Dapsone (Page 2 of 4)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no available data on dapsone gel, 7.5%, use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. The systemic absorption of dapsone in humans following topical application is low relative to oral dapsone administration [see Clinical Pharmacology (12.3)]. In animal reproduction studies, oral doses of dapsone administered to pregnant rats and rabbits during organogenesis that resulted in systemic exposures more than 400 times the systemic exposure at the maximum recommended human dose (MRHD) of dapsone gel, 7.5%, resulted in embryocidal effects. When orally administered to rats from the onset of organogenesis through the end of lactation at systemic exposures approximately 500 times the exposure at the MRHD, dapsone resulted in increased stillbirths and decreased pup weight [see Data].

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Dapsone has been shown to have an embryocidal effect in rats and rabbits when administered orally daily to females during organogenesis at dosages of 75 mg/kg/day and 150 mg/kg/day, respectively. These dosages resulted in systemic exposures that represented approximately 1,407 times [rats] and 425 times [rabbits] the systemic exposure observed in human females as a result of use of the MRHD of dapsone gel, 7.5%, based on AUC comparisons. 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 563 times the systemic exposure that is associated with the MRHD of dapsone gel, 7.5%, based on AUC comparisons). No effects were observed on the viability, physical development, behavior, learning ability, or reproductive function of surviving pups.

8.2 Lactation

Risk Summary

There is no information regarding the presence of topical dapsone in breastmilk, the effects on the breastfed infant or the effects on milk production. Orally administered dapsone appears in human milk and could result in hemolytic anemia and hyperbilirubinemia especially in infants with G6PD deficiency. Systemic absorption of dapsone following topical application is low relative to oral dapsone administration.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for dapsone gel, 7.5% and any potential adverse effects on the breastfed child from dapsone gel, 7.5% or from the underlying maternal condition.

8.4 Pediatric Use

The safety and effectiveness of dapsone gel, 7.5% for the topical treatment of acne vulgaris have been established in patients 12 years of age and older. Use of dapsone gel, 7.5% in patients for this indication is supported by evidence from adequate and well-controlled clinical trials in 1,066 subjects 12 years of age and older [see Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].

The safety profile for dapsone gel, 7.5% in clinical trials was similar to the vehicle control group.

Safety and effectiveness of dapsone gel, 7.5%, have not been established in pediatric patients below the age of 9 years.

Pediatric use information is approved for Almirall LLC’s Aczone ® (dapsone) Gel. However, due to Almirall LLC’s marketing exclusivity rights, this drug product is not labeled with that information.

8.5 Geriatric Use

Clinical trials of dapsone gel, 7.5%, did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

8.6 Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency

Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency may be more prone to methemoglobinemia and hemolysis [see Warnings and Precautions (5.1)].

Dapsone gel, 5 % and vehicle were evaluated in a randomized, double-blind, cross-over design clinical study of 64 subjects 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 dapsone gel, 5% treatment periods. Some of these subjects developed laboratory changes suggestive of hemolysis, but there was no evidence of clinically significant hemolytic anemia in this study [see Warnings and Precautions (5.1)].

11 DESCRIPTION

Dapsone Gel, 7.5%, contains dapsone, a sulfone, in an aqueous gel base for topical dermatologic use. Dapsone Gel, 7.5% is an off-white to yellow color homogeneous gel with suspended particles, no phase separation and sedimentation, free of lumps and foreign matter. Chemically, dapsone has an empirical formula of C 12 H 12 N 2 O 2 S. It is a White to creamy white crystalline powder that has a molecular weight of 248.30. Dapsone’s chemical name is 4-[(4′-aminobenzene) sulfonyl] aniline and its structural formula is:

structure

Each gram of dapsone gel, 7.5% contains 75 mg of dapsone, USP in a gel of diethylene glycol monoethyl ether, methylparaben, carbomer homopolymer type C, sodium hydroxide and purified water.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of dapsone gel in treating acne vulgaris is not known.

12.3 Pharmacokinetics

In a pharmacokinetic study, male and female subjects 16 years of age or older with acne vulgaris (N=19) applied 2 grams of dapsone gel, 7.5% to the face, upper chest, upper back and shoulders once daily for 28 days. Steady state for dapsone was reached within 7 days of dosing. On Day 28, the mean dapsone maximum plasma concentration (C max ) and area under the concentration-time curve from 0 to 24 hours post dose (AUC 0-24h ) were 13.0 ± 6.8 ng/mL and 282 ± 146 ng•h/mL, respectively. The systemic exposure from dapsone gel, 7.5% is expected to be about 1% of that from a 100 mg oral dose.

Long-term safety studies were not conducted with dapsone gel, 7.5%, however, in a long-term clinical study of dapsone gel, 5% treatment (twice daily), periodic blood samples were collected up to 12 months to determine systemic exposure of dapsone and its metabolites in approximately 500 subjects. Based on the measurable dapsone concentrations from 408 subjects (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 to 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 subjects.

Pediatric use information is approved for Almirall LLC’s Aczone ® (dapsone) Gel. However, due to Almirall LLC’s marketing exclusivity rights, this drug product is not labeled with that information.

12.4 Microbiology

In Vivo Activity: No microbiology or immunology studies were conducted during dapsone gel, 7.5% clinical studies.

Drug Resistance: No dapsone resistance studies were conducted during dapsone gel clinical studies therefore there are no data available as to whether dapsone treatment may have resulted in decreased susceptibility of Propionibacterium acnes , an organism associated with acne, or to other antimicrobials that may be used to treat acne. Therapeutic resistance to dapsone has been reported for Mycobacterium leprae , when patients have been treated with oral dapsone.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 340 times the systemic exposure observed in humans as a result of use of the MRHD of dapsone gel, 7.5%, based on AUC comparisons).

No evidence of potential to induce carcinogenicity was observed 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.

Dapsone was negative in a bacterial reverse mutation assay (Ames test), and was negative in a micronucleus assay conducted in mice. Dapsone was positive (clastogenic) in a chromosome aberration assay conducted with Chinese hamster ovary (CHO) cells.

The effects of dapsone on fertility and general reproductive performance were assessed in male and female rats following oral dosing. Dapsone reduced sperm motility at dosages of 3 mg/kg/day or greater (approximately 22 times the systemic exposure that is associated with the MRHD of dapsone gel, 7.5%, based on AUC comparisons) when administered daily beginning 63 days prior to mating and continuing through the mating period. 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 187 times the systemic exposure that is associated with the MRHD of dapsone gel, 7.5%, based on AUC comparisons), presumably due to reduced numbers or effectiveness of sperm, indicating impairment of fertility. When administered to female rats at a dosage of 75 mg/kg/day (approximately 1,407 times the systemic exposure that is associated with the MRHD of dapsone gel, 7.5%, 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 probably were secondary to maternal toxicity.

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