Dapsone Gel, 5%

1 INDICATIONS AND USAGE Dapsone gel, 5%, is indicated for the topical treatment of acne vulgaris. Dapsone gel is indicated for the topical treatment of acne vulgaris.

2 DOSAGE AND ADMINISTRATION 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, ophthal mic, or intravaginal use ( 2 ).

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 10%) are oiliness/ peeling, dryness and erythema at the application site. To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals at 1-833-285-4151 or FDA at 1-800-FDA-1088or 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 trials 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) 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% NOS = Not otherwise specified One subjects 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)

12.3 Pharmacokinetics An open-label study compared the pharmacokinetics of dapsone after dapsone gel, 5%, (110 ± 60 mg/day) was applied twice daily (~BSA 22.5%) for 14 days (n=18) with a single 100 mg dose of oral dapsone administered to a subgroup of patients (n=10) in a crossover design. On Day 14 the mean dapsone AUC 0 - 24h was 415 ± 224 ng•h/mL for dapsone gel, 5%, whereas following a single 100 mg dose of oral dapsone the AUC 0-infinity was 52,641 ± 36,223 ng•h/mL. Exposure after the oral dose of 100 mg dapsone was approximately 100 times greater than after the topical dapsone gel, 5% dose, twice a day. In a long-term safety study of dapsone gel, 5% treatment, periodic blood samples were collected up to 12 months to determine systemic exposure of dapsone and its metabolites in approximately 500 patients. Based on the measurable dapsone concentrations from 408 patients (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 12-15 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 patients.