Aczone Gel

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hematological Effects

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.

There was no evidence of clinically relevant hemolysis or anemia in patients treated with ACZONE Gel (dapsone) , 5%, including patients who were G6PD deficient. Some subjects with G6PD deficiency using ACZONE Gel (dapsone) developed laboratory changes suggestive of mild hemolysis.

If signs and symptoms suggestive of hemolytic anemia occur, ACZONE Gel (dapsone) , 5% should be discontinued. ACZONE Gel (dapsone) , 5% should not be used in patients who are taking oral dapsone or antimalarial medications because of the potential for hemolytic reactions. Combination of ACZONE Gel (dapsone) , 5%, with trimethoprim/sulfamethoxazole (TMP/SMX) may increase the likelihood of hemolysis in patients with G6PD deficiency.

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 ACZONE Gel (dapsone) , 5% treatment.

Skin

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 ACZONE Gel (dapsone) , 5% treatment.

Patient Counseling Information

See FDA Approved-Patient Labeling

Information for Patients

  1. Patients should use ACZONE Gel (dapsone) , 5%, as directed by the physician. ACZONE Gel, 5%, is for external topical use only. ACZONE Gel (dapsone) , 5%, is not for oral, ophthalmic or intravaginal use.
  2. Patients should not use this medication for any disorder other than that for which it was prescribed.
  3. Patients should report any signs of adverse reactions to their physician.
  4. Protect ACZONE Gel (dapsone) , 5%, from freezing.
  5. See Patient Labeling for additional information on safety, efficacy, general use, and storage of ACZONE Gel (dapsone) , 5%.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Dapsone was not mutagenic in a bacterial reverse mutation assay (Ames test) using S. typhimurium and E. coli, 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.

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 Gel (dapsone) , 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.

Use In Specific Populations

Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well controlled studies in pregnant women. Dapsone has been shown to have an embryocidal effect in rats and rabbits when administered orally in doses of 75 mg/kg/day and 150 mg/kg/day (approximately 800 and 500 times the systemic exposure observed in human females as a result of use of the maximum recommended topical dose, based on AUC comparisons), respectively. These effects were probably secondary to maternal toxicity. ACZONE Gel (dapsone) , 5%, should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Although systemic absorption of dapsone following topical application of ACZONE Gel, 5%, is minimal relative to oral dapsone administration, it is known that dapsone is excreted in human milk. Because of the potential for oral dapsone to cause adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue ACZONE Gel (dapsone) , 5%, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and efficacy was evaluated in 1169 children aged 12-17 years old treated with ACZONE Gel (dapsone) , 5%, in the clinical studies. The adverse event rate for ACZONE Gel (dapsone) , 5%, was similar to the vehicle control group. Safety and efficacy was not studied in pediatric patients less than 12 years of age, therefore ACZONE Gel (dapsone) , 5%, is not recommended for use in this age group.

Geriatric Use

Clinical studies of ACZONE Gel (dapsone) , 5%, did not include sufficient number of patients aged 65 and over to determine whether they respond differently from younger patients.

G6PD Deficiency

ACZONE Gel (dapsone) , 5% and vehicle were evaluated in a randomized, double-blind, cross-over design clinical study of 64 patients with G6PD deficiency and acne vulgaris. Subjects were Black (88%), Asian (6%), Hispanic (2%) or of other racial origin (5%). Blood samples were taken at Baseline, Week 2, and Week 12 during both vehicle and ACZONE Gel (dapsone) , 5% treatment periods. There were 56 out of 64 subjects who had a Week 2 blood draw and applied at least 50% of treatment applications. Table 3 contains results from testing of relevant hematology parameters for these two treatment periods. ACZONE Gel (dapsone) was associated with a 0.32 g/dL drop in hemoglobin after two weeks of treatment, but hemoglobin levels generally returned to baseline levels at Week 12.

Table 3: Mean Hemoglobin, Bilirubin, and Reticulocyte Levels in Acne Subjects with G6PD Deficiency in ACZONE/Vehicle Cross-Over Study

  ACZONE Vehicle
N Mean N Mean
Hemoglobin (g/dL) Pre-treatment 53 13.44 56 13.36
2 weeks 53 13.12 55 13.34
12 weeks 50 13.42 50 13.37
Bilirubin (mg/dL) Pre-treatment 54 0.58 56 0.55
2 weeks 53 0.65 55 0.56
12 weeks 50 0.61 50 0.62
Reticulocytes (%) Pre-treatment 53 1.30 55 1.34
2 weeks 53 1.51 55 1.34
12 weeks 50 1.48 50 1.41

There were no changes from baseline in haptoglobin or lactate dehydrogenase during ACZONE or vehicle treatment at either the 2-week or 12-week time point.

The proportion of subjects who experienced decreases in hemoglobin ≥ 1 g/dL was similar between ACZONE Gel (dapsone) , 5% and vehicle treatment (8 of 58 subjects had such decreases during ACZONE treatment compared to 7 of 56 subjects during vehicle treatment among subjects with at least one on-treatment hemoglobin assessment). Subgroups based on gender, race, or G6PD enzyme activity did not display any differences in laboratory results from the overall study group. There was no evidence of clinically significant hemolytic anemia in this study. Some of these subjects developed laboratory changes suggestive of mild hemolysis.

Last reviewed on RxList: 3/28/2008
This monograph has been modified to include the generic and brand name in many instances.

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