PRECAUTIONS
General
Glucose 6-phosphate dehydrogenase levels should be obtained in all patients prior to initiating therapy with ACZONE™ 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™ 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™ 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™ Gel, 5%, were included in the clinical study program. Safety of ACZONE™ 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™ Gel, 5%). Psychosis was reported in 2 of 2372 patients treated with ACZONE™ Gel, 5%, and in 0 of 1660 patients treated with vehicle.
Information for Patients
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Patients should use ACZONE™ Gel, 5%, as directed by the physician. ACZONE™ Gel, 5%, is for external topical use only. ACZONE™ Gel, 5%, is not for oral, ophthalmic or intravaginal use.
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Patients should not use this medication for any disorder other than that for which it was prescribed.
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Patients should tell their physician if they have any history of anemia or an enzyme deficiency (such as G6PD deficiency).
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Patients should be informed as to the need for laboratory evaluation prior to starting ACZONE™ Gel, 5%.
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Patients should report any signs of adverse reactions to their physician.
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Protect ACZONE™ Gel, 5%, from freezing and light. Return to the original carton after application to protect from light.
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See Patient Information for additional information on safety, efficacy, general use, and storage of ACZONE™ Gel, 5%.
Laboratory Tests
Glucose 6-phosphate dehydrogenase levels should be obtained in all patients prior to initiating therapy with ACZONE™ 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.
Drug Interactions
A drug-drug interaction study evaluated the effect of the use of ACZONE™ 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Dapsone was not mutagenicin 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.
In studies conducted for ACZONE™ 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™ 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.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Dapsone has been shown to have an embryocidal effect in rats and rabbits when given 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. There are no adequate and well controlled studies in pregnant women. ACZONE™ Gel, 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, 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, 5%, in the clinical studies. The adverse event rate for ACZONE™ Gel, 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, 5%, is not recommended for use in this age group.
Geriatric Use
Clinical studies of ACZONE™ Gel, 5%, did not include sufficient number of patients aged 65 and over to determine whether they respond differently from younger patients.
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