Dapsone

• Aphthous Ulcers, Severe (off-label use):
• Oral:
• Initial: Begin with a daily dose of 25 mg for 3 days.
• Increase the dose by 25 mg daily every 3 days up to 100 mg daily for 3 days.
• Subsequently, increase the dose by 25 mg daily every 7 days up to 150 mg daily.
• Administer in 2 divided doses (75 mg dose is given in 3 divided doses).
• Maintenance: Use a dosage of 100 to 150 mg daily in 2 divided doses, with or without concomitant colchicine.
• Bullous Systemic Lupus Erythematosus (off-label use):
• Oral: Start with a dose of 50 mg once daily initially, with or without immunosuppressive therapy.
• The dosage range is 25 to 200 mg daily.
• Dermatitis Herpetiformis (adjunctive agent):
• Oral:
• Initial: Begin with a daily dose of 25 to 50 mg.
• Increase the dose as needed to achieve a range of 100 to 200 mg daily for full control.
• Once the rash is under control, gradually taper the dose to a minimum maintenance dosage based on clinical response.
• Immune Thrombocytopenia (alternative agent) (off-label use):
• Oral: Administer a dosage of 50 to 100 mg daily or 1 to 2 mg/kg/day.
• The duration of therapy should be at least 21 days.
• Leprosy:
• Oral: Use a daily dose of 100 mg as part of an appropriate combination regimen.
• The treatment duration is 12 months for tuberculoid (paucibacillary) disease and 24 months for lepromatous (multibacillary) disease.
• Pemphigus Vulgaris (adjunctive agent) (off-label use):
• Oral:
• Begin with a daily dose of 25 mg for 7 days.
• Increase the dose by 25 mg daily every 7 days up to 100 mg daily for 7 days (4 weeks total therapy).
• Administer in 2 divided doses (a 75 mg dose is given in 3 divided doses).
• The usual dose range is 50 to 200 mg daily.
• Taper and discontinue gradually based on lesion response.
• Pneumocystis Pneumonia in Patients with HIV (alternative agent) (off-label use):
• Oral:
• Prophylaxis (primary or secondary): Administer 100 mg once daily or in 2 divided doses as monotherapy.
• Prophylaxis in combination with weekly pyrimethamine and leucovorin: Use a dosage of 50 mg daily or 200 mg weekly.
• Treatment for mild to moderate disease: Administer 100 mg once daily in combination with trimethoprim for 21 days.
• Pyoderma Gangrenosum (alternative agent) (off-label use):
• Oral: Use a dosage of 50 to 200 mg daily.
• Relapsing Polychondritis (off-label use):
• Oral: Administer a daily dosage of 25 to 200 mg.
• T. Gondii Encephalitis in Patients with HIV (alternative to preferred therapy) (off-label use):
• Primary prophylaxis: Administer 50 mg daily or 200 mg weekly in combination with weekly pyrimethamine and leucovorin.
• Continue until CD4 count is >200 cells/mm3 for >3 months in response to antiretroviral therapy (ART).

Acne Vulgaris:

Important Considerations: This treatment is recommended for patients who have not responded adequately to initial treatments (Ref). Avoid using it simultaneously with benzoyl peroxide, as it may cause temporary yellow-orange discoloration of the skin and facial hair.

Topical Treatment:

• Gel 5%: Apply a small amount, equivalent to the size of a pea, in a thin layer to the affected areas twice daily.
• Gel 7.5%: Apply a small amount, equivalent to the size of a pea, in a thin layer to the entire face once daily. It may also be applied to other affected areas of the body once daily.

• Oral Tablets: Dapsone is available in oral tablet form, typically in strengths of 25 mg, 50 mg, or 100 mg. These tablets are taken by mouth with water.
• Topical Gel: Dapsone is also available as a topical gel formulation, commonly known as Dapsone Gel. The gel is applied externally to the skin for dermatological use. The strength of the topical gel is 5% dapsone.

• Dermatitis Herpetiformis:
• Infants, Children, and Adolescents:
• Initial oral dose: 0.5 to 2 mg/kg/day in 1 to 2 divided doses.
• Maximum initial daily dose in adults: 50 mg/day.
• Adjust the dose as needed to achieve control.
• Usual adult dose: 300 mg/dose.
• For chronic therapy, the dose may be decreased to a range of 0.125 to 0.5 mg/kg/day.
• Idiopathic Thrombocytopenic Purpura (ITP), Refractory:
• Limited data available for Children ≥3 years and Adolescents:
• Oral dose: 1 to 2 mg/kg/day for at least 2 months.
• Response rates in children and adults have been similar.
• Adverse effects may include hemolysis and erythematous rash.
• Methemoglobinemia may occur at a higher incidence in pediatric patients.
• Leprosy:
• Treatment should be managed in consultation with a leprosy expert.
• Recommended duration and dosing vary based on the type of leprosy:
• Paucibacillary (Tuberculoid) Leprosy (1 to 5 patches):
• Infants, Children, and Adolescents: Oral dose of 1 mg/kg/dose once daily for 12 months.
• Use in combination with rifampin.
• Multibacillary (Lepromatous) Leprosy (≥6 patches):
• Infants, Children, and Adolescents: Oral dose of 1 mg/kg/dose once daily for 24 months.
• Use in combination with rifampin and clofazimine.
• Linear IgA Bullous Dermatosis (LABD):
• Limited data available for Infants, Children, and Adolescents:
• Oral dose: 0.5 to 2 mg/kg/day in 1 to 2 divided doses.
• Prednisone may be used in combination.
• Maximum reported daily dose: 4 mg/kg/day.
• Usual adult dose: 25 to 150 mg/day.
• Pneumocystis jirovecii Pneumonia (PCP), Alternative Agent:
• Prophylaxis (primary or secondary) for HIV-exposed/-infected individuals:
• Infants and Children: Oral dose of 2 mg/kg/dose once daily or 4 mg/kg/dose once weekly.
• Adolescents: Oral dose of 100 mg/day or 50 mg once daily in combination with weekly pyrimethamine and leucovorin.
• Toxoplasma gondii, Primary Prophylaxis in HIV-exposed/-infected patients, Alternative Agent:
• Infants and Children: Oral dose of 2 mg/kg/dose once daily in combination with pyrimethamine and leucovorin.
• Adolescents: Oral dose of 50 mg once daily in combination with weekly pyrimethamine and leucovorin.

Treatment for Acne Vulgaris:

• Gel 7.5%:
• Children ≥9 years and Adolescents:
• Topical application: Use a pea-sized amount of gel and apply it to the entire face once daily.
• It can also be applied as a thin layer to other affected areas of the body once daily.
• If there is no improvement after 12 weeks of therapy, reevaluate the patient's condition.
• Gel 5%:
• Children ≥12 years and Adolescents:

• Topical application: Use a pea-sized amount of gel and apply it to the acne-affected areas twice daily.
• If there is no improvement after 12 weeks of therapy, reevaluate the patient's condition.

General Information:

• Dapsone (dapsone topical gel 5%) is intended for external dermatological use only and should not be used in the eyes.
• Physicians should inquire about any history of drug sensitivity before prescribing Dapsone.

Carcinogenesis and Mutagenesis:

• Dapsone has shown increased numerical and structural aberrations in a chromosome aberration assay in Chinese hamster ovary (CHO) cells.
• Dapsone did not exhibit mutagenic effects in a bacterial reverse mutation assay (Ames test) and micronucleus assay in mice.
• Hematologic:

Hemolysis:

• Oral dapsone treatment has been associated with dose-related hemolysis and hemolytic anemia.
• Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency are more susceptible to hemolysis caused by certain drugs.
• Dapsone treatment in patients, including those with G6PD deficiency, did not show clinically significant hemolysis or anemia.
• If signs or symptoms of hemolytic anemia occur, Dapsone should be discontinued.
• Dapsone should not be used in patients taking oral dapsone or antimalarial medications due to the risk of hemolytic reactions.
• Agranulocytosis (characterized by lethargy, weakness, fever, sore throat, and signs of infection) has been reported with oral dapsone treatment, although not observed in clinical trials with topical dapsone.
• The combination of Dapsone with trimethoprim/sulfamethoxazole (TMP/SMX) may increase the likelihood of hemolysis in patients with G6PD deficiency .

Methemoglobinemia:

• Cases of methemoglobinemia have been reported with the use of dapsone gel, especially in patients with glucose-6-phosphate dehydrogenase deficiency or congenital/idiopathic methemoglobinemia.
• Dapsone Gel, 5%, should be avoided in patients with congenital or idiopathic methemoglobinemia.
• Signs and symptoms of methemoglobinemia may appear hours after exposure, characterized by a slate grey cyanosis in the mucous membranes, lips, and nail beds.
• Patients should discontinue Dapsone Gel, 5%, and seek immediate medical attention if cyanosis occurs.
• Dapsone can elevate methemoglobin levels, particularly when used with methemoglobin-inducing agents .

Neurologic:

• Although not observed in clinical trials with topical dapsone, peripheral neuropathy (motor loss and muscle weakness) has been reported with oral dapsone treatment.

Ophthalmologic:

• Patients should avoid contact between Dapsone and their eyes. In case of accidental contact, rinsing with a large amount of water is advised.

Psychiatric:

• Depression and psychosis were reported in a small number of patients during clinical trials, with slightly higher incidences in those treated with Dapsone compared to the vehicle.

Sexual Function/Reproduction:

• In rats, dapsone showed effects on sperm count, motility, and density, as well as changes in the testes and epididymis at oral dosages exceeding the Maximum Recommended Human Dose (MRHD).
• No adverse effects on mating or fertility were observed, and the effects on sperm parameters and reproductive organs were reversible after a recovery period.
• No adequate and well-controlled fertility studies have been conducted in men.

Skin:

• Although not observed in clinical trials with topical dapsone, skin reactions such as toxic epidermal necrolysis, erythema multiforme, dermatitis, erythema nodosum, and urticaria have been reported with oral dapsone treatment.

● Nausea

● Vomiting

● Decreased appetite

● Dizziness

● Blurred vision

● Tinnitus (ringing in the ears)

● Headache

● Insomnia

● Heightened skin sensitivity to sunlight

Less Common:

● Musculoskeletal Discomfort: Experience of back, leg, or stomach pains.

● Cyanosis: Appearance of bluish color in fingernails, lips, or skin.

● Respiratory Difficulty: Difficulty in breathing.

● Fever: Presence of elevated body temperature.

● Decreased Appetite: Loss of appetite.

● Pallor: Paleness of the skin.

● Skin Reaction: Development of a skin rash.

● Fatigue: Unusual tiredness or weakness.

Rare:

● Dermatological Issues: Itching, dryness, redness, scaling, or peeling of the skin, or hair loss.

● Mood and Mental Changes: Alterations in mood or other mental states.

● Peripheral Neuropathy: Numbness, tingling, pain, burning, or weakness in the hands or feet.

● Sore Throat: Irritation or discomfort in the throat.

● Abnormal Bleeding or Bruising: Unusual bleeding or bruising tendencies.

● Jaundice: Yellowing of the eyes or skin.

● Nausea

● Vomiting

● Decreased appetite

● Dizziness

● Blurred vision

● Tinnitus (ringing in the ears)

● Headache

● Insomnia

● Heightened skin sensitivity to sunlight

Absorption:

Systemic Absorption and Steady State

● Systemic absorption of dapsone topical gel 5% was minimal, and steady state was achieved by week one.

● After the last dose, plasma concentrations remained constant for the first 12 hours and then declined with a half-life of approximately 30 hours.

● Increasing the topical dose had negligible impact on plasma kinetic parameters.

Comparison with Oral Dose

● The pharmacokinetics of dapsone topical gel 5% (twice daily for 14 days) were compared to a single 100 mg oral dose of dapsone after a 14-day washout period.

● Total systemic exposure from topical application for 2 weeks, covering the maximum intended area of use, was 112 to 145 times lower than that of a single oral 100 mg dose.

● Table 5 provides a comparison of pharmacokinetics for dapsone and n-acetyldapsone between topical and oral administration.

Urinary Excretion

● In three patients, urinary excretion of dapsone hydroxylamine over an eight-hour period was 32 to 119 times lower after 15 days of topical dapsone treatment compared to a single oral 100 mg dose.

Table 5 - Pharmacokinetic Comparison

● The table presents the analyte (dapsone and n-acetyl dapsone), along with parameters such as Cmax (peak concentration), AUC (area under the curve), and half-life for both topical (Day 14) and oral single dose administrations.

● The ratios (oral/topical) are also provided for comparison.

Distribution and Protein Binding

● Approximately 70% of dapsone is bound to plasma proteins.

● Sulphones, including dapsone, are distributed throughout total body water and various tissues, including the liver, kidney, and skin, following oral administration.

● In vitro skin penetration studies showed high concentrations of dapsone in the stratum corneum, dermis, and epidermis, with minimal penetration into the receiver cell.

Metabolism

● Dapsone undergoes acetylation in the liver and is hydroxylated to the hydroxylamine metabolite by various enzymes, including CYP 3A4, 2E1, 2C8, and particularly 2C9 ..

Excretion

● Approximately 70-80% of dapsone is excreted in the urine as mono-M-glucuronide and mono-M-sulfamate, along with other metabolites.