Dapsone

INDICATIONS AND USAGE ACZONE ® (dapsone) Gel, 7.5%, is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. ACZONE ® Gel, 7.5%, is a sulfone indicated for the topical treatment of acne vulgaris in patients 9 years of age and older ( 1 ).

DOSAGE AND ADMINISTRATION Dermatitis herpetiformis The dosage should be individually titrated starting in adults with 50 mg daily and correspondingly smaller doses in children. If full control is not achieved within the range of 50 to 300 mg daily, higher doses may be tried. Dosage should be reduced to a minimum maintenance level as soon as possible. In responsive patients there is a prompt reduction in pruritus followed by clearance of skin lesions. There is no effect on the gastrointestinal component of the disease. Dapsone levels are influenced by acetylation rates. Patients with high acetylation rates, or who are receiving treatment affecting acetylation may require an adjustment in dosage. A strict gluten free diet is an option for the patient to elect, permitting many to reduce or eliminate the need for Dapsone; the average time for dosage reduction is 8 months with a range of 4 months to 2 ½ years and for dosage elimination 29 months with a range of 6 months to 9 years. Leprosy In order to reduce secondary Dapsone resistance, the WHO Expert Committee on Leprosy and the USPHS at Carville, LA, recommended that Dapsone should be commenced in combination with one or more anti-leprosy drugs. In the multidrug program Dapsone should be maintained at the full dosage of 100 mg daily without interruption (with corresponding smaller doses for children) and provided to all patients who have sensitive organisms with new or recrudescent disease or who have not yet completed a two year course of Dapsone monotherapy. For advice and other drugs, the USPHS at Carville, LA (1-800-642-2477) should be contacted. Before using other drugs consult appropriate product labeling. In bacteriologically negative tuberculoid and indeterminate disease, the recommendation is the coadministration of Dapsone 100 mg daily with six months of Rifampin 600 mg daily. Under WHO, daily Rifampin may be replaced by 600 mg Rifampin monthly, if supervised. The Dapsone is continued until all signs of clinical activity are controlled - usually after an additional six months. Then Dapsone should be continued for an additional three years for tuberculoid and indeterminate patients and for five years for borderline tuberculoid patients. In lepromatous and borderline lepromatous patients, the recommendation is the co-administration of Dapsone 100 mg daily with two years of Rifampin 600 mg daily. Under WHO daily Rifampin may be replaced by 600 mg Rifampin monthly, if supervised. One may elect the concurrent administration of a third anti-leprosy drug, usually either Clofazimine 50 to 100 mg daily or Ethionamide 250 to 500 mg daily. Dapsone 100 mg daily is continued 3 to 10 years until all signs of clinical activity are controlled with skin scrapings and biopsies are negative for one year. Dapsone should then be continued for an additional 10 years for borderline patients and for life for lepromatous patients. Secondary Dapsone resistance should be suspected whenever a lepromatous or borderline lepromatous patient receiving Dapsone treatment relapses clinically and bacteriologically, solid staining bacilli being found in the smears taken from the new active lesions. If such cases show no response to regular and supervised Dapsone therapy within three to six months or good compliance for the past 3 to 6 months can be assured, Dapsone resistance should be considered confirmed clinically. Determination of drug sensitivity using the mouse footpad method is recommended and, after prior arrangement, is available without charge from the USPHS, Carville, LA. Patients with proven Dapsone resistance should be treated with other drugs. LEPROSY REACTIONAL STATES Abrupt changes in clinical activity occur in leprosy with any effective treatment and are known as reactional states. The majority can be classified into two groups. The "Reversal" reaction (Type 1) may occur in borderline or tuberculoid leprosy patients often soon after chemotherapy is started. The mechanism is presumed to result from a reduction in the antigenic load: the patient is able to mount an enhanced delayed hypersensitivity response to residual infection leading to swelling ("Reversal") of existing skin and nerve lesions. If severe, or if neuritis is present, large doses of steroids should always be used. If severe, the patient should be hospitalized. In general anti-leprosy treatment is continued and therapy to suppress the reaction is indicated such as analgesics, steroids, or surgical decompression of swollen nerve trunks. USPHS at Carville, LA should be contacted for advice in management. Erythema nodosum leprosum (ENL) (lepromatous reaction) (Type 2 reaction) occurs mainly in lepromatous patients and small numbers of borderline patients. Approximately 50% of treated patients show this reaction in the first year. The principal clinical features are fever and tender erythematous skin nodules sometimes associated with malaise, neuritis, orchitis, albuminuria, joint swelling, iritis, epistaxis or depression. Skin lesions can become pustular and/or ulcerate. Histologically there is a vasculitis with an intense polymorphonuclear infiltrate. Elevated circulating immune complexes are considered to be the mechanism of reaction. If severe, patients should be hospitalized. In general, anti-leprosy treatment is continued. Analgesics, steroids, and other agents available from USPHS, Carville, LA, are used to suppress the reaction.

WARNINGS AND PRECAUTIONS Methemoglobinemia: Cases of methemoglobinemia have been reported. Discontinue dapsone gel if signs of methemoglobinemia occur ( 5.1 ). Hemolysis: Some patients with Glucose-6-phosphate Dehydrogenase (G6PD) deficiency using topical dapsone developed laboratory changes suggestive of hemolysis ( 5.1 ) ( 8.6 ). 5.1 Hematological Effects Methemoglobinemia Cases of methemoglobinemia, with resultant hospitalization, have been reported postmarketing in association with twice daily dapsone gel, 5%, treatment. Patients with glucose-6-phosphate dehydrogenase deficiency or congenital or idiopathic methemoglobinemia are more susceptible to drug-induced methemoglobinemia. Avoid use of dapsone gel, 7.5% in those patients with congenital or idiopathic methemoglobinemia. Signs and symptoms of methemoglobinemia may be delayed some hours after exposure. Initial signs and symptoms of methemoglobinemia are characterized by a slate grey cyanosis seen in e.g., buccal mucous membranes, lips, and nail beds. Advise patients to discontinue dapsone gel, 7.5% and seek immediate medical attention in the event of cyanosis. Dapsone can cause elevated methemoglobin levels particularly in conjunction with methemoglobin-inducing agents [see Drug Interactions ( 7.4 )] . He molysis Oral dapsone treatment has produced dose-related hemolysis and hemolytic anemia. Individuals with glucose-6 -phosphate dehydrogenase (G6PD) deficiency are more prone to hemolysis with the use of certain drugs. G6PD deficiency is most prevalent in populations of African, South Asian, Middle Eastern, and Mediterranean ancestry. In clinical trials, there was no evidence of clinically relevant hemolysis or hemolytic anemia in subjects treated with topical dapsone. Some subjects with G6PD deficiency using dapsone gel, 5%, twice daily developed laboratory changes suggestive of hemolysis [see Use in Specific Populations ( 8.6 )]. Discontinue dapsone gel, 7.5%, if signs and symptoms suggestive of hemolytic anemia occur. Avoid use of dapsone gel, 7.5% in patients who are taking oral dapsone or antimalarial medications because of the potential for hemolytic reactions. Combination of dapsone gel, 7.5%, with trimethoprim/sulfamethoxazole (TMP/SMX) may increase the likelihood of hemolysis in patients with G6PD deficiency [see Drug Interactions ( 7.1 )] . 5.2 Peripheral Neuropathy Peripheral neuropathy (motor loss and muscle weakness) has been reported with oral dapsone treatment. No events of peripheral neuropathy were observed in clinical trials with topical dapsone treatment. 5.3 Skin Reactions Skin reactions (toxic epidermal necrolysis, erythema multiforme, morbilliform and scarlatiniform reactions, bullous and exfoliative dermatitis, erythema nodosum, and urticaria) have been reported with oral dapsone treatment. These types of skin reactions were not observed in clinical trials with topical dapsone treatment.

CONTRAINDICATIONS Hypersensitivity to Dapsone and/or its derivatives.

DRUG INTERACTIONS Trimethoprim/sulfamethoxazole (TMP/SMX) increases the level of dapsone and its metabolites ( 7.1 ). Topical benzoyl peroxide used at the same time as dapsone may result in temporary local yellow or orange skin discoloration ( 7.2 ). 7.1 Trimethoprim-Sulf a methoxazole A drug-drug interaction study evaluated the effect of the use of dapsone gel, 5%, in combination with double strength (160 mg/800 mg) trimethoprim-sulfamethoxazole (TMP/SMX). During co-administration, systemic levels of TMP and SMX were essentially unchanged. However, levels of dapsone and its metabolites increased in the presence of TMP/SMX. Systemic exposure (AUC 0-12 ) of dapsone and N-acetyl-dapsone (NAD) were increased by about 40% and 20% respectively in the presence of TMP/SMX. Notably, systemic exposure (AUC 0-12 ) of dapsone hydroxylamine (DHA) was more than doubled in the presence of TMP/SMX. Exposure from the proposed topical dose is about 1% of that from the 100 mg oral dose, even when co-administered with TMP/SMX. 7.2 Topical Benzoyl Peroxide Topical application of dapsone gel followed by benzoyl peroxide in subjects with acne vulgaris resulted in a temporary local yellow or orange discoloration of the skin and facial hair (reported by 7 out of 95 subjects in a clinical study) with resolution in 4 to 57 days. 7.3 Drug Interactions with Oral Dapsone Certain concomitant medications (such as rifampin, anticonvulsants, St. John’s wort) may increase the formation of dapsone hydroxylamine, a metabolite of dapsone associated with hemolysis. With oral dapsone treatment, folic acid antagonists such as pyrimethamine have been noted to possibly increase the likelihood of hematologic reactions. 7.4 Concomitant Use with Drugs that Induce Methemoglobinemia Concomitant use of dapsone gel with drugs that induce methemoglobinemia such as sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para‐aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and quinine may increase the risk for developing methemoglobinemia [ see Warnings and Precautions ( 5.1 )] . 7.3 Drug Interactions with Oral Dapsone Certain concomitant medications (such as rifampin, anticonvulsants, St. John’s wort) may increase the formation of dapsone hydroxylamine, a metabolite of dapsone associated with hemolysis. With oral dapsone treatment, folic acid antagonists such as pyrimethamine have been noted to possibly increase the likelihood of hematologic reactions.

ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 10%) are oiliness/peeling, dryness and erythema at the application site ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc. at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Serious adverse reactions reported in subjects treated with dapsone gel, 5%, during clinical trials included but were not limited to the following: Nervous system/Psychiatric – Suicide attempt, tonic clonic movements. Gastrointestinal – Abdominal pain, severe vomiting, pancreatitis. Other – Severe pharyngitis In the clinical trials, a total of 12 out of 4032 subjects were reported to have depression (3 of 1660 treated with vehicle and 9 of 2372 treated with dapsone gel, 5%). Psychosis was reported in 2 of 2372 subjects treated with dapsone gel, 5%, and in 0 of 1660 subjects treated with vehicle. Combined contact sensitization/irritation studies with dapsone gel, 5%, in 253 healthy subjects resulted in at least 3 subjects with moderate erythema. Dapsone gel, 5%, did not induce phototoxicity or photoallergy in human dermal safety studies. Dapsone gel, 5%, was evaluated for 12 weeks in four controlled trlals for local cutaneous events in 1819 subjects. The most common events reported from these studies include oiliness/peeling, dryness, and erythema. These data are shown by severity in Table 1 below. Table 1 – Application Site Adverse Reactions by Maximum Severity Dapsone Gel 5% (N=1819) Vehicle (N=1660) Application Site Event Mild Moderate Severe Mild Moderate Severe Erythema 9% 5% <1% 9% 6% <1% Dryness 14% 3% <1% 14% 4% <1% Oiliness/Peeling 13% 6% <1% 15% 6% <1% The adverse reactions occurring in at least 1% of subjects in either arm in the four vehicle controlled trials are presented in Table 2. Table 2 – Adverse Reactions Occurring in at least 1% of Subjects Dapsone Gel 5% (N=1819) Vehicle (N=1660) NOS = Not otherwise specified Application Site Reaction NOS 18% 20% Application Site Dryness 16% 17% Application Site Erythema 13% 14% Application Site Burning 1% 2% Application Site Pruritus 1% 1% Pyrexia 1% 1% Nasopharyngitis 5% 6% Upper Respiratory Tract Inf. NOS 3% 3% Sinusitis NOS 2% 1% Influenza 1% 1% Pharyngitis 2% 2% Cough 2% 2% Joint Sprain 1% 1% Headache NOS 4% 4% One subject treated with dapsone gel in the clinical trials had facial swelling which led to discontinuation of medication. In addition, 486 subjects were evaluated in a 12 month safety trial. The adverse event profile in this trial was consistent with that observed in the vehicle-controlled trials. 6.2 Experience with Oral Use of Dapsone Although not observed in the clinical trials with dapsone gel (topical dapsone) serious adverse reactions have been reported with oral use of dapsone, including agranulocytosis, hemolytic anemia, peripheral neuropathy (motor loss and muscle weakness), and skin reactions (toxic epidermal necrolysis, erythema multiforme, morbilliform and scarlatiniform reactions, bullous and exfoliative dermatitis, erythema nodosum, and urticaria). 6.3 Postmarketing Experience Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of topical dapsone: methemoglobinemia, rash (including erythematous rash, application site rash) and swelling of face (including lip swelling, eye swelling).

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of dapsone gel in treating acne vulgaris is not known. 12.3 Pharmacokinetics In a pharmacokinetic study, male and female subjects 16 years of age or older with acne vulgaris (N=19) applied 2 grams of dapsone gel, 7.5% to the face, upper chest, upper back and shoulders once daily for 28 days. Steady state for dapsone was reached within 7 days of dosing. On Day 28, the mean dapsone maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 24 hours post dose (AUC 0 to 24h ) were 13.0 ± 6.8 ng/mL and 282 ± 146 ng∙h/mL, respectively. The systemic exposure from dapsone gel, 7.5% is expected to be about 1% of that from a 100 mg oral dose. Long-term safety studies were not conducted with dapsone gel, 7.5%, however, in a long-term clinical study of dapsone gel, 5% treatment (twice daily), periodic blood samples were collected up to 12 months to determine systemic exposure of dapsone and its metabolites in approximately 500 subjects. Based on the measurable dapsone concentrations from 408 subjects (M=192, F=216), obtained at Month 3, neither gender nor race appeared to affect the pharmacokinetics of dapsone. Similarly, dapsone exposures were approximately the same between the age groups of 12 to 15 years (N=155) and those greater than or equal to 16 years (N=253). There was no evidence of increasing systemic exposure to dapsone over the study year in these subjects. In an open label safety and pharmacokinetic study in pediatric subjects 9 to 11 years of age with acne vulgaris, a subset of subjects (N = 16) received once daily topical application of approximately 2 grams of dapsone gel, 7.5%, to the entire face, shoulders, upper chest and upper back for 8 days. On Day 8, the systemic concentrations were at or near steady state and the mean ± SD systemic concentration of dapsone at 10 hours post dose was 20 ± 12.5 ng/mL. 12.4 Microbiology In Vivo Activity : No microbiology or immunology studies were conducted during dapsone gel, 7.5% clinical studies. Drug Resistance : No dapsone resistance studies were conducted during dapsone gel clinical studies therefore there are no data available as to whether dapsone treatment may have resulted in decreased susceptibility of Propionibacterium acnes , an organism associated with acne, or to other antimicrobials that may be used to treat acne. Therapeutic resistance to dapsone has been reported for Mycobacterium leprae , when patients have been treated with oral dapsone.