (doses ranging from 400 to 1000 mg). The most common signs and symptoms reported at initial presentation included cyanosis (30 patients; 69.8%), dyspnea (25 patients; 58.1%), decreased mental status (13 patients; 30.2%), and headache (5 patients; 11.6%). Other symptoms observed included nausea, vomiting, dizziness, general weakness, and seizures. Pneumonia was the most common complication following dapsone poisoning (22 patients; 51.2%), with death occurring in 10 patients as a result of pneumonia and multi-organ failure (Cha et al, 2016).

C) COMA

1) WITH POISONING/EXPOSURE

a) Coma has occurred in overdose (Woodhouse et al, 1983; Wagner et al, 1995).

D) SECONDARY PERIPHERAL NEUROPATHY

1) WITH THERAPEUTIC USE

a) Patients taking dapsone as chronic therapy have developed peripheral neuropathies (Daneshmend & Homeida, 1981; Waldinger et al, 1984; Snavely & Hodges, 1984; JEF Reynolds , 1999).
b) These are primarily axonal motor neuropathies developing within 5 years of beginning therapy, are usually associated with doses of 300 mg/day or greater, may be more likely to develop in patients who are slow acetylators of dapsone, and tend to improve after discontinuance of the drug (Waldinger et al, 1984; Snavely & Hodges, 1984).

2) WITH POISONING/EXPOSURE

a) Three cases of a motor neuropathy followed oral overdoses of dapsone. A distal motor axonopathy confirmed the diagnosis (Sirsat et al, 1987).

E) ALTERED MENTAL STATUS

1) WITH POISONING/EXPOSURE

a) A retrospective review was conducted of patients who presented to the ED of a Korean tertiary care hospital from 2006 to 2014 with acute dapsone poisoning. A total of 43 patients were identified with a median dapsone dose ingested of 600 mg (doses ranging from 400 to 1000 mg). The most common signs and symptoms reported at initial presentation included cyanosis (30 patients; 69.8%), dyspnea (25 patients; 58.1%), decreased mental status (13 patients; 30.2%), and headache (5 patients; 11.6%). Other symptoms observed included nausea, vomiting, dizziness, general weakness, and seizures. Pneumonia was the most common complication following dapsone poisoning (22 patients; 51.2%), with death occurring in 10 patients as a result of pneumonia and multi-organ failure (Cha et al, 2016).

Gastrointestinal

3.8.2)

A) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) Nausea and vomiting have been reported following overdose (Lambert et al, 1982; Rajagopalan & Rao, 1967; Elonen et al, 1979). Severe abdominal pain may also be noted.
b) A retrospective review was conducted of patients who presented to the ED of a Korean tertiary care hospital from 2006 to 2014 with acute dapsone poisoning. A total of 43 patients were identified with a median dapsone dose ingested of 600 mg (doses ranging from 400 to 1000 mg). The most common signs and symptoms reported at initial presentation included cyanosis (30 patients; 69.8%), dyspnea (25 patients; 58.1%), decreased mental status (13 patients; 30.2%), and headache (5 patients; 11.6%). Other symptoms observed included nausea, vomiting, dizziness, general weakness, and seizures. Pneumonia was the most common complication following dapsone poisoning (22 patients; 51.2%), with death occurring in 10 patients as a result of pneumonia and multi-organ failure (Cha et al, 2016).

Hepatic

3.9.2)

A) LIVER DAMAGE

1) WITH THERAPEUTIC USE

a) Jaundice, elevated bilirubin, and elevated transaminase levels may occur either following overdose, with chronic therapy, or as part of "Sulfone Syndrome", which generally develops within 2 months of therapy (Lee & Nashed, 2003; Johnson et al, 1986; Leoung et al, 1986; Berlin et al, 1985).
b) Transient hepatitis was reported in an adult following therapeutic use (Mok et al, 1998).

Genitourinary

3.10.2)

A) BLOOD IN URINE

1) WITH POISONING/EXPOSURE

a) Hematuria may occur several days following an acute overdose (Woodhouse et al, 1983a).

Acid-Base

3.11.2)

A) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 15-year-old girl developed lactic acidosis (pH 7.36, PaCO2 26 mmHg, PaO2 123 mmHg, bicarbonate 14 mmol/L, lactate 8.5 mmol/L) and methemoglobinemia after intentionally ingesting 7.2 g of dapsone. Upon presentation to the emergency department she was cyanotic, confused, agitated, tachycardic, tachypneic, and had an O2 saturation of 89% on 15 L/min via a nonrebreather mask. She was intubated ventilated for 5 days. Other therapy included gastric lavage, IV methylene blue, ascorbic acid, folinic acid, and multiple dose activated charcoal. However, after initially dropping to 9.9%, methemoglobin levels rebounded to 18.7% (within 10 hours of presentation). Continuous veno-venous hemofiltration was initiated and maintained for 75 hours effectively lowering dapsone to subtherapeutic levels. She was discharged to home on day 11 with no sequelae (Masurkar et al, 2011).
b) CASE REPORT: Acidosis with arterial blood gas values of pH 7.30, pO2 71.5 mmHg, pCO2 26.8 mmHg, and HCO3 13.7 was reported in an 18-month-old child who ingested 100 mg and developed methemoglobinemia (Reigart et al, 1983).

B) ALKALOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Alkalosis and hyperventilation with arterial blood gas values of pH 7.5, pO2 67 mmHg, and pCO2 33 mmHg were reported in an adult patient who ingested 15 grams (Berlin et al, 1985).

Hematologic

3.13.2)

A) METHEMOGLOBINEMIA

1) WITH THERAPEUTIC USE

a) Increasing use of dapsone in higher doses for the treatment of Pneumocystis carinii pneumonia in HIV-infected patients has lead to methemoglobinemia in some individuals in this patient population (Lee & Nashed, 2003; Reiter & Cimoch, 1987).
b) CASE REPORT/TOPICAL: A 19-year-old woman, with a history of depression and acne, presented to the emergency department with cyanotic lips and fingers. Medication history included daily administration of citalopram and oral contraceptives. Vital signs indicated tachycardia (heart rate of 109 beats per min) and an oxygen saturation of 85% on room air. Laboratory analysis revealed a methemoglobin level of 20.3%. Following treatment with a single 100-mg IV dose of methylene blue, her signs and symptoms resolved. A repeat methemoglobin level, obtained 2 hours later, was 1.9%. Urine drug screening demonstrated the presence of citalopram and dapsone. Interview of the patient revealed that she had been applying a "pea-sized" amount of topical dapsone, to treat her acne, twice daily for 7 days prior to presentation. With continued observation, the patient remained asymptomatic and was discharged home (Swartzentruber et al, 2015).

2) WITH POISONING/EXPOSURE

a) SUMMARY

1) Methemoglobinemia and related cyanosis are a commonly reported toxic manifestation after dapsone overdose (Cha et al, 2016; Masurkar et al, 2011; Lambert et al, 1982; Berlin et al, 1985; Nayak et al, 1989; Erstad, 1992; Chawla et al, 1993; McGoldrick & Bailie, 1995; MacDonald & McGuigan, 1997; Casey & Tracey, 1999).

b) CASE REPORTS

1) PEDIATRIC

a) CASE REPORT: A 15-year-old-girl presented to the emergency department with methemoglobinemia and altered mental status after intentionally ingesting 7.2 g of dapsone. Coingestants included small amounts of azathioprine, methotrexate, methylprednisolone and prednisolone. Upon presentation she was cyanotic, confused, agitated, tachycardic, tachypneic, and had an O2 saturation of 89% on 15 L/min via a nonrebreather mask. Her temperature and blood pressure were within normal limits. Arterial blood gas analysis showed lactic acidosis. Laboratory analysis revealed a dapsone level of 59.82 mcg/mL (therapeutic: 1 to 3.5 mcg/mL) and a metabolite monoacetyldapsone (MADDS) level of 16 mcg/mL. She was intubated and ventilated for 5 days. Other therapy included IV methylene blue, gastric lavage, multidose activated charcoal, IV ascorbic acid, and IV folinic acid. Initially, methemoglobin levels dropped to 9.9% (46.8% at admission). However, within 10 hours of presentation, levels rebounded to 18.7%. Continuous veno-venous hemofiltration was initiated and maintained for 75 hours effectively lowering dapsone and MADDS to subtherapeutic levels. She was discharged to home on day 11 with no sequelae (Masurkar et al, 2011).
b) Ingestion of as little as 100 mg has caused significant methemoglobinemia in an 18-month-old child (Reigart et al, 1983).
c) Persistent recurrent methemoglobinemia occurred in a 3.5-year-old girl following an ingestion of an unknown amount of dapsone. The initial methemoglobin level was 44.7%. The dapsone concentration 24 hours after admission was 3.9 mcg/mL. Mild residual cyanosis resolved within 2 weeks of admission (Linakis et al, 1989).
d) Elevated methemoglobinemia levels were reported in a 3-year-old boy ingesting 100 mg of dapsone and 12.5 mg of pyrimethamine (MacDonald & McGuigan, 1997). 2.5 hours post ingestion, methemoglobinemia level was 44% Initial therapy with methylene blue reduced the level to 6%, but it rebounded to almost 15% 64 hours postingestion. Monitoring for 2 to 3 days in children was suggested.

2) ADULT

a) Ingestion of 2.5 to 3 g or more has produced significant methemoglobinemia in adults (Woodhouse et al, 1983a; Elonen et al, 1979; Berlin et al, 1985).
b) CASE REPORT: An 18-year-old girl presented to the hospital after ingesting 2 g of dapsone in a suicide attempt. Her clinical course included hemolysis, jaundice, and progressive bluish discoloration of her lips and limbs. A high PaO2 in conjunction with cyanosis and dark blood lead to the diagnosis of methemoglobinemia. Her methemoglobin level on day 3 was 3.8 g/dL. She was treated with methylene blue 1 mg/kg with 100 mL normal saline IV over 20 minutes. By hospital day 8, the cyanosis and methemoglobin level had decreased significantly and by day 11 all clinical signs and symptoms had subsided, laboratory tests had returned to normal and she was discharged (Shadnia et al, 2006).
c) CASE REPORT: An 84-year-old woman presented to the emergency department with altered mental status and cyanosis after ingesting 7 dapsone tablets. Vital signs indicated hypotension (106/49 mmHg), tachycardia (118 bpm), tachypnea (28 breaths/min) and an oxygen saturation of 85% on room air. Arterial blood gas analysis revealed a PaCO2 of 27 mmHg and a PaO2 of 113 mmHg, and her initial methemoglobin concentration was 51.9% that peaked at 64.4% approximately 7 hours post-presentation. Due to the unavailability of methylene blue, the patient was treated with high-dose vitamin C (10 g intravenously) every 6 hours, resulting in gradual improvement in her mental status, cyanosis, and methemoglobin concentration, and she was subsequently discharged approximately 6 days post-presentation (Park et al, 2014).
d) CASE REPORT: A 30-year-old woman with linear bullous immunoglobulin A dermatosis treated with dapsone 50 mg daily, but suspected of taking larger daily doses for several weeks, developed methemoglobinemia (methemoglobin level of 32%), retinal ischemia resulting in decreased visual acuity (20/200 of the right eye and 20/400 of the left eye), and hemolytic anemia (hemoglobin level 7.4 g/dL, reticulocytes 12.6%, platelet count 157,000/mm(3), schistocytes 2% to 5%, haptoglobin level less than 10 mg/dL). Liquid chromatography revealed a serum dapsone and N-acetyl dapsone (metabolite) concentrations of 20,044 mcg/mL (therapeutic range 1 to 3.5 +/-0.5 mcg/mL) and 16,095 mcg/mL, respectively. Methylene blue (1 mg/kg IV, repeated twice during the first day) was co-administered with vitamin C (500 mg IV three times daily), resulting in a decrease in her hemoglobin level to 10% to 15%; however, her hemolytic anemia worsened, with a nadir hemoglobin level of 5.4 g/dL, schistocytes of greater than 8%, platelet count of 85,000/mm(3), and a haptoglobin level of less than 10 mg/dL. Further laboratory analysis of the patient revealed that she had traits for sickle cell anemia and alpha-thalassemia. Following an exchange transfusion, her hemolytic anemia and methemoglobinemia resolved, with evidence of visual improvement (20/100 of the right eye, 20/125 of the left eye) at her 6-month follow-up (Hanuschk et al, 2015).

B) CYANOSIS

1) WITH POISONING/EXPOSURE

a) Cold perspiration and bluish-grey cyanosis (most likely due to methemoglobinemia) of skin, lips, tongue, and fingertips have been reported (Lambert et al, 1982; Rajagopalan & Rao, 1967; Elonen et al, 1979; Wagner et al, 1995). Cyanosis may persist for 10 days after an overdose (Nagaraj et al, 1987).
b) A retrospective review was conducted of patients who presented to the ED of a Korean tertiary care hospital from 2006 to 2014 with acute dapsone poisoning. A total of 43 patients were identified with a median dapsone dose ingested of 600 mg (doses ranging from 400 to 1000 mg). The most common signs and symptoms reported at initial presentation included cyanosis (30 patients; 69.8%), dyspnea (25 patients; 58.1%), decreased mental status (13 patients; 30.2%), and headache (5 patients; 11.6%). Other symptoms observed included nausea, vomiting, dizziness, general weakness, and seizures. Pneumonia was the most common complication following dapsone poisoning (22 patients; 51.2%), with death occurring in 10 patients as a result of pneumonia and multi-organ failure (Cha et al, 2016).

C) SULFHEMOGLOBINEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Two cases of sulfhemoglobinemia have been reported after ingestion of 3 g of dapsone (Lambert et al, 1982; Chawla et al, 1993). One patient developed methemoglobinemia with sulfhemoglobinemia occurring 4 days later (Lambert et al, 1982). The other patient developed methemoglobinemia with sulfhemoglobinemia occurring 24 hours later (Chawla et al, 1993).

D) HEMOLYTIC ANEMIA

1) WITH THERAPEUTIC USE

a) SUMMARY

1) A glucose-6-phosphate dehydrogenase deficient individual has about a 2-fold increase in sensitivity toward dapsone-induced hemolytic anemia (Goldfrank et al, 1998; Grossman et al, 1995; Jollow et al, 1995). In rats, the hemolytic activity of dapsone appeared to reside in its N-hydroxy metabolites (Grossman & Jollow, 1988; Grossman et al, 1995).

b) RISK FACTORS

1) A dose-related hemolytic anemia is a common side effect during therapeutic use (Leoung, 1986; Lang, 1979). In one study, the concomitant administration of vitamin E did not prevent hemolysis (Kelly et al, 1984).
2) Individuals with hemoglobin AE (hemoglobin E trait) and hemoglobin EE (hemoglobin E homozygotes), ordinarily hematologically benign conditions, are at risk for developing Heinz body hemolytic anemia when taking oxidant medication.
3) Two cases of dapsone-associated Heinz body hemolytic anemia were described in 2 Cambodian women after they emigrated to the US (Lachant & Tanaka, 1987). The authors speculated that the hemolytic anemia was probably caused by N-hydroxylamine metabolites of dapsone, not the parent drug (Grossman & Jollow, 1988).

2) WITH POISONING/EXPOSURE

a) Heinz body hemolytic anemia is common after overdose (Lambert et al, 1982; Berlin et al, 1985; Neuvonen et al, 1983; Elonen et al, 1979).
b) CASE REPORT: A 30-year-old woman with linear bullous immunoglobulin A dermatosis treated with dapsone 50 mg daily, but suspected of taking larger daily doses for several weeks, developed methemoglobinemia (methemoglobin level of 32%), retinal ischemia resulting in decreased visual acuity (20/200 of the right eye and 20/400 of the left eye), and hemolytic anemia (hemoglobin level 7.4 g/dL, reticulocytes 12.6%, platelet count 157,000/mm(3), schistocytes 2% to 5%, haptoglobin level less than 10 mg/dL). Liquid chromatography revealed a serum dapsone and N-acetyl dapsone (metabolite) concentrations of 20,044 mcg/mL (therapeutic range 1 to 3.5 +/-0.5 mcg/mL) and 16,095 mcg/mL, respectively. Methylene blue (1 mg/kg IV, repeated twice during the first day) was co-administered with vitamin C (500 mg IV three times daily), resulting in a decrease in her hemoglobin level to 10% to 15%; however, her hemolytic anemia worsened, with a nadir hemoglobin level of 5.4 g/dL, schistocytes of greater than 8%, platelet count of 85,000/mm(3), and a haptoglobin level of less than 10 mg/dL. Further laboratory analysis of the patient revealed that she had traits for sickle cell anemia and alpha-thalassemia. Following an exchange transfusion, her hemolytic anemia and methemoglobinemia resolved, with evidence of visual improvement (20/100 of the right eye, 20/125 of the left eye) at her 6-month follow-up (Hanuschk et al, 2015).
c) A retrospective review was conducted, of patients who presented to the ED of a Korean tertiary care hospital from 2006 to 2014 with a diagnosis of acute dapsone overdose, in order to determine the prevalence of hemolytic anemia following dapsone poisoning. Of 43 patients who were included in the review, 30 patients (69.8%) had developed hemolytic anemia believed to be secondary to dapsone overdose. The ingested dapsone dose was significantly higher in the hemolytic anemia group than in the non-hemolytic group (13 patients; 30.2%), with a median dose of 500 mg in the hemolytic anemia group (dose ranging from 700 to 1250 mg) compared to a median dose of 400 mg in the non-hemolytic group (dose ranging from 350 to 600 mg). According to laboratory data from the hemolytic anemia group, the median hemoglobin decline from baseline was 4.3 g/dL, occurring the day after admission and persisting for more than 6 days post-admission. All 43 patients developed methemoglobinemia with no significant differences in methemoglobin levels between the groups; however, the days of ICU admission and total admission were significantly longer in the hemolytic group than in the non-hemolytic group, with a median of 4 days (range 1 to 16 days) and 13 days (range 7 to 16 days) of ICU and total admission, respectively, in the hemolytic group compared to 0 days (range 0 to 5 days) and 5 days (range from 3 to 7 days) of ICU and total admission, respectively, in the non-hemolytic group. Although 10 of the 43 patients died from complications, including pneumonia and multi-organ failure, there were no significant differences in the rate of mortality between the 2 groups (Cha et al, 2016).

E) APLASTIC ANEMIA

1) WITH THERAPEUTIC USE

a) One case of aplastic anemia was reported during therapeutic use (Foucauld et al, 1985). Agranulocytosis, neutropenia, and thrombocytopenia have also occurred with therapeutic use (Leoung et al, 1986; Reynolds & Prasad, 1982; Potter et al, 1989).

F) PORPHYRIA DUE TO TOXIC EFFECT OF SUBSTANCE

1) WITH THERAPEUTIC USE

a) Dapsone has been associated with clinical exacerbation of porphyria and is NOT indicated in porphyric patients (JEF Reynolds , 1999).

Dermatologic

3.14.2)

A) CYANOSIS

1) WITH POISONING/EXPOSURE

a) Cold perspiration and bluish-grey cyanosis (most likely due to methemoglobinemia) of skin, lips, tongue, and fingertips have been commonly reported following intentional and unintentional ingestions (Lambert et al, 1982; Elonen et al, 1979; Rajagopalan & Rao, 1967; McGoldrick & Bailie, 1995; Casey & Tracey, 1999), and occurred in an elderly immunosuppressed patient within 9 days of starting therapy (Ward & McCarthy, 1998). Cyanosis may persist for 10 days after an overdose (Nagaraj et al, 1987; Sheela et al, 1993).
b) Clinical cyanosis has been reported following only moderate increases in methemoglobin level (10 g/dL) in an adult (McGoldrick & Bailie, 1995).
c) A retrospective review was conducted of patients who presented to the ED of a Korean tertiary care hospital from 2006 to 2014 with acute dapsone poisoning. A total of 43 patients were identified with a median dapsone dose ingested of 600 mg (doses ranging from 400 to 1000 mg). The most common signs and symptoms reported at initial presentation included cyanosis (30 patients; 69.8%), dyspnea (25 patients; 58.1%), decreased mental status (13 patients; 30.2%), and headache (5 patients; 11.6%). Other symptoms observed included nausea, vomiting, dizziness, general weakness, and seizures. Pneumonia was the most common complication following dapsone poisoning (22 patients; 51.2%), with death occurring in 10 patients as a result of pneumonia and multi-organ failure (Cha et al, 2016).

B) MACULOPAPULAR ERUPTION

1) WITH POISONING/EXPOSURE

a) A generalized erythematous maculopapular rash developed in an adult following therapeutic use; the lesions gradually improved with prednisolone (Mok et al, 1998).

Reproductive

3.20.1)

A) Generally, dapsone is contraindicated in pregnancy due to its ability to produce anemia or methemoglobinemia. Dapsone is considered Pregnancy Category C by the manufacturer.

3.20.2)

A) LACK OF INFORMATION

1) Generally, dapsone is contraindicated in pregnancy due to its ability to produce anemia or methemoglobinemia. The manufacturer recommends that due to a lack of animal studies or controlled human experience, dapsone should be given to pregnant women ONLY if clearly indicated (Prod Info Dapsone(R), 1997).
2) Although dapsone does cross the placenta (Zuidema et al, 1986), there is evidence that dapsone has been administered safely in pregnancy.

a) CASE REPORT - A 26-year-old mother was administered 100 mg of dapsone/day from the 24th through the 28th week of pregnancy and delivered a normal child at 30 weeks gestation (Diamond, 1976).

3.20.3)

A) PREGNANCY CATEGORY

1) Dapsone is considered Pregnancy Category C by the manufacturer (Prod Info Dapsone(R), 1997).

3.20.4)

A) BREAST MILK

1) SUMMARY - Dapsone is excreted in breast milk in substantial amounts (Prod Info Dapsone(R), 1997). Hemolytic reactions can occur in neonates. Based on its tumorigenicity in animal studies, careful evaluation of continuing the drug must be considered in nursing women.
2) CASE REPORT - Two cases of neonatal hemolytic anemia presumed to be due to dapsone in the breast milk have been reported (Zuidema et al, 1986). The presence of the antileprosy drug in the breast milk may, however, protect the child from infection (Zuidema et al, 1986).
3) The amount of dapsone ingested by an infant from the breast milk of a mother ingesting dapsone 100 mg prophylactically is unlikely to be harmful to the infant, but the amount of dapsone in its blood stream will not be sufficient to protect it from a malarial infection, and may promote the selection of drug resistant malaria parasite strains (Edstein et al, 1986).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS80-08-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Dapsone
b) Carcinogen Rating: 3

1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

3.21.2)

A) At the time of this review, the manufacturer does not report any carcinogenic potential.

3.21.4)

A) CARCINOMA

1) Dapsone was reported to cause mesenchymal tumors in the spleen and peritoneum of male rats and female mice and thyroid carcinoma in female rats (Prod Info DAPSONE oral tablets, 2009).
2) Dapsone has been shown to be carcinogenic in experimental animals given chronic doses much larger than those used in human therapy (Griciute & Tomatis, 1980; Lang, 1979; Anon, 1977; Peters, 1976).

B) LACK OF EFFECT

1) In a 12-month photocarcinogenicity study in hairless mice, the topical application of dapsone topical gels up to 5% concentration did not increase the formation rate of ultraviolet light-induced skin tumors (Prod Info ACZONE(R) topical gel, 2016; Prod Info ACZONE(R) topical gel, 2015).
2) No evidence of carcinogenicity potential was seen in a study of dapsone topical gel 3%, 5%, or 10% applied dermally to Tg.AC transgenic mice for 26 weeks, and the 3% formulation was determined to be the maximum tolerated dosage (Prod Info ACZONE(R) topical gel, 2016; Prod Info ACZONE(R) topical gel, 2015).
3) Dapsone was not carcinogenic in rats orally administered dosages up to 15 mg/kg/day (approximately 340 times the systemic exposure from the maximum recommended human dose of 7.5% dapsone gel based on AUC) for life (Prod Info ACZONE(R) topical gel, 2016; Prod Info ACZONE(R) topical gel, 2015).

Genotoxicity

A)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) G6PD levels should be analyzed prior to the initiation of oral therapy.
B) Monitor pulse oximetry. Monitor CBC and urinalysis for evidence of hemolysis.
C) Obtain a methemoglobin concentration in patients with cyanosis or symptoms of methemoglobinemia.
D) Dapsone levels are not readily available and are not clinically useful.

4.1.2)

A) HEMATOLOGIC

1) Monitor methemoglobin levels (SEE: Range of Toxicity section for interpretation).
2) If cyanosis fails to clear after treatment of presumed methemoglobinemia with methylene blue, or recurs late in the clinical course, sulfhemoglobinemia may be present (Lambert et al, 1982). While sulfhemoglobin levels are not readily available, they may be useful to confirm the diagnosis and avoid unnecessary treatment with methylene blue.
3) Monitor CBC, differential, and platelet count. Studies of hemolysis such as haptoglobin and free hemoglobin, and reticulocyte counts may be useful to monitor hemolysis. Other tests may include red cell fragility, Heinz bodies, and lactic acid dehydrogenase to aid in the diagnosis of latent methemoglobinemia and hemolytic anemia.

B) ACID/BASE

1) Monitor arterial blood gases for acid-base disturbances and decreased oxygenation. Calculated oxygen saturation may not accurately reflect oxygenation; oxygen saturation should be measured from oxygen tension (Erstad, 1992).

C) BLOOD/SERUM CHEMISTRY

1) Monitor liver function tests.
2) Dapsone blood levels have not been well correlated with the severity of clinical symptomatology, but can be useful to confirm the diagnosis.

a) Therapeutic doses of 50 to 100 mg/day correspond with steady state serum concentrations of 1 to 3.5 +/- 0.5 mcg/mL (0.004 to 0.014 +/- 0.002 mmol/L) (Zuidema et al, 1986).
b) Plasma levels of monoacetyldapsone in patients with AIDS given 100 mg of dapsone daily were 0.87 +/- 0.6 mcg/mL (range 0.3 to 1.9) (Lee et al, 1989).

4.1.3)

A) URINALYSIS

1) Monitor urine for hemoglobinuria.
2) If hemolysis occurs, monitor urine flow for adequate urine output.

B) SPECIFIC AGENT

1) Dapsone and monoacetyldapsone (MADDS) levels can be measured in urine, and if available may be useful to follow urinary excretion.

4.1.4)

A) OTHER

1) G6PD levels should be analyzed prior to the initiation of oral therapy.

Methods

A)

1) Dapsone and its major metabolite, monoacetyldapsone (MADDA) can be quantitated in blood and urine with Gas-Liquid Chromatography (GLC), High Performance Liquid Chromatography (HPLC), High Performance Thin Layer Chromatography (HPTLC), and fluorometric methods (Zuidema et al, 1986; Berlin et al, 1985).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients exhibiting significant symptoms should be admitted, potentially to an ICU depending on symptoms, until symptoms resolve.

6.3.1.2) HOME CRITERIA/ORAL

A) In general, children with inadvertent ingestions should be evaluated, as methemoglobinemia has developed after 100 mg ingestions in toddlers. Patients with uncertain exposures and who are asymptomatic may be monitored at home, but all others should be evaluated at a health care facility.

6.3.1.3) CONSULT CRITERIA/ORAL

A) For the acutely ill patient, the following may need to be consulted: an intensivists (to assess for possible mechanical ventilation), a hematologist (to rule out other causes of anemia), and a nephrologist (to assess for potential dialysis). If available, a toxicologist can help guide therapy, and poison centers should be notified of all exposures.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Any patient who is experiencing symptoms or who had a self-harm attempt should be sent to a health care facility for observation. Observe asymptomatic patients for 4 to 6 hours. Admit patients with severe symptoms, those who develop methemoglobinemia requiring treatment, or patients who are still symptomatic at the end of observation.
B) Cases of prolonged methemoglobinemia have been reported after dapsone overdose (Lambert et al, 1982; Berlin et al, 1985). Patients may require several days of inpatient observation.

Monitoring

A)

B)

C)

D)

Oral Exposure

6.5.1)

A) EMESIS/NOT RECOMMENDED

1) Ipecac-induced vomiting is not recommended.

B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

B) GASTRIC LAVAGE

1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).

a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.

2) PRECAUTIONS:

a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.

3) LAVAGE FLUID:

a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.

4) COMPLICATIONS:

a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).

5) CONTRAINDICATIONS:

a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.

C) MULTIPLE-DOSE ACTIVATED CHARCOAL

1) Volunteer studies and case reports of poisoned patients suggest than multiple doses of activated charcoal increase the clearance of dapsone. This therapy has not been shown to affect outcome after overdose, or to decrease the likelihood of methemoglobinemia or hemolysis. It should be considered in patients with a life threatening amount of dapsone.
2) 20 grams 4 times a day for several days following an overdose may decrease the half-life and increase the elimination of dapsone and its metabolites (Elonen et al, 1979). Neuvonen et al (1980) demonstrated a 3 to 5 fold increase in dapsone and monoacetyldapsone elimination by using charcoal 80 g/day for 1 to 2 days postingestion. This may be due to secretion of dapsone into the gut, and subsequent reabsorption.
3) CASE SERIES/PEDIATRIC: In a series of 18 children under the age of 14 years who were acutely exposed to dapsone with methemoglobin levels greater than 20% (range: 23.5% to 49.7%), all children received activated charcoal in multiple doses (1 g/kg, 3 to 6 times/day, 3 to 16 doses, median=8 doses) (Bucaretchi et al, 1998). In 12 of 14 children with a methemoglobin level greater than 30.0%, methylene blue 1% to 2% was given as a single dose of 1 to 2 mg/kg infused over 5 minutes; no further doses were required. The authors reported that this treatment was considered safe and effective in this series.
4) MULTIPLE DOSE ACTIVATED CHARCOAL

a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).

6.5.3)

A) SUPPORT

1) Treatment is largely supportive, intravenous fluids and antiemetics may be necessary for patients with persistent vomiting. Symptomatic methemoglobinemia should be treated with methylene blue.

B) MONITORING OF PATIENT

1) G6PD levels should be analyzed prior to the initiation of oral therapy.
2) Monitor pulse oximetry. Monitor CBC and urinalysis for evidence of hemolysis.
3) Obtain a methemoglobin concentration in patients with cyanosis or symptoms of methemoglobinemia.
4) Dapsone levels are not readily available and are not clinically useful.

C) METHEMOGLOBINEMIA

1) SUMMARY

a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.

2) METHYLENE BLUE

a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).

3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)

a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.

4) CAUTION: Methylene blue reduction depends on G6PD and should NOT be given to fully expressed G6PD deficient patients (Prod Info Dapsone, 1997).
5) CASE REPORT: Methylene blue has precipitated Heinz body hemolytic anemia in a 45-year-old man who was treated for methemoglobinemia following dapsone overdose (Goldstein, 1974).
6) CONTINUOUS INFUSION

a) Dapsone has a long half-life which provides a continuing oxidative stress that can cause rebound methemoglobinemia. In patients with significant methemoglobinemia following an overdose of dapsone, treatment with methylene blue should begin with an IV bolus dose (1 to 2 mg/kg), followed by a continuous IV infusion of methylene blue (initial rate 0.1 to 0.15 mg/kg). Titrate the dose based on the concentration of methemoglobin (Dawson & Whyte, 1989).
b) INTERMITTENT vs CONTINUOUS THERAPY: In one study of 11 children with accidental dapsone ingestion (dose range, 350 to 600 mg), continuous intravenous methylene blue therapy was more effective in reducing blood methemoglobin level than intermittent regimen. Children were randomized to receive either intermittent methylene blue therapy (group 1; n=5; 2 mg/kg/doses every 6 hours) or continuous intravenous regimen (group 2; n=6; 2 mg/kg over 6 hours). On admission, the mean blood methemoglobin levels for group 1 and 2 were 52.7 +/- 2.52 and 52.8 +/- 3.02, respectively. The reduction in methemoglobin levels in group 2 was statistically significant after 12, 24, 36, 48 and 72 hours of methylene blue therapy as compared to group 1. After 72 hours, the mean methemoglobin levels for group 1 and 2 were 20.060 +/- 1.496 and 11.2 +/- 1.414, respectively (P= 0.001) (Prasad et al, 2008).
c) CASE REPORT: Methylene blue was given as a continuous infusion in one case of prolonged methemoglobinemia induced by dapsone overdose (Berlin et al, 1985), but cannot be considered standard therapy at this time.
d) CASE REPORT: A 31-year-old man developed rebound methemoglobinemia after receiving several doses of methylene blue (100 mg IV) following an intentional polydrug exposure which included dapsone. The patient was started on a continuous infusion of methylene blue at 0.2 mg/kg/hour for 3.5 hours (Wells & Haroldson, 1997). Total dose was 473 mg (6.3 mg/kg) with no sequelae or rebound methemoglobinemia reported.
e) In a case series of 18 children under the age of 14 who were acutely exposed to dapsone, 12 of 14 children with a methemoglobin level greater than 30%, were given methylene blue 1% to 2% as a single dose of 1 to 2 mg/kg infused over 5 minutes. Aggressive decontamination with multiple-dose activated charcoal was also administered. The authors reported that this treatment was considered safe and effective in this series (Bucaretchi et al, 1998).

7) NONSTANDARD PREPARATIONS: It was reported that an adult with a methemoglobin level of 56% and moderate hypoxia (P02 42.9 mmHg, O2 saturation 75.3%) was given commercially available methylene blue (used for mycobacterial staining) when an intravenous formulation was not readily available. Improvement was noted within 2 hours of administration with no sequelae reported (Sheela et al, 1993).
8) MONITORING: Monitor the CBC closely for evidence of hemolytic anemia. Transfusion could be required if the hematocrit falls precipitously or if there are signs of hemodynamic instability. Monitor methemoglobin levels frequently; clinical features of cyanosis should NOT guide therapy as methylene blue causes grayish blue discoloration of skin. Maintain an adequate urine output.

D) CIMETIDINE

1) DAPSONE toxicity appears related to dapsone metabolism. Animal studies have shown a decrease in methemoglobin formation when cimetidine was given concurrently with a once a day dosing (Coleman et al, 1991). When tested in humans given 400 mg of cimetidine three times daily for 3 days before and 4 days after dapsone, drug concentrations increased 30% (less metabolism) (Coleman & Tingle, 1992). This has not been tried in the overdose situation.
2) Another in vitro study showed no inhibition of methemoglobin formation by cimetidine (Tingle et al, 1990).

E) KETOCONAZOLE

1) Ketoconazole has been shown to reduce dapsone-caused methemoglobinemia in vitro, (Tingle et al, 1990) but may be too toxic a compound to use in dapsone poisoning (Coleman & Tingle, 1992).

F) ASCORBIC ACID

1) CASE REPORT: An 84-year-old woman developed methemoglobinemia (peak methemoglobin concentration of 64.4%) after ingesting 7 dapsone tablets. Due to the unavailability of methylene blue, the patient was administered 10 g vitamin C intravenously for 10 minutes. Approximately 15 hours post- presentation, her methemoglobin concentration decreased to 38% and a second 10-g dose was administered. The patient's methemoglobin concentration rebounded to 46.9% 21 hours post-presentation, necessitating a third dose of vitamin C, resulting in clinical improvement and a decreased methemoglobin concentration of 21.5% (27 hours post-presentation). Due to the possibility of rebounding, the patient was then started on intravenous administration of vitamin C 10 g every 6 hours until her methemoglobin concentration decreased to less than 10%. Treatment was discontinued approximately 54 hours post-presentation and she was subsequently discharged after 6 days. During vitamin C treatment, the patient occasionally experienced nausea and epigastric discomfort, but there were no renal complications reported (Park et al, 2014).
2) CASE REPORT: A 30-year-old woman with linear bullous immunoglobulin A dermatosis treated with dapsone 50 mg daily, but suspected of taking larger daily doses for several weeks, developed methemoglobinemia (methemoglobin level of 32%), retinal ischemia resulting in decreased visual acuity (20/200 of the right eye and 20/400 of the left eye), and hemolytic anemia (hemoglobin level 7.4 g/dL, reticulocytes 12.6%, platelet count 157,000/mm(3), schistocytes 2% to 5%, haptoglobin level less than 10 mg/dL). Liquid chromatography revealed a serum dapsone and N-acetyl dapsone (metabolite) concentrations of 20,044 mcg/mL (therapeutic range 1 to 3.5 +/-0.5 mcg/mL) and 16,095 mcg/mL, respectively. Methylene blue (1 mg/kg IV, repeated twice during the first day) was co-administered with vitamin C (500 mg IV three times daily), resulting in a decrease in her hemoglobin level to 10% to 15%; however, her hemolytic anemia worsened, with a nadir hemoglobin level of 5.4 g/dL, schistocytes of greater than 8%, platelet count of 85,000/mm(3), and a haptoglobin level of less than 10 mg/dL. Further laboratory analysis of the patient revealed that she had traits for sickle cell anemia and alpha-thalassemia. Following an exchange transfusion, her hemolytic anemia and methemoglobinemia resolved, with evidence of visual improvement (20/100 of the right eye, 20/125 of the left eye) at her 6-month follow-up (Hanuschk et al, 2015).

Enhanced Elimination

A)

1) The use of charcoal hemoperfusion was reported in a case of clinical deterioration despite treatment with charcoal and methylene blue. They saw, after 4 hours of hemoperfusion, a reduction of the t1/2 to 90 minutes with significant clinical improvement (Endre et al, 1983).

B)

1) SUMMARY: Hemodialysis appears to be equally as effective as multiple-dose charcoal in enhancing elimination of dapsone and its metabolites.
2) Hemodialysis (without charcoal hemoperfusion) was tried by Neuvonen et al (1983). Three separate 5 hour periods were used. During each period the dapsone t1/2 was reduced to approximately 10 hours, but due to a rebound effect the t1/2 over the total period was 26 hours.
3) Szajewski et al (1972) also reported that hemodialysis was effective in a patient (Szajewski et al, 1972).

C)

1) In a 15-year-old girl with an intentional dapsone ingestion, continuous veno-venous hemofiltration (CVVH) was initiated and maintained for 75 hours when treatment with gastric lavage, IV methylene blue, and activated charcoal failed to effectively lower toxic dapsone levels. Initial treatment included IV methylene blue (150 mg in 3 divided doses), gastric lavage, and activated charcoal. In the ICU, multi-dose activated charcoal (MDAC) (25 mg) was continued every 6 hours, IV methylene blue (0.1 mg/kg/hr), IV ascorbic acid 1 g every 6 hours, and IV folinic acid at 15 mg/day. However, after initially dropping to 9.9% (46.8% at presentation), methemoglobin levels rebounded to 18.7% within 10 hours of presentation. Continuous hemofiltration was initiated and maintained for 75 hours, during CVVH dapsone and metabolite monoacetyldapsone concentrations decreased from 59.82 and 16 mcg/mL, respectively to subtherapeutic levels. Dapsone half-life was 12.7 hours during CVVH and 40.9 hours after CVVH. Monacetyldapsone half-life was 12.6 hours during CVVH and 48.6 hour after CVVH. MDAC was discontinued on day 2 due to the development of an ileus. The patient was discharged to home on day 11 with no sequelae (Masurkar et al, 2011).

D)

1) Plasma exchange removed only 2% of an ingested dose in 1 patient; the authors did not feel it was beneficial (Berlin et al, 1985).
2) Exchange transfusion brought only temporary decreases in methemoglobinemia in a patient who ingested 10 g (Szajewski et al, 1972).
3) Exchange transfusion appeared to be beneficial in a 2-year-old boy who ingested an unknown amount of dapsone and did not respond to 2 doses of methylene blue (0.2 mL/kg of 1% solution) given intravenously 1 hour apart. Methemoglobin levels decreased from 46% to 25% (determined by spectrophotometry). His clinical condition improved and he was extubated after the exchange. Methemoglobin levels were 16.3% 2 weeks later (Kumar et al, 1988).
4) CASE REPORT: A 30-year-old woman with linear bullous immunoglobulin A dermatosis treated with dapsone 50 mg daily, but suspected of taking larger daily doses for several weeks, developed methemoglobinemia (methemoglobin level of 32%), retinal ischemia resulting in decreased visual acuity (20/200 of the right eye and 20/400 of the left eye), and hemolytic anemia (hemoglobin level 7.4 g/dL, reticulocytes 12.6%, platelet count 157,000/mm(3), schistocytes 2% to 5%, haptoglobin level less than 10 mg/dL). Liquid chromatography revealed a serum dapsone and N-acetyl dapsone (metabolite) concentrations of 20,044 mcg/mL (therapeutic range 1 to 3.5 +/-0.5 mcg/mL) and 16,095 mcg/mL, respectively. Methylene blue (1 mg/kg IV, repeated twice during the first day) was co-administered with vitamin C (500 mg IV three times daily), resulting in a decrease in her hemoglobin level to 10% to 15%; however, her hemolytic anemia worsened, with a nadir hemoglobin level of 5.4 g/dL, schistocytes of greater than 8%, platelet count of 85,000/mm(3), and a haptoglobin level of less than 10 mg/dL. Further laboratory analysis of the patient revealed that she had traits for sickle cell anemia and alpha-thalassemia. Following an exchange transfusion (1041 mL was exchanged), her hemolytic anemia and methemoglobinemia resolved, with evidence of visual improvement (20/100 of the right eye, 20/125 of the left eye) at her 6-month follow-up (Hanuschk et al, 2015).

E)

1) Volunteer studies and case reports of poisoned patients suggest than multiple doses of activated charcoal crease the clearance of dapsone. This therapy has not been shown to affect outcome after overdose, or to decrease the likelihood of methemoglobinemia or hemolysis. It should be considered in patients with a life threatening amount of dapsone.
2) Twenty grams 4 times a day for several days following an overdose may decrease the half-life and increase the elimination of dapsone and its metabolites (Elonen et al, 1979). Neuvonen et al (1980) demonstrated a 3 to 5 fold increase in dapsone and monoacetyldapsone elimination by using charcoal 80 g/day for 1 to 2 days postingestion. This may be due to secretion of dapsone into the gut, and subsequent reabsorption.
3) CASE SERIES/PEDIATRIC: In a series of 18 children under the age of 14 years who were acutely exposed to dapsone with methemoglobin levels greater than 20% (range 23.5% to 49.7%), all children received activated charcoal in multiple doses (1 g/kg, 3 to 6 times/day, 3 to 16 doses, median=8 doses) (Bucaretchi et al, 1998). In 12 of 14 children with a methemoglobin level greater than 30.0%, methylene blue 1% to 2% was given as a single dose of 1 to 2 mg/kg infused over 5 minutes; no further doses were required. The authors reported that this treatment was considered safe and effective in this series.
4) MULTIPLE DOSE ACTIVATED CHARCOAL

a) ADULT DOSE: Optimal dose not established. After an initial dose of 50 to 100 grams of activated charcoal, subsequent doses may be administered every 1, 2 or 4 hours at a dose equivalent to 12.5 grams/hour (Vale et al, 1999), do not exceed: 0.5 g/kg charcoal every 2 hours (Ghannoum & Gosselin, 2013; Mauro et al, 1994). There is some evidence that smaller more frequent doses are more effective at enhancing drug elimination than larger less frequent doses (Park et al, 1983; Ilkhanipour et al, 1992). PEDIATRIC DOSE: Optimal dose not established. After an initial dose of 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) (Chyka & Seger, 1997), subsequent doses may be administered every 1, 2 or 4 hours (Vale et al, 1999) in a dose equivalent to 6.25 grams/hour in children 1 to 12 years old.
b) Activated charcoal should be continued until the patient's clinical and laboratory parameters, including drug concentrations if available, are improving (Vale et al, 1999). The patient should be frequently assessed for the ability to protect the airway and evidence of decreased peristalsis or intestinal obstruction.
c) Use of cathartics has not been shown to increase drug elimination and may increase the likelihood of vomiting. Routine coadministration of a cathartic is NOT recommended (Vale et al, 1999).
d) AGENTS AMENABLE TO MDAC THERAPY: The following properties of a drug that are likely to allow MDAC therapy to be effective include: small volume of distribution, low protein binding, prolonged half-life, low intrinsic clearance, and a nonionized state at physiologic pH (Chyka, 1995; Ghannoum & Gosselin, 2013).
e) Vomiting is a common adverse effect; antiemetics may be necessary.
f) CONTRAINDICATIONS: Absolute contraindications include an unprotected airway, intestinal obstruction, a gastrointestinal tract that is not intact and agents that may increase the risk of aspiration (eg, hydrocarbons). Relative contraindications include decreased peristalsis (eg, decreased bowel sounds, abdominal distention, ileus, severe constipation) (Vale et al, 1999; Mauro et al, 1994).
g) COMPLICATIONS: Include constipation, intestinal bleeding, bowel obstruction, appendicitis, charcoal bezoars, and aspiration which may be complicated by acute respiratory failure, adult respiratory distress syndrome or bronchiolitis obliterans (Ghannoum & Gosselin, 2013; Ray et al, 1988; Atkinson et al, 1992; Gomez et al, 1994; Mizutani et al, 1991; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Mina et al, 2002; Harsch, 1986; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002).

Abstracts

Case Reports

A)

1) ORAL

a) A 26-year-old man ingested 15 grams of dapsone (Berlin et al, 1985). On admission 10 hours after ingestion, the patient presented with cyanosis, tachycardia, restlessness, and vomiting. Arterial blood gases were: pH of 7.5, pCO2 of 33 mmHg, and pO2 of 67 mmHg on 35% FiO2. The patient had a methemoglobin level of almost 50% on admission.

1) Hemolytic anemia and mild elevations in liver transaminases developed. The patient was treated with both boluses and a continuous infusion of methylene blue, forced diuresis, multiple-dose oral activated charcoal, and plasma exchange.
2) Approximately, 2% of the ingested dose was removed with this technique. Despite a high blood level of approximately 80 mcg/mL (0.32 mmol/L), the patient recovered fully.

b) Following a 10 g ingestion in a 45-year-old man, marked methemoglobinemia, cyanosis, confusion, headache and signs of hemolysis were observed (Elonen et al, 1979). Therapy with methylene blue and activated charcoal were reported to decrease the dapsone and metabolite half-life. Methemoglobinemia resolved after 7 days. The authors concluded that activated charcoal for several days may be helpful in accelerating drug elimination.
c) Goldstein (1974) reported that methylene blue treatment for methemoglobinemia may be dangerous. Heinz body hemolytic anemia was precipitated in a 45-year-old Caucasian man following its use for methemoglobinemia following a dapsone overdose (Goldstein, 1974).
d) Dapsone overdose (1 to 10 g) was described in 3 patients by Neuvonen et al (1983). All presented with cyanosis and nausea; 2 experienced severe emesis. Headache, hallucinations, and respiratory or metabolic acidosis were observed. Acute cyanosis was related to methemoglobinemia, which was followed by late hemolysis within 1 to 2 weeks (Neuvonen et al, 1983).

1) Administration of activated charcoal (20 g orally QID) increased the rate of dapsone elimination, indicating enterohepatic circulation of the drug (charcoal was administered 2 days after ingestion).
2) The efficacy of oral charcoal was comparable to the effects of hemodialysis in increasing dapsone elimination, as well as its metabolite monoacetyldapsone. Activated charcoal is suggested as the agent of first choice in dapsone intoxication (Neuvonen et al, 1983).

2) INJECTION

a) Following an injection of 375 mg in a 20-year-old woman, symptoms of severe nausea, giddiness and cold perspiration with tongue and fingertip cyanosis were observed (Rajagopalan & Rao, 1967).

1) Grayish to black blood compatible with methemoglobinemia was treated with methylene blue 50 mg every 6 hours. A negative methemoglobinemia was observed after 4 days; the white blood count remained within normal limits.
2) Tachycardia (pulse rate of 150/minute) remained throughout hospitalization with a discharged heart rate of 100 beats/minute. The authors were unable to explain the persistence of the tachycardia.

B)

1) INFANT

a) ORAL

1) An 18-month-old infant who ingested a single 100 mg dapsone tablet developed cyanosis 3 to 4 hours after ingestion. Cyanosis, a methemoglobin level of 27%, and arterial blood gas findings of mild acidosis (pH 7.30, pCO2 26.8 mmHg, HCO3 13.7 mEq/L) were noted on admission. There were no other findings and the child was in no obvious distress. Methylene blue 1 mg/kg was administered in the emergency department. The cyanosis cleared initially, but rapidly reappeared. Multiple doses of oral activated charcoal were then administered, the methemoglobin level decreased to 2.3% by 64 hours after ingestion, and the child recovered fully (Reigart et al, 1983).

2) ORAL

a) One study reported tachycardia, a methemoglobin level of 4.3 g/100 mL, a hemoglobin drop to 10.2 g/100 mL after a week, vomiting, and purpuric spots in 2 children age 3 years and 23 months ingesting unknown quantities of dapsone (Cook, 1970).

Range Of Toxicity

Minimum Lethal Exposure

A)

B)

1) An ingestion of 1450 mg was lethal in a 16-year-old boy (Elonen et al, 1979).
2) An estimated ingestion of 5 g of dapsone was fatal in an adult, despite treatment. Methemoglobin level peaked at 66.6%. The patient died from septic multiorgan failure syndrome 10 days after admission (Wagner et al, 1995).

Maximum Tolerated Exposure

A)

1) In the same study, 30 of the 43 patients developed hemolytic anemia secondary to dapsone poisoning. The ingested dapsone dose was significantly higher in the hemolytic anemia group than in the non-hemolytic group 13 patients; 30.2%), with a median dose of 500 mg in the hemolytic anemia group (dose ranging from 700 to 1250 mg) compared to a median dose of 400 mg in the non-hemolytic group (dose ranging from 350 to 600 mg) (Cha et al, 2016).

B)

1) ADULT

a) Three to 15 g have resulted in severe intoxication in adults (Endre et al, 1983; Elonen et al, 1979; Chawla et al, 1993).

1) Symptoms of methemoglobinemia began as early as 2 hours after exposure and up to 40 hours later in 3 adults following intentional dapsone and polydrug exposure; dose ranges were between 1.4 to 6 g (Casey & Tracey, 1999).

b) A man survived an ingestion of 100 mg dapsone, 100 mg clofazimine, and 2 tablets of rifampicin (600 mg). The maximum plasma concentration of dapsone and monoacetyldapsone was 20.7 mcg/mL and 15 mcg/mL, respectively (Hoetelmans et al, 1996).

2) PEDIATRIC

a) A 15-year-old girl who intentionally ingested 7.2 g of dapsone, along with small amounts of azathioprine, methotrexate, methylprednisolone and prednisolone, presented to the emergency department with an altered mental status, methemoglobinemia and lactic acidosis. Initial treatment included mechanical ventilation, IV methylene blue, and multiple dose activated charcoal. Continuous veno-venous hemofiltration was added and maintained for 75 hours to effectively lower dapsone concentrations. She recovered completely (Masurkar et al, 2011).
b) A 14-year-old girl survived a deliberate ingestion of a 8 to 9 g of dapsone (Ferguson & Lavery, 1997).
c) Twelve hundred mg produced severe intoxication in an adolescent boy, and 500 mg produced no symptoms in a 10-year-old boy (Elonen et al, 1979).

3) INFANT

a) An 18-month-old infant developed methemoglobinemia and acidosis after ingesting 100 mg (Reigart et al, 1983).
b) A 2-year-old boy developed central cyanosis, irritability, and unconsolable crying 20 hours after ingesting an unknown amount of dapsone. There were no signs of hemolysis on peripheral smear. Cyanosis and irritability responded completely to 2 IV doses of 1% methylene blue (1 mg/kg) given slowly over 5 minutes; 4 hours apart (Nayak et al, 1989).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) ADULT

a) An adult developed severe symptoms but survived after ingesting 15 g. The highest measured dapsone level was 80 mcg/mL (Berlin et al, 1985).
b) Two adults who developed severe symptoms but survived after ingesting 10 grams each had levels of 120 mcg/mL and 30 mcg/mL (Elonen et al, 1979; Neuvonen et al, 1983).
c) An 18-year-old girl who ingested 10 g had a blood level of 12 mg/100 mL (Szajewski et al, 1972).
d) Another adult ingested 4 grams, developed severe symptoms, and had a measured level of 22.3 mcg/mL (Endre et al, 1983).

2) PEDIATRIC

a) A child who ingested an unknown amount and died had a level of 150 mcg/mL, while a child who survived after developing severe symptoms following ingestion of an unknown amount had a level of 73 mcg/mL (Elonen et al, 1979).
b) A 15-year-old-girl intentionally ingested 7.2 g of dapsone and presented to the emergency department with a dapsone level of 59.82 mcg/mL (therapeutic: 1 to 3.5 mcg/mL), a metabolite monoacetyldapsone (MADDS) level of 16 mcg/mL, and a methemoglobin level of 46.8% (58.5 g/L). She was treated aggressively, including continuous veno-venous hemofiltration, and gradually improved (Masurkar et al, 2011).
c) A 3.5-year-old girl had recurrent episodes of cyanosis during a 48-hour period of hospitalization. The initial methemoglobin level was 44.7%. Methylene blue 1 mg/kg was administered IV over 5 minutes on admission and again at 48 hours after admission. Her 24-hour dapsone level was 3.9 mcg/mL. Mild residual cyanosis resolved within 2 weeks of presentation. The amount of dapsone ingested was not determined (Linakis et al, 1989).

3) GENERAL

a) In most case reports, methemoglobin levels (expressed as percentage of total hemoglobin) correlated well with symptoms, when the underlying medical condition of the patient was taken into consideration (Hall et al, 1986):

1) 15% to 20%: Clinical cyanosis and chocolate-brown blood becoming evident; patient is usually asymptomatic
2) 20% to 45%: Headache, lethargy, dizziness, fatigue, syncope, dyspnea
3) 45% to 55%: Increasing CNS depression
4) 55% to 70%: Coma, seizures, arrhythmias, shock
5) Greater than 70%: High incidence of mortality

Workplace Standards

A)

1) Not Listed

B)

1) Not Listed

C)

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Dapsone

a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D)

1) Not Listed

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) DISEASE STATE

1) ACNE VULGARIS

a) 5% TOPICAL GEL: Apply a pea-sized amount in a thin layer to the acne-affected area twice daily (Prod Info ACZONE(R) topical gel, 2013).
b) 7.5% TOPICAL GEL: Apply a pea-sized amount in a thin layer to the entire face once daily. A thin layer may also be applied to other affected areas once daily (Prod Info ACZONE(R) topical gel, 2016).

2) DERMATITIS HERPETIFORMIS

a) ORAL RECOMMENDED DOSE: Initial titration starts at 50 mg and can be increased to 300 mg daily. Higher doses may be used if full control is not achieved; however, doses should be decreased to a minimum maintenance level as soon as possible (Prod Info DAPSONE oral tablets, 2009).

3) LEPROSY

a) ORAL RECOMMENDED DOSE: 100 mg a day in combination with other anti-leprosy medications (Prod Info DAPSONE oral tablets, 2009).

7.2.2)

A) DISEASE STATE

1) ACNE VULGARIS

a) 5% TOPICAL GEL, 12 YEARS AND OLDER: Apply a pea size amount of 5% gel in a thin layer to the acne-affected area twice daily (Prod Info ACZONE(R) topical gel, 2013).
b) 5% TOPICAL GEL, LESS THAN 12 YEARS: Safety and efficacy have not been established in pediatric patients less than 12 years of age, and is not recommended for this population (Prod Info ACZONE(R) topical gel, 2013).
c) 7.5% TOPICAL GEL, 12 YEARS AND OLDER: Apply a pea-sized amount in a thin layer to the entire face once daily. A thin layer may also be applied to other affected areas once daily (Prod Info ACZONE(R) topical gel, 2016).
d) 7.5% TOPICAL GEL, LESS THAN 12 YEARS: Safety and efficacy have not been established in pediatric patients less than 12 years of age (Prod Info ACZONE(R) topical gel, 2016).

2) DERMATITIS HERPETIFORMIS

a) ORAL RECOMMENDED DOSE: Pediatric patients are treated similarly to adults but with correspondingly smaller doses (Prod Info DAPSONE oral tablets, 2009).

3) LEPROSY

a) ORAL RECOMMENDED DOSE: Pediatric patients are treated similarly to adults but with correspondingly smaller doses (Prod Info DAPSONE oral tablets, 2009).

4) PNEUMOCYSTIS CARINII PROPHYLAXIS

a) RECOMMENDED DOSE: Primary and Secondary Prophylaxis: 1 month of age and older with human immunodeficiency virus: 2 mg/kg orally once a day or 4 mg/kg orally once weekly; MAXIMUM DOSE: 100 mg/day or 200 mg/weekly dose (Centers for Disease Control and Prevention et al, 2009a)

Pharmacology Toxicology

Pharmacologic Mechanism

A)

Toxicologic Mechanism

A)

Physicochemical

Physical Characteristics

A)

Molecular Weight

A)

Animal Toxicology

References

General Bibliography

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DAPSONE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Summary

Therapeutic Dose

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

General Bibliography