Dapsone (dapsone)

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Dapsone is applied topically to the skin as a 5% gel.

Dapsone topical gel is for external use only. The gel should not be used orally or intravaginally and contact with the mouth and eyes should be avoided.

The acne affected area should be gently cleansed and dried prior to application of dapsone 5% gel. A pea-sized amount of the gel should be applied in a thin layer and rubbed in gently and completely.

Dapsone 5% gel is gritty with visible drug substance particles. Hands should be washed after applying the gel.

Dapsone 5% gel should be stored at 20-25degreesC, but may be exposed to temperatures ranging from 15-30degreesC. The gel should not be frozen.

Although only small amounts of dapsone are absorbed systemically following topical application to skin, the possibility that drug interactions could occur should be considered. Concomitant use of oral dapsone and certain drugs (e.g., rifampin, anticonvulsants, St. John's wort) may increase the formation of dapsone hydroxylamine, a dapsone metabolite associated with hemolysis. In addition, concomitant use of oral dapsone and folic acid antagonists (e.g., pyrimethamine) may increase the likelihood of adverse hematologic effects.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Dapsone/Didanosine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. Suspected to be due to decreased dissolution of dapsone in the gastrointestinal tract, reducing the bioavailability of dapsone.

CLINICAL EFFECTS: Decreased pharmacological effect of dapsone.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration times of didanosine packets and dapsone by at least two hours. Didanosine chewable tablets did not significantly affect dapsone plasma concentrations.

DISCUSSION: Eleven of 28 patients receiving dapsone for the prophylaxis of pneumocystis carinii pneumonia (PCP) developed PCP when didanosine packets (contains sodium citrate buffer) was administered concurrently.(1) In an earlier unpublished study, 2 of 162 patients treated with dapsone and zidovudine developed PCP.(2) The difference in the treatment groups was attributed to poor dissolution of dapsone resulting from the effects of the citrate-phosphate buffer contained in the packets of didanosine. In two separate studies, didanosine chewable tablets that do not contain sodium citrate buffer did not significantly affect the plasma concentration of dapsone. Two separate randomized, two-period, two treatment, crossover studies with a 21 day washout between treatment groups showed that didanosine, antacids, and other excipients used in didanosine chewable tablets did not significantly affect dapsone plasma concentrations.(3)

Dapsone/Rifamycins

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown but likely involves induction of hepatic enzymes resulting in increased clearance of dapsone.(1-3)

CLINICAL EFFECTS: Concurrent use may lead to decreased levels and clinical effects of dapsone when it is used for treatment or prophylaxis of Pneumocystis jiroveci pneumonia (PCP).(1-5) Since dapsone is extremely potent for treatment of leprosy, this interaction is not clinically relevant in the setting of leprosy.(5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US Department of Health and Human Service guidelines for prevention and treatment of opportunistic infections in patients with HIV recommend avoiding concomitant administration of dapsone with rifamycins if possible and considering use of alternatives to dapsone.(4) Since dapsone is extremely potent for treatment of leprosy, this interaction is not clinically relevant in the setting of leprosy.(5)

DISCUSSION: When given with rifampin, dapsone levels have been found to decrease by 7- to 10-fold.(3,4) In a trial of 16 HIV-positive patients, rifabutin (300 mg daily) lowered the area-under-curve (AUC) of dapsone (50 mg daily) by 27% to 40%.(2,4) Although dapsone dose adjustment is not necessary when it is used for leprosy, the implications of this interaction when dapsone is used for PCP is unknown. Mycobacterium leprae is very sensitive to dapsone, with a minimum inhibitory concentration (MIC) of 2.5 to 10 mcg/L. In contrast, the MIC of dapsone against P. jiroveci is 100 to 10,000 mcg/L. Dapsone concentrations reached with typical PCP therapy is in the range of 100 to 7,000 mcg/L. Thus, a 10-fold reduction in dapsone levels could result in dapsone levels below the MIC for PCP.(5)

Dapsone/Saquinavir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Saquinavir, a strong CYP3A4 inhibitor, may inhibit the metabolism of dapsone at CYP3A4.(1)

CLINICAL EFFECTS: Concurrent administration may result in increased levels and adverse effects of dapsone. Higher dapsone levels may increase risk for agranulocytosis, aplastic anemia, and other blood dyscrasias; dose-related hemolysis; toxic hepatitis and cholestatic jaundice; cutaneous reactions including exfoliative dermatitis; and peripheral neuropathy.(2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of saquinavir states concurrent administration of saquinavir/ritonavir with drugs that are CYP3A4 substrates including dapsone is not recommended.(1) Patient monitoring should include frequent complete blood counts and liver function tests. Dapsone should be discontinued if a significant reduction in leukocytes, platelets or hemopoiesis occurs.(2)

DISCUSSION: In a study of 16 healthy subjects, saquinavir/ritonavir (1000/100 mg BID) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (7.5 mg single dose) 1144% and 327%, respectively.(1) Midazolam is a sensitive CYP3A4 substrate.(3)

There are no moderate interactions for this drug.

Manufacturer states none known.

• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• Hemoglobin H disease
• Hemolytic anemia from pyruvate kinase and g6PD deficiencies
• Methemoglobinemia

• Anemia
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency
• NADH methemoglobin reductase deficiency

• Disease of liver

Adverse effects reported in 10% or more of patients receiving topical dapsone 5% gel are oiliness/peeling, dryness, and erythema at the application site.

More Frequent

• Allergic dermatitis
• Hemolytic anemia
• Methemoglobinemia
• Skin rash
• Urticaria

Rare or Very Rare

• Agranulocytosis
• Altered mental status
• Anemia
• Blood dyscrasias
• Depression
• Drug-induced psychosis
• Exfoliative dermatitis
• Fever
• Glucose-6-phosphate dehydrogenase (g6Pd) deficiency anemia
• Hemolysis
• Hepatocellular damage
• Jaundice
• Lymphadenopathy
• Malaise
• Methemoglobinemia
• Mood changes
• Pancreatitis
• Peripheral neuropathy
• Pharyngitis
• Pruritus of skin
• Severe vomiting
• Suicidal
• Tonic clonic seizure

More Frequent

• Abnormal desquamation
• Dry skin
• Erythema
• Oily skin
• Pruritus of skin

Less Frequent

• Fever
• Sinusitis
• Skin irritation

Rare or Very Rare

• Acute abdominal pain
• Anorexia
• Cough
• Facial edema
• Gastrointestinal irritation
• Headache disorder
• Headache disorder
• Insomnia
• Nausea
• Nervousness
• Skin rash
• Vomiting

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Safety and efficacy of topical dapsone 5% gel have not been established in children younger than 12 years of age.

Category C. (See Users Guide)

Oral dapsone has been associated with embryocidal effects in rats and rabbits when used in dosages approximately 800 and 500 times, respectively, the systemic exposure (based on AUC) observed in human females receiving the maximum recommended dosage of topical dapsone 5% gel. These effects were probably secondary to maternal toxicity.

Topical dapsone 5% gel should be used during pregnancy only if potential benefits outweigh potential risks to the fetus.

Dapsone is distributed into milk following oral administration. Systemic absorption is low following topical application of dapsone 5% gel; however, because of the potential to cause adverse reactions in nursing infants, discontinue nursing or discontinue topical dapsone therapy.

There is insufficient experience with topical dapsone 5% gel in geriatric patients 65 years of age or older to determine whether such individuals respond differently than younger individuals.