DAPSONE

Dapsone gel, 5%, contains dapsone, USP a sulfone, in an aqueous gel base for topical dermatologic use. Dapsone gel, 5% is a gritty translucent material with visible drug substance particles. Chemically, dapsone has an empirical formula of C 12 H 12 N 2 O 2 S. It is a white, odorless crystalline powder that has a molecular weight of 248. Dapsone's chemical name is 4,4'-diaminodiphenylsulfone and its structural formula is: Each gram of dapsone gel, 5%, contains 50 mg of dapsone, USP, in a gel of carbomer homopolymer type C, diethylene glycol monoethyl ether, methylparaben, purified water and sodium hydroxide. Chemical Structure

Dapsone Gel, 5%, is indicated for the topical treatment of acne vulgaris. Dapsone gel is indicated for the topical treatment of acne vulgaris ( 1 ).

For topical use only. Not for oral, ophthalmic, or intravaginal use. After the skin is gently washed and patted dry, apply approximately a pea-sized amount of dapsone gel, 5%, in a thin layer to the acne affected areas twice daily. Rub in dapsone gel, 5%, gently and completely. Dapsone gel, 5%, is gritty with visible drug substance particles. Wash hands after application of dapsone gel, 5%. If there is no improvement after 12 weeks, treatment with dapsone gel, 5%, should be reassessed. Apply twice daily ( 2 ). Apply approximately a pea-sized amount of dapsone gel, 5%, in a thin layer to the acne affected area ( 2 ). If there is no improvement after 12 weeks, treatment with dapsone gel, 5%, should be reassessed ( 2 ). For topical use only. Not for oral, ophthalmic, or intravaginal use ( 2 ).

None. None ( 4) .

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).

Trimethoprim/sulfamethoxazole (TMP/SMX) increases the level of dapsone and its metabolites ( 7.1 ). Topical benzoyl peroxide used at the same time as dapsone gel may result in temporary local yellow or orange skin discoloration ( 7.2 ). 7.1 Trimethoprim-Sulfamethoxazole 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) ] .

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from freezing.