Aczone Information
Aczone (Dapsone) Description
Aczone (Dapsone) ™ Gel, 5%, contains dapsone, a sulfone, in an aqueous gel base for topical dermatologic use. Aczone (Dapsone) ™ Gel is a gritty, translucent material with visible drug substance particles. Chemically, dapsone has an empirical formula of CHNOS. 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 Aczone (Dapsone) ™ (dapsone) Gel, 5%, contains 50 mg of dapsone, USP, in a gel of carbomer 980; diethylene glycol monoethyl ether, NF; methylparaben, NF; sodium hydroxide, USP; and purified water, USP.
Aczone (Dapsone) Clinical Pharmacology
In Vivo Activity:
*Matsuoka, M. A. Dec 2000. Mycobacterium leprae isolate resistant to dapsone, rifampin, ofloxacin and sparfloxacin. Int J Lepr Other Mycobact Dis. 68(4):452-5.
Two randomized, double blind, vehicle controlled, clinical studies were conducted to evaluate Aczone (Dapsone) ™ Gel, 5%, for the treatment of patients with acne vulgaris (N=1475 and 1525). The studies were designed to enroll patients 12 years of age and older with 20 to 50 inflammatory and 20 to 100 non-inflammatory lesions at baseline. In these studies patients applied either Aczone (Dapsone) ™ Gel, 5%, or vehicle control twice daily for up to 12 weeks. Efficacy was evaluated in terms of success on the Global Acne Assessment Score (no or minimal acne) and in the percent reduction in inflammatory, non-inflammatory, and total lesions.
The Global Acne Assessment Score was a 5-point scale as follows:
0. None: no evidence of facial acne vulgaris
1. Minimal: few non-inflammatory lesions (comedones) are present; a few inflammatory lesions (papules/pustules) may be present
2. Mild: several to many non-inflammatory lesions (comedones) are present; a few inflammatory lesions (papules/pustules) are present
3. Moderate: many non-inflammatory (comedones) and inflammatory lesions (papules/pustules) are present; no nodulo-cystic lesions are allowed
4. Severe: significant degree of inflammatory disease; papules/pustules are a predominant feature; a few nodulo-cystic lesions may be present; comedones may be present.
The success rates on the Global Acne Assessment Score (no or minimal acne) at Week 12 are presented in Table 1.
Table 2 presents the mean percent reduction in inflammatory, non-inflammatory, and total lesions from baseline to Week 12.
The clinical studies enrolled about equal proportions of male and female subjects. Female patients tended to have greater percent reductions in lesions and greater success on the Global Acne Assessment Score than males. The breakdown by race in the clinical studies was about 73% Caucasian, 14% Black, 9% Hispanic, and 2% Asian. Efficacy results were similar across the racial subgroups.
Aczone (Dapsone) Indications And Usage
Aczone (Dapsone) ™ Gel, 5%, is indicated for the topical treatment of acne vulgaris.
Glucose 6-phosphate dehydrogenase (G6PD) levels should be obtained prior to initiating therapy with Aczone (Dapsone) ™ Gel, 5%. In patients with a history of anemia and predisposition to increased hemolytic effect with dapsone (e.g., glucose-6-phosphate dehydrogenase deficiency), closer follow-up for blood hemoglobin levels and reticulocyte counts should be implemented (see ). Alternatively, other therapies for acne than Aczone (Dapsone) ™ Gel, 5%, may be considered.
Aczone (Dapsone) Contraindications
Aczone (Dapsone) ™ Gel, 5%, is contraindicated in persons with a hypersensitivity to dapsone or any other component of the formulation.
Aczone (Dapsone) Precautions
Glucose 6-phosphate dehydrogenase levels should be obtained in all patients prior to initiating therapy with Aczone (Dapsone) ™ Gel, 5%. Baseline complete blood counts, including a reticulocyte count, should be obtained in patients who are G6PD deficient or with a history of anemia. Routine follow-up for complete blood count and reticulocyte count should be implemented for patients at risk. If signs, symptoms or laboratory evidence of anemia develop during treatment, use of Aczone (Dapsone) ™ Gel, 5%, should be discontinued. Dose-related hemolysis is the most common adverse event seen in patients treated with oral Dapsone (with or without glucose-6-phosphate dehydrogenase deficiency). Hemolysis may be exaggerated in individuals with G6PD deficiency, methemoglobin reductase deficiency, or hemoglobin M.
While clinical studies conducted did not demonstrate evidence of clinically significant anemia, an increased reticulocyte count and a decreased hemoglobin level were noted to be associated in a G6PD deficient patient treated with Aczone (Dapsone) ™ Gel, 5%, for acne vulgaris who had a complete blood count performed. Only 25 patients with low plasma glucose 6-phosphate dehydrogenase activity treated with Aczone (Dapsone) ™ Gel, 5%, were included in the clinical study program. Safety of Aczone (Dapsone) ™ Gel, 5%, has not been fully evaluated in patients with G6PD deficiency.
Although not observed in the clinical trials with 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).
In the clinical trials, a total of 12 out of 4032 patients were reported to have depression (3 of 1660 treated with vehicle and 9 of 2372 treated with Aczone (Dapsone) ™ Gel, 5%). Psychosis was reported in 2 of 2372 patients treated with Aczone (Dapsone) ™ Gel, 5%, and in 0 of 1660 patients treated with vehicle.
A drug-drug interaction study evaluated the effect of the use of Aczone (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 (AUC0-12) of dapsone and N-acetyl-dapsone (NAD) were increased by about 40% and 20% respectively in presence of TMP/SMX. Notably, systemic exposure (AUC0-12) 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.
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.
Dapsone was not mutagenicin a bacterial reverse mutation assay (Ames test) using and , with and without metabolic activation and was negative in a micronucleus assay conducted in mice. Dapsone increased both numerical and structural aberrations in a chromosome aberration assay conducted with Chinese hamster ovary (CHO) cells.
In studies conducted for Aczone (Dapsone) ™ Gel, 5%, dapsone was not carcinogenic to rats when orally administered to females for 92 weeks or males for 100 weeks at dose levels up to 15 mg/kg/day (approximately 160 times the systemic exposure observed in human males and 300 times the systemic exposure observed in human females as a result of use of the maximum recommended topical dose, based on AUC comparisons).
No evidence of potential to induce carcinogenicity was obtained in a dermal study in which dapsone gel was topically applied to Tg.AC transgenic mice for approximately 26 weeks. Dapsone concentrations of 3%, 5%, and 10% were evaluated; 3% material was judged to be the maximum tolerated dosage.
Aczone (Dapsone) ™ Gel, 5%, did not increase the rate of formation of ultra violet light-induced skin tumors when topically applied to hairless mice in a 12-month photocarcinogenicity study.
The effects of dapsone on fertility and general reproduction performance were assessed in male and female rats following oral (gavage) dosing. Dapsone reduced sperm motility at dosages of 3 mg/kg/day or greater (approximately 17 times the systemic exposure observed in human males as a result of use of the maximum recommended topical dose, based on AUC comparisons). The mean numbers of embryo implantations and viable embryos were significantly reduced in untreated females mated with males that had been dosed at 12 mg/kg/day or greater (approximately 70 times the systemic exposure observed in human males as a result of use of the maximum recommended topical dose, based on AUC comparisons), presumably due to reduced numbers or effectiveness of sperm, indicating impairment of fertility. Dapsone had no effect on male fertility at dosages of 2 mg/kg/day or less (approximately 13 times the systemic exposure observed in human males as a result of use of the maximum recommended topical dose, based on AUC comparisons). When administered to female rats at a dosage of 75 mg/kg/day (approximately 800 times the systemic exposure observed in human females as a result of use of the maximum recommended topical dose, based on AUC comparisons) for 15 days prior to mating and for 17 days thereafter, dapsone reduced the mean number of implantations, increased the mean early resorption rate, and reduced the mean litter size. These effects were probably secondary to maternal toxicity.
Dapsone was assessed for effects on perinatal/postnatal pup development and postnatal maternal behavior and function in a study in which dapsone was orally administered to female rats daily beginning on the seventh day of gestation and continuing until the twenty-seventh day postpartum. Maternal toxicity (decreased body weight and food consumption) and developmental effects (increase in stillborn pups and decreased pup weight) were seen at a dapsone dose of 30 mg/kg/day (approximately 500 times the systemic exposure observed in human females as a result of use of the maximum recommended topical dose, based on AUC comparisons). No effects were observed on the viability, physical development, behavior, learning ability, or reproductive function of surviving pups.
Aczone (Dapsone) Adverse Reactions
While clinical studies conducted with Aczone (Dapsone) ™ Gel, 5%, for acne vulgaris did not demonstrate evidence of clinically significant anemia, an increased reticulocyte count and a decreased hemoglobin level were found in a G6PD deficient patient who had a complete blood count performed. Only 25 patients with low plasma glucose 6-phosphate dehydrogenase activity treated with Aczone (Dapsone) ™ Gel, 5%, were included in the clinical study program.
Serious adverse events reported in patients treated with Aczone (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
Combined contact sensitization/irritation studies with Aczone (Dapsone) ™ Gel, 5%, in 253 healthy subjects resulted in at least 3 subjects with moderate erythema. Aczone (Dapsone) ™ Gel, 5%, did not induce phototoxicity or photoallergy in human dermal safety studies.
Aczone (Dapsone) ™ Gel, 5%, was evaluated for 12 weeks in four controlled studies for local cutaneous events in 1819 patients. The most common events reported from these studies include oiliness/peeling, dryness, and erythema. These data are shown by severity in Table 3 below.
There were no significant differences in the adverse event rates between Aczone (Dapsone) ™ Gel, 5%, and vehicle control treated patients. The adverse events occurring in at least 1% of patients in either arm in the four vehicle controlled studies are presented in Table 4.
One patient treated with topical dapsone in the clinical trials had facial swelling which led to discontinuation of medication.
In addition, 486 patients were evaluated in a 12 month safety study. The adverse event profile in this study was consistent with that observed in the vehicle-controlled studies.
Aczone (Dapsone) Overdosage
Aczone (Dapsone) ™ Gel, 5%, is not for oral use. If oral ingestion occurs, medical advice should be sought.
Aczone (Dapsone) Dosage And Administration
After the skin is gently washed and patted dry, apply approximately a pea-sized amount of Aczone (Dapsone) ™Gel, 5%, in a thin layer to the acne affected areas twice daily. Rub in Aczone (Dapsone) ™Gel, 5%, gently and completely. Aczone (Dapsone) ™ Gel, 5%, is gritty with visible drug substance particles present. Wash hands after application of Aczone (Dapsone) ™ Gel, 5%.
If there is no improvement after 12 weeks, appropriateness of treatment with Aczone (Dapsone) ™ Gel, 5%, should be reassessed.
Aczone (Dapsone) How Supplied
Aczone (Dapsone) ™(dapsone) Gel, 5%, is supplied in the following size tubes:
Professional Sample
5 % NDC 0469-5005-03 Product Code 500503
3 gram laminate tube
Commercially Available as:
5 % NDC 0469-5005-30 Product Code 500530
30 gram plastic tube
Storage conditions:
Store at controlled room temperature, 20-25 °C (68-76 °F), excursions permitted to 15–30 ºC (59–86 ºF). Protect from freezing and light. Return to the original carton after application.
Rx Only
Manufactured by QLT USA, Inc., Fort Collins, CO 80525
