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<table width="600" styleCode="Noautorules"><col width="90%" align="left"/><col width="10%" align="left"/><tbody><tr valign="bottom"><td>Indications and Usage (<linkHtml href="#s_0100">1</linkHtml>)</td><td>09/2019</td></tr></tbody></table>

1 INDICATIONS AND USAGE ACZONE ® (dapsone) Gel, 7.5%, is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. ACZONE ® Gel, 7.5%, is a sulfone indicated for the topical treatment of acne vulgaris in patients 9 years of age and older ( 1 ).

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 ACZONE Gel, 7.5%, in a thin layer to the entire face once daily. In addition, a thin layer may be applied to other affected areas once daily. Rub in ACZONE Gel, 7.5%, gently and completely. If there is no improvement after 12 weeks, treatment with ACZONE Gel, 7.5% should be reassessed. Apply once daily ( 2 ). Apply approximately a pea-sized amount of ACZONE Gel, 7.5%, in a thin layer to the entire face. A thin layer can also be applied to other affected areas ( 2 ). If there is no improvement after 12 weeks, treatment with ACZONE Gel, 7.5% should be reassessed ( 2 ). For topical use only. Not for oral, ophthalmic, or intravaginal use ( 2 ).

5 WARNINGS AND PRECAUTIONS Methemoglobinemia: Cases of methemoglobinemia have been reported. Discontinue ACZONE Gel if signs of methemoglobinemia occur ( 5.1 ). Hemolysis: Some patients with Glucose-6-phosphate Dehydrogenase (G6PD) deficiency using topical dapsone developed laboratory changes suggestive of hemolysis ( 5.1 )( 8.6 ). 5.1 Hematological Effects Methemoglobinemia Cases of methemoglobinemia, with resultant hospitalization, have been reported postmarketing in association with twice daily dapsone gel, 5%, treatment. Patients with glucose-6-phosphate dehydrogenase deficiency or congenital or idiopathic methemoglobinemia are more susceptible to drug-induced methemoglobinemia. Avoid use of ACZONE Gel, 7.5% in those patients with congenital or idiopathic methemoglobinemia. Signs and symptoms of methemoglobinemia may be delayed some hours after exposure. Initial signs and symptoms of methemoglobinemia are characterized by a slate grey cyanosis seen in e.g., buccal mucous membranes, lips, and nail beds. Advise patients to discontinue ACZONE Gel, 7.5% and seek immediate medical attention in the event of cyanosis. Dapsone can cause elevated methemoglobin levels particularly in conjunction with methemoglobin-inducing agents [see Drug Interactions ( 7.4 )]. Hemolysis 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. In clinical trials, there was no evidence of clinically relevant hemolysis or hemolytic anemia in subjects treated with topical dapsone. Some subjects with G6PD deficiency using dapsone gel, 5 %, twice daily developed laboratory changes suggestive of hemolysis [see Use in Specific Populations ( 8.6 )]. Discontinue ACZONE Gel, 7.5%, if signs and symptoms suggestive of hemolytic anemia occur. Avoid use of ACZONE Gel, 7.5% in patients who are taking oral dapsone or antimalarial medications because of the potential for hemolytic reactions. Combination of ACZONE Gel, 7.5%, with trimethoprim/sulfamethoxazole (TMP/SMX) may increase the likelihood of hemolysis in patients with G6PD deficiency [see Drug Interactions ( 7.1 )] . 5.2 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 dapsone treatment. 5.3 Skin Reactions 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 dapsone treatment.

6 ADVERSE REACTIONS Most common (incidence ≥ 0.9%) adverse reactions are application site dryness and pruritus ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Almirall at 1-866-665-2782 or FDA at 1-800-FDA-1088 or 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. A total of 2161 subjects were treated with ACZONE Gel, 7.5%, for 12 weeks in 2 controlled clinical trials. The population ranged in age from 12 to 63 years, was 56% female, and 58% Caucasian. Adverse drug reactions that were reported in at least 0.9% of subjects treated with ACZONE Gel, 7.5% appear in Table 1 below. Table 1. Adverse Reactions Occurring in at Least 0.9% of Subjects with Acne Vulgaris in 12-week Controlled Clinical Trials ACZONE Gel, 7.5% (N=2161) Vehicle (N=2175) Application Site Dryness 24 (1.1%) 21 (1.0%) Application Site Pruritus 20 (0.9%) 11 (0.5%) 6.2 Experience with Oral Use of Dapsone 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). 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).

<table ID="table1" width="750" styleCode="Noautorules"><caption>Table 1. Adverse Reactions Occurring in at Least 0.9% of Subjects with Acne Vulgaris in 12-week Controlled Clinical Trials </caption><col width="25%" align="left"/><col width="25%" align="center"/><col width="25%" align="center"/><tbody><tr valign="top"><td styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold"/></td><td styleCode="Toprule Botrule Rrule"><content styleCode="bold">ACZONE Gel, 7.5% (N=2161)</content></td><td styleCode="Toprule Botrule Rrule"><content styleCode="bold">Vehicle (N=2175)</content></td></tr><tr><td styleCode="Botrule Lrule Rrule">Application Site Dryness</td><td styleCode="Botrule Rrule">24 (1.1%) </td><td styleCode="Botrule Rrule">21 (1.0%) </td></tr><tr><td styleCode="Botrule Lrule Rrule">Application Site Pruritus </td><td styleCode="Botrule Rrule">20 (0.9%)</td><td styleCode="Botrule Rrule">11 (0.5%)</td></tr></tbody></table>

7 DRUG INTERACTIONS No formal drug-drug interaction studies were conducted with ACZONE Gel, 7.5%. Trimethoprim/sulfamethoxazole (TMP/SMX) increases the systemic level of dapsone and its metabolites ( 7.1 ). Topical benzoyl peroxide used at the same time as ACZONE Gel, 7.5% may result in temporary local yellow or orange skin discoloration ( 7.2 ). 7.1 Trimethoprim-Sulfamethoxazole A drug-drug interaction study evaluated the effect of the use of 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. The systemic exposure from ACZONE Gel, 7.5% is expected to be about 1% of that from the 100 mg oral dose, even when co-administered with TMP/SMX. 7.2 Topical Benzoyl Peroxide Topical application of dapsone gel followed by benzoyl peroxide in patients with acne vulgaris may result in a temporary local yellow or orange discoloration of the skin and facial hair. 7.3 Drug Interactions with Oral Dapsone 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. 7.4 Concomitant Use with Drugs that Induce Methemoglobinemia Concomitant use of ACZONE Gel, 7.5% with drugs that induce methemoglobinemia such as sulfonamides, acetaminophen, acetanilide, aniline dyes, benzocaine, chloroquine, dapsone, naphthalene, nitrates and nitrites, nitrofurantoin, nitroglycerin, nitroprusside, pamaquine, para‐aminosalicylic acid, phenacetin, phenobarbital, phenytoin, primaquine, and quinine may increase the risk for developing methemoglobinemia [see Warnings and Precautions ( 5.1 )] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on ACZONE Gel, 7.5%, use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. The systemic absorption of ACZONE 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 ACZONE 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 2-4% and 15-20%, 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 1407 times [rats] and 425 times [rabbits] the systemic exposure observed in human females as a result of use of the MRHD of ACZONE 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 ACZONE 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 ACZONE Gel, 7.5% and any potential adverse effects on the breastfed child from ACZONE Gel, 7.5% or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ACZONE Gel, 7.5% for the topical treatment of acne vulgaris have been established in patients 9 years of age and older.

al need for ACZONE Gel, 7.5% and any potential adverse effects on the breastfed child from ACZONE Gel, 7.5% or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ACZONE Gel, 7.5% for the topical treatment of acne vulgaris have been established in patients 9 years of age and older. Use of ACZONE Gel, 7.5% in patients 9 to 11 years of age for this indication is supported by evidence from adequate and well-controlled clinical trials in 1066 subjects 12 years of age and older and with additional pharmacokinetic and safety data in pediatric subjects 9 to 11 years of age from an open label study of 100 subjects with acne [see Adverse Reactions ( 6.1 ), and Clinical Pharmacology ( 12.3 )] . The safety profile for ACZONE Gel, 7.5% in clinical trials was similar to the vehicle control group. Safety and effectiveness of ACZONE Gel, 7.5%, have not been established in pediatric patients below the age of 9 years. 8.5 Geriatric Use Clinical trials of ACZONE 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 )] . ACZONE 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 ACZONE 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 )] .

8.1 Pregnancy Risk Summary There are no available data on ACZONE Gel, 7.5%, use in pregnant women to inform a drug-associated risk for adverse developmental outcomes. The systemic absorption of ACZONE 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 ACZONE 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 2-4% and 15-20%, 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 1407 times [rats] and 425 times [rabbits] the systemic exposure observed in human females as a result of use of the MRHD of ACZONE 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 ACZONE 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.

8.4 Pediatric Use The safety and effectiveness of ACZONE Gel, 7.5% for the topical treatment of acne vulgaris have been established in patients 9 years of age and older. Use of ACZONE Gel, 7.5% in patients 9 to 11 years of age for this indication is supported by evidence from adequate and well-controlled clinical trials in 1066 subjects 12 years of age and older and with additional pharmacokinetic and safety data in pediatric subjects 9 to 11 years of age from an open label study of 100 subjects with acne [see Adverse Reactions ( 6.1 ), and Clinical Pharmacology ( 12.3 )] . The safety profile for ACZONE Gel, 7.5% in clinical trials was similar to the vehicle control group. Safety and effectiveness of ACZONE Gel, 7.5%, have not been established in pediatric patients below the age of 9 years.

11 DESCRIPTION ACZONE (dapsone) Gel, 7.5%, contains dapsone, a sulfone, in an aqueous gel base for topical dermatologic use. ACZONE Gel, 7.5% is an off-white to yellow gel with suspended particles. Chemically, dapsone has an empirical formula of C 12 H 12 N 2 O 2 S. It is a white or slightly yellow-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: Each gram of ACZONE Gel, 7.5%, contains 75 mg of dapsone, USP, in a gel of diethylene glycol monoethyl ether, methylparaben, acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80, and purified water. Chemical Structure

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 ACZONE 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 (Cmax) 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 ACZONE 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 ACZONE 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 12-15 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. In an open label safety and pharmacokinetic study in pediatric subjects 9 to 11 years of age with acne vulgaris, a subset of subjects (N = 16) received once daily topical application of approximately 2 grams of ACZONE Gel, 7.5%, to the entire face, shoulders, upper chest and upper back for 8 days. On Day 8, the systemic concentrations were at or near steady state and the mean ± SD systemic concentration of dapsone at 10 hours post dose was 20 ± 12.5 ng/mL. 12.4 Microbiology In Vivo Activity : No microbiology or immunology studies were conducted during ACZONE 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.

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 ACZONE 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 (Cmax) 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 ACZONE 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 ACZONE 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 12-15 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. In an open label safety and pharmacokinetic study in pediatric subjects 9 to 11 years of age with acne vulgaris, a subset of subjects (N = 16) received once daily topical application of approximately 2 grams of ACZONE Gel, 7.5%, to the entire face, shoulders, upper chest and upper back for 8 days. On Day 8, the systemic concentrations were at or near steady state and the mean ± SD systemic concentration of dapsone at 10 hours post dose was 20 ± 12.5 ng/mL.

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 ACZONE 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 ACZONE 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 ACZONE 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 1407 times the systemic exposure that is associated with the MRHD of ACZONE 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.

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 ACZONE 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 ACZONE 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 ACZONE 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 1407 times the systemic exposure that is associated with the MRHD of ACZONE 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.

14 CLINICAL STUDIES The safety and efficacy of once daily use of ACZONE Gel, 7.5%, was assessed in two 12-week multicenter, randomized, double-blind, vehicle-controlled trials. Efficacy was assessed in a total of 4340 subjects 12 years of age and older. The majority of the subjects had moderate acne vulgaris, 20 to 50 inflammatory and 30 to 100 non-inflammatory lesions at baseline, and were randomized to receive either ACZONE Gel, 7.5% or vehicle. Treatment response was defined at Week 12 as the proportion of subjects who were rated “none” or “minimal” with at least a two-grade improvement from baseline on the Global Acne Assessment Score (GAAS), and mean absolute change from baseline in both inflammatory and non-inflammatory lesion counts. A GAAS score of “none” corresponded to no evidence of facial acne vulgaris. A GAAS score of “minimal” corresponded to a few non-inflammatory lesions (comedones) being present and to a few inflammatory lesions (papules/pustules) that may be present. The GAAS success rate, mean reduction, and percent reduction in acne lesion counts from baseline after 12 weeks of treatment are presented in the following table. Table 2. Clinical Efficacy of ACZONE ® Gel at Week 12 in Subjects with Acne Vulgaris Trial 1 Trial 2 ACZONE ® Gel, 7.5% (N=1044) Vehicle (N=1058) ACZONE ® Gel, 7.5% (N=1118) Vehicle (N=1120) Global Acne Assessment Score GAAS Success (Score 0 or 1) 30% 21% 30% 21% Inflammatory Lesions Mean absolute reduction 16.1 14.3 15.6 14.0 Mean percent reduction 56% 49% 54% 48% Non-inflammatory Lesions Mean absolute reduction 20.7 18.0 20.8 18.7 Mean percent reduction 45% 39% 46% 41%

<table ID="table2" width="750" styleCode="Noautorules"><caption>Table 2. Clinical Efficacy of ACZONE^&#xAE; Gel at Week 12 in Subjects with Acne Vulgaris</caption><col width="20%" align="left"/><col width="20%" align="center"/><col width="20%" align="center"/><col width="20%" align="center"/><col width="20%" align="center"/><tbody><tr valign="top"><td styleCode="Toprule Botrule Lrule Rrule"/><td colspan="2" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Trial 1</content></td><td colspan="2" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Trial 2</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule"/><td styleCode="Botrule Rrule"><content styleCode="bold">ACZONE^&#xAE; Gel, 7.5% (N=1044)</content></td><td styleCode="Botrule Rrule"><content styleCode="bold">Vehicle (N=1058)</content></td><td styleCode="Botrule Rrule"><content styleCode="bold">ACZONE^&#xAE; Gel, 7.5% (N=1118)</content></td><td styleCode="Botrule Rrule"><content styleCode="bold">Vehicle (N=1120)</content></td></tr><tr valign="top"><td colspan="5" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Global Acne Assessment Score</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule" align="center">GAAS Success (Score 0 or 1)</td><td styleCode="Botrule Rrule">30%</td><td styleCode="Botrule Rrule">21%</td><td styleCode="Botrule Rrule">30%</td><td styleCode="Botrule Rrule">21%</td></tr><tr valign="top"><td colspan="5" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Inflammatory Lesions</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule" align="center">Mean absolute reduction</td><td styleCode="Botrule Rrule">16.1</td><td styleCode="Botrule Rrule">14.3</td><td styleCode="Botrule Rrule">15.6</td><td styleCode="Botrule Rrule">14.0</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule" align="center">Mean percent reduction</td><td styleCode="Botrule Rrule">56%</td><td styleCode="Botrule Rrule">49%</td><td styleCode="Botrule Rrule">54%</td><td styleCode="Botrule Rrule">48%</td></tr><tr valign="top"><td colspan="5" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Non-inflammatory Lesions</content></td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule" align="center">Mean absolute reduction</td><td styleCode="Botrule Rrule">20.7</td><td styleCode="Botrule Rrule">18.0</td><td styleCode="Botrule Rrule">20.8</td><td styleCode="Botrule Rrule">18.7</td></tr><tr valign="top"><td styleCode="Botrule Lrule Rrule" align="center">Mean percent reduction</td><td styleCode="Botrule Rrule">45%</td><td styleCode="Botrule Rrule">39%</td><td styleCode="Botrule Rrule">46%</td><td styleCode="Botrule Rrule">41%</td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING ACZONE Gel is an off-white to yellow gel with suspended particles. It is supplied in an airless pump containing a polypropylene bottle with a high density polyethylene piston. ACZONE (dapsone) Gel, 7.5%, is supplied in the following sizes: NDC 16110-526-30 30 gram pump NDC 16110-526-60 60 gram pump NDC 16110-526-90 90 gram pump Storage : Store at 20°C-25°C (68°F-77°F), excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Protect from freezing.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Hematological Effects Inform patients that methemoglobinemia can occur with topical dapsone treatment. Advise patients to seek immediate medical attention if they develop cyanosis [see Warnings and Precautions ( 5.1 )] . Inform patients who have G6PD deficiency that hemolytic anemia may occur with topical dapsone treatment. Advise patients to seek medical attention if they develop signs and symptoms suggestive of hemolytic anemia [see Warnings and Precautions ( 5.1 )] . Important Administration Instructions Advise patients to apply ACZONE Gel, 7.5%, once daily to the entire face [see Dosage and Administration ( 2 )] . ACZONE Gel, 7.5% is for topical use only. Do not apply ACZONE Gel, 7.5% to eyes, mouth, or mucous membranes. Distributed by: Almirall, LLC. Malvern, PA 19355 Aczone ® is a registered trademark of Almirall, LLC © 2019 Almirall, LLC. All rights reserved. Patented.

This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 12/2021 Patient Information ACZONE ® (AK-zōn) (dapsone) Gel, 7.5% Important: For use on skin only (topical use). Do not use ACZONE Gel, 7.5% in your mouth, eyes, or vagina. What is ACZONE Gel, 7.5%? ACZONE Gel, 7.5%, is a prescription medicine used on the skin (topical) to treat acne in people 9 years and older. ACZONE Gel, 7.5%, has not been studied in children under 9 years of age. Before you use ACZONE Gel, 7.5%, tell your doctor about all of your medical conditions, including if you: have a glucose-6-phosphate dehydrogenase deficiency (G6PD) have higher than normal levels of methemoglobin in your blood (methemoglobinemia) are pregnant or plan to become pregnant. It is not known if ACZONE Gel, 7.5% will harm your unborn baby. are breastfeeding or plan to breastfeed. ACZONE Gel, 7.5% can pass into your breast milk and may harm your baby. You and your doctor should decide if you will use ACZONE Gel, 7.5%, or breastfeed. You should not do both. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially, tell your doctor if you are using acne medicines that contain benzoyl peroxide. Use of benzoyl peroxide with ACZONE Gel, 7.5% at the same time may cause your skin or facial hair to temporarily turn yellow or orange at the site of application. How do I use ACZONE Gel, 7.5%? Use ACZONE Gel, 7.5% exactly as your doctor tells you to use it. Apply ACZONE Gel, 7.5% one time a day. Gently wash and pat dry the areas of your skin where you will apply ACZONE Gel, 7.5%. Apply a pea-sized amount of ACZONE Gel, 7.5% in a thin layer to the entire face. A thin layer may also be applied to other affected areas as instructed by your doctor. Rub ACZONE Gel, 7.5% in gently and completely. Wash your hands after applying ACZONE Gel, 7.5%. If your acne does not get better after using ACZONE Gel, 7.5% for 12 weeks, talk to your doctor about continuing treatment. What are the possible side effects of ACZONE Gel, 7.5%? ACZONE Gel, 7.5% may cause serious side effects, including: Decrease of oxygen in your blood caused by a certain type of abnormal red blood cell (methemoglobinemia). Stop using ACZONE Gel, 7.5% and get medical help right away if your lips, nail beds, or the inside of your mouth turns grey or blue. Breakdown of red blood cells (hemolytic anemia). Some people with G6PD deficiency using ACZONE Gel, 7.5% may develop mild hemolytic anemia. Stop using ACZONE Gel, 7.5% and tell your doctor right away if you get any of the following signs and symptoms: back pain dark brown urine shortness of breath fever tiredness or weakness yellow or pale skin The most common side effects of ACZONE Gel, 7.5% include dryness and itching of the skin being treated. These are not all of the possible side effects of ACZONE Gel, 7.5%. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ACZONE Gel, 7.5%? Store ACZONE Gel, 7.5%, at room temperature 68°F to 77°F (20°C to 25°C). Protect ACZONE Gel, 7.5% from freezing. Keep ACZONE Gel, 7.5% and all medicines out of the reach of children. General information about the safe and effective use of ACZONE Gel, 7.5%. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet.

e 68°F to 77°F (20°C to 25°C). Protect ACZONE Gel, 7.5% from freezing. Keep ACZONE Gel, 7.5% and all medicines out of the reach of children. General information about the safe and effective use of ACZONE Gel, 7.5%. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ACZONE Gel, 7.5% for a condition for which it was not prescribed. Do not give ACZONE Gel, 7.5% to other people, even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about ACZONE Gel, 7.5% that is written for health professionals. What are the ingredients in ACZONE Gel, 7.5%? Active ingredient: dapsone Inactive ingredients: diethylene glycol monoethyl ether, methylparaben, acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80, and purified water. Distributed by: Almirall, LLC Malvern, PA 19355 Aczone ® is a registered trademark of Almirall, LLC © 2019 Almirall, LLC. All rights reserved. Patented. For more information, call 1-866-665-2782

<table width="100%" styleCode="Noautorules"><col width="77%" align="left"/><col width="23%" align="left"/><tfoot><tr valign="top"><td align="left"><paragraph styleCode="footnote">This Patient Information has been approved by the U.S. Food and Drug Administration.</paragraph></td><td align="right"><paragraph styleCode="footnote">Issued: 12/2021</paragraph></td></tr></tfoot><tbody><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule" align="center"><paragraph><content styleCode="bold">Patient Information</content></paragraph><paragraph><content styleCode="bold">ACZONE^&#xAE;</content> (AK-z&#x14D;n) (dapsone) Gel, 7.5% </paragraph></td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><paragraph><content styleCode="bold">Important: </content>For use on skin only (topical use). Do not use ACZONE Gel, 7.5% in your mouth, eyes, or vagina.</paragraph></td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><paragraph><content styleCode="bold">What is ACZONE Gel, 7.5%?</content></paragraph><paragraph>ACZONE Gel, 7.5%, is a prescription medicine used on the skin (topical) to treat acne in people 9 years and older.</paragraph><paragraph>ACZONE Gel, 7.5%, has not been studied in children under 9 years of age.</paragraph></td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><paragraph><content styleCode="bold">Before you use ACZONE Gel, 7.5%, tell your doctor about all of your medical conditions, including if you:</content></paragraph><list listType="unordered" styleCode="Disc"><item>have a glucose-6-phosphate dehydrogenase deficiency (G6PD)</item><item>have higher than normal levels of methemoglobin in your blood (methemoglobinemia)</item><item>are pregnant or plan to become pregnant. It is not known if ACZONE Gel, 7.5% will harm your unborn baby. </item><item>are breastfeeding or plan to breastfeed. ACZONE Gel, 7.5% can pass into your breast milk and may harm your baby. You and your doctor should decide if you will use ACZONE Gel, 7.5%, or breastfeed. You should not do both.</item></list><paragraph><content styleCode="bold">Tell your doctor about all the medicines you take, </content>including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially, tell your doctor if you are using acne medicines that contain benzoyl peroxide. Use of benzoyl peroxide with ACZONE Gel, 7.5% at the same time may cause your skin or facial hair to temporarily turn yellow or orange at the site of application.</paragraph></td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><paragraph><content styleCode="bold">How do I use ACZONE Gel, 7.5%?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Use ACZONE Gel, 7.5% exactly as your doctor tells you to use it.</item><item>Apply ACZONE Gel, 7.5% one time a day.</item><item>Gently wash and pat dry the areas of your skin where you will apply ACZONE Gel, 7.5%. </item><item>Apply a pea-sized amount of ACZONE Gel, 7.5% in a thin layer to the entire face.

"Disc"><item>Use ACZONE Gel, 7.5% exactly as your doctor tells you to use it.</item><item>Apply ACZONE Gel, 7.5% one time a day.</item><item>Gently wash and pat dry the areas of your skin where you will apply ACZONE Gel, 7.5%. </item><item>Apply a pea-sized amount of ACZONE Gel, 7.5% in a thin layer to the entire face. A thin layer may also be applied to other affected areas as instructed by your doctor.</item><item>Rub ACZONE Gel, 7.5% in gently and completely.</item><item>Wash your hands after applying ACZONE Gel, 7.5%.</item><item>If your acne does not get better after using ACZONE Gel, 7.5% for 12 weeks, talk to your doctor about continuing treatment.</item></list></td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><paragraph><content styleCode="bold">What are the possible side effects of ACZONE Gel, 7.5%?</content></paragraph><paragraph><content styleCode="bold">ACZONE Gel, 7.5% may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Decrease of oxygen in your blood caused by a certain type of abnormal red blood cell (methemoglobinemia).</content> Stop using ACZONE Gel, 7.5% and get medical help right away if your lips, nail beds, or the inside of your mouth turns grey or blue.</item><item><content styleCode="bold">Breakdown of red blood cells (hemolytic anemia). </content>Some people with G6PD deficiency using ACZONE Gel, 7.5% may develop mild hemolytic anemia. Stop using ACZONE Gel, 7.5% and tell your doctor right away if you get any of the following signs and symptoms: <list listType="unordered" styleCode="circle"><item>back pain</item><item>dark brown urine </item><item>shortness of breath</item><item>fever </item><item>tiredness or weakness</item><item>yellow or pale skin</item></list></item></list><paragraph>The most common side effects of ACZONE Gel, 7.5% include dryness and itching of the skin being treated. These are not all of the possible side effects of ACZONE Gel, 7.5%. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </paragraph></td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><paragraph><content styleCode="bold">How should I store ACZONE Gel, 7.5%?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Store ACZONE Gel, 7.5%, at room temperature 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C).</item><item>Protect ACZONE Gel, 7.5% from freezing.</item></list><paragraph><content styleCode="bold">Keep ACZONE Gel, 7.5% and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><paragraph><content styleCode="bold">General information about the safe and effective use of ACZONE Gel, 7.5%.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ACZONE Gel, 7.5% for a condition for which it was not prescribed. Do not give ACZONE Gel, 7.5% to other people, even if they have the same symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about ACZONE Gel, 7.5% that is written for health professionals.</paragraph></td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><paragraph><content styleCode="bold">What are the ingredients in ACZONE Gel, 7.5%?

symptoms you have. It may harm them. You can ask your doctor or pharmacist for information about ACZONE Gel, 7.5% that is written for health professionals.</paragraph></td></tr><tr><td colspan="2" styleCode="Toprule Botrule Lrule Rrule"><paragraph><content styleCode="bold">What are the ingredients in ACZONE Gel, 7.5%? </content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content> dapsone</paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content> diethylene glycol monoethyl ether, methylparaben, acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80, and purified water.</paragraph> <paragraph styleCode="footnote">Distributed by: Almirall, LLC</paragraph><paragraph styleCode="footnote">Malvern, PA 19355</paragraph> <paragraph>Aczone^&#xAE; is a registered trademark of Almirall, LLC</paragraph><paragraph styleCode="footnote">&#xA9; 2019 Almirall, LLC. All rights reserved.</paragraph><paragraph styleCode="footnote">Patented.</paragraph> <paragraph styleCode="footnote">For more information, call 1-866-665-2782</paragraph></td></tr></tbody></table>

DESCRIPTION Dapsone-USP, 4,4'-diaminodiphenylsulfone (DDS), is a primary treatment for Dermatitis herpetiformis. It is an antibacterial drug for susceptible cases of leprosy. It is a white, odorless crystalline powder, practically insoluble in water and in-soluble in fixed and vegetable oils. Dapsone is issued on prescription in tablets of 25 and 100 mg for oral use. Inactive Ingredients: Colloidal Silicon Dioxide, Corn Starch, Magnesium Stearate and Microcrystalline Cellulose. Chemical Structure

CLINICAL PHARMACOLOGY Actions The mechanism of action in Dermatitis herpetiformis has not been established. By the kinetic method in mice, Dapsone is bactericidal as well as bacteriostatic against Mycobacterium leprae. Absorption and Excretion Dapsone, when given orally, is rapidly and almost completely absorbed. About 85 percent of the daily intake is recoverable from the urine mainly in the form of water-soluble metabolites. Excretion of the drug is slow and a constant blood level can be maintained with the usual dosage. Blood Levels Detected a few minutes after ingestion, the drug reaches peak concentration in 4 to 8 hours. Daily administration for at least eight days is necessary to achieve a plateau level. With doses of 200 mg daily, this level averaged 2.3 mcg/ml with a range of 0.1 to 7.0 mcg/ml. The half-life in the plasma in different individuals varies from ten hours to fifty hours and averages twenty-eight hours. Repeat tests in the same individual are constant. Daily administration (50 to 100 mg) in leprosy patients will provide blood levels in excess of the usual minimum inhibitory concentration even for patients with a short Dapsone half-life.

WARNINGS The patient should be warned to respond to the presence of clinical signs such as sore throat, fever, pallor, purpura or jaundice. Deaths associated with the administration of Dapsone have been reported from agranulocytosis, aplastic anemia and other blood dyscrasias. Complete blood counts should be done frequently in patients receiving Dapsone. The FDA Dermatology Advisory Committee recommended that, when feasible, counts should be done weekly for the first month, monthly for six months and semi-annually thereafter. If a significant reduction in leucocytes, platelets or hemopoiesis is noted, Dapsone should be discontinued and the patient followed intensively. Folic acid antagonists have similar effects and may increase the incidence of hematologic reactions; if coadministered with Dapsone the patient should be monitored more frequently. Patients on weekly pyrimethamine and Dapsone have developed agranulocytosis during the second and third month of therapy. Severe anemia should be treated prior to initiation of therapy and hemoglobin monitored. Hemolysis and methemoglobin may be poorly tolerated by patients with severe cardiopulmonary disease. Cutaneous reactions, especially bullous, include exfoliative dermatitis and are probably one of the most serious, though rare, complications of sulfone therapy. They are directly due to drug sensitization. Such reactions include toxic erythema, erythema multiforme, toxic epidermal necrolysis, morbilliform and scarlatiniform reactions, urticaria and erythema nodosum. If new or toxic dermatologic reactions occur, sulfone therapy must be promptly discontinued and appropriate therapy instituted. Leprosy reactional states, including cutaneous, are not hypersensitivity reactions to Dapsone and do not require discontinuation. See special section.

PRECAUTIONS General Hemolysis and Heinz body formation may be exaggerated in individuals with a glucose-6-phosphate dehydrogenase (G6PD) deficiency, or methemoglobin reductase deficiency, or hemoglobin M. This reaction is frequently dose-related. Dapsone should be given with caution to these patients or if the patient is exposed to other agents or conditions such as infection or diabetic ketosis capable of producing hemolysis. Drugs or chemicals which have produced significant hemolysis in G6PD or methemoglobin reductase deficient patients include Dapsone, sulfanilamide, nitrite, aniline, phenylhydrazine, napthalene, niridazole, nitro-furantoin and 8-amino-antimalarials such as primaquine. Toxic hepatitis and cholestatic jaundice have been reported early in therapy. Hyperbilirubinemia may occur more often in G6PD deficient patients. When feasible, baseline and subsequent monitoring of liver function is recommended; if abnormal, Dapsone should be discontinued until the source of the abnormality is established. Drug Interactions Rifampin lowers Dapsone levels 7 to 10-fold by accelerating plasma clearance; in leprosy this reduction has not required a change in dosage. Folic acid antagonists such as pyrimethamine may increase the likelihood of hematologic reactions. A modest interaction has been reported for patients receiving 100 mg Dapsone daily in combination with trimethoprim 5 mg/kg q6h. On Day 7, the serum Dapsone levels averaged 2.1 ± 1.0 mcg/mL in comparison to 1.5 ± 0.5 mcg/mL for Dapsone alone. On Day 7, trimethoprim levels averaged 18.4 ± 5.2 mcg/mL in comparison to 12.4 ± 4.5 mcg/mL for patients not receiving Dapsone. Thus, there is a mutual interaction between Dapsone and trimethoprim in which each raises the level of the other about 1.5 times. A crossover study 1 designed to assess the potential of a drug interaction between Dapsone, 100 mg/day and trimethoprim, 200 mg every 12 hours, in eight asymptomatic HIV positive volunteers (average CD4 count 524 cells/mm 3 ) demonstrated that there was not a significant drug intreraction between Dapsone and trimethoprim. However, an earlier report 2 also by Lee et al, in 78 HIV infected patients with acute Pneumocystis carinii pneumonia, receiving Dapsone, 100 mg/day and higher trimethoprim dose, 20 mg/kg/day, demonstrated that the serum levels of Dapsone were increased by 40% and trimethoprim levels were increased by 48% when the drugs were administered concurrently. Carcinogenesis, mutagenesis Dapsone has been found carcinogenic (sarcomagenic) for male rats and female mice causing mesenchymal tumors in the spleen and peritoneum, and thyroid carcinoma in female rats. Dapsone is not mutagenic with or without microsomal activation in S. typhimurium tester strains 1535, 1537,1538, 98, or 100. Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Dapsone. Extensive, but uncontrolled experience and two published surveys on the use of Dapsone in pregnant women have not shown that Dapsone increases the risk of fetal abnormalities if administered during all trimesters of pregnancy or can affect reproduction capacity. Because of the lack of animal studies or controlled human experience, Dapsone should be given to a pregnant woman only if clearly needed. In general, for leprosy, USPHS at Carville recommends maintenance of Dapsone. Dapsone has been important for the management of some pregnant D.H. patients.

ect reproduction capacity. Because of the lack of animal studies or controlled human experience, Dapsone should be given to a pregnant woman only if clearly needed. In general, for leprosy, USPHS at Carville recommends maintenance of Dapsone. Dapsone has been important for the management of some pregnant D.H. patients. Nursing Mothers Dapsone is excreted in breast milk in substantial amounts. Hemolytic reactions can occur in neonates. See section on hemolysis. Because of the potential for tumorgenicity shown for Dapsone in animal studies a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of drug to the mother. Pediatric Use Pediatric patients are treated on the same schedule as adults but with correspondingly smaller doses. Dapsone is generally not considered to have an effect on the later growth, development and functional development of the pediatric patient.

General Hemolysis and Heinz body formation may be exaggerated in individuals with a glucose-6-phosphate dehydrogenase (G6PD) deficiency, or methemoglobin reductase deficiency, or hemoglobin M. This reaction is frequently dose-related. Dapsone should be given with caution to these patients or if the patient is exposed to other agents or conditions such as infection or diabetic ketosis capable of producing hemolysis. Drugs or chemicals which have produced significant hemolysis in G6PD or methemoglobin reductase deficient patients include Dapsone, sulfanilamide, nitrite, aniline, phenylhydrazine, napthalene, niridazole, nitro-furantoin and 8-amino-antimalarials such as primaquine. Toxic hepatitis and cholestatic jaundice have been reported early in therapy. Hyperbilirubinemia may occur more often in G6PD deficient patients. When feasible, baseline and subsequent monitoring of liver function is recommended; if abnormal, Dapsone should be discontinued until the source of the abnormality is established.

Drug Interactions Rifampin lowers Dapsone levels 7 to 10-fold by accelerating plasma clearance; in leprosy this reduction has not required a change in dosage. Folic acid antagonists such as pyrimethamine may increase the likelihood of hematologic reactions. A modest interaction has been reported for patients receiving 100 mg Dapsone daily in combination with trimethoprim 5 mg/kg q6h. On Day 7, the serum Dapsone levels averaged 2.1 ± 1.0 mcg/mL in comparison to 1.5 ± 0.5 mcg/mL for Dapsone alone. On Day 7, trimethoprim levels averaged 18.4 ± 5.2 mcg/mL in comparison to 12.4 ± 4.5 mcg/mL for patients not receiving Dapsone. Thus, there is a mutual interaction between Dapsone and trimethoprim in which each raises the level of the other about 1.5 times. A crossover study 1 designed to assess the potential of a drug interaction between Dapsone, 100 mg/day and trimethoprim, 200 mg every 12 hours, in eight asymptomatic HIV positive volunteers (average CD4 count 524 cells/mm 3 ) demonstrated that there was not a significant drug intreraction between Dapsone and trimethoprim. However, an earlier report 2 also by Lee et al, in 78 HIV infected patients with acute Pneumocystis carinii pneumonia, receiving Dapsone, 100 mg/day and higher trimethoprim dose, 20 mg/kg/day, demonstrated that the serum levels of Dapsone were increased by 40% and trimethoprim levels were increased by 48% when the drugs were administered concurrently.

Carcinogenesis, mutagenesis Dapsone has been found carcinogenic (sarcomagenic) for male rats and female mice causing mesenchymal tumors in the spleen and peritoneum, and thyroid carcinoma in female rats. Dapsone is not mutagenic with or without microsomal activation in S. typhimurium tester strains 1535, 1537,1538, 98, or 100.

Pregnancy Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Dapsone. Extensive, but uncontrolled experience and two published surveys on the use of Dapsone in pregnant women have not shown that Dapsone increases the risk of fetal abnormalities if administered during all trimesters of pregnancy or can affect reproduction capacity. Because of the lack of animal studies or controlled human experience, Dapsone should be given to a pregnant woman only if clearly needed. In general, for leprosy, USPHS at Carville recommends maintenance of Dapsone. Dapsone has been important for the management of some pregnant D.H. patients.

Teratogenic Effects Pregnancy Category C Animal reproduction studies have not been conducted with Dapsone. Extensive, but uncontrolled experience and two published surveys on the use of Dapsone in pregnant women have not shown that Dapsone increases the risk of fetal abnormalities if administered during all trimesters of pregnancy or can affect reproduction capacity. Because of the lack of animal studies or controlled human experience, Dapsone should be given to a pregnant woman only if clearly needed. In general, for leprosy, USPHS at Carville recommends maintenance of Dapsone. Dapsone has been important for the management of some pregnant D.H. patients.

Nursing Mothers Dapsone is excreted in breast milk in substantial amounts. Hemolytic reactions can occur in neonates. See section on hemolysis. Because of the potential for tumorgenicity shown for Dapsone in animal studies a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of drug to the mother.

Pediatric Use Pediatric patients are treated on the same schedule as adults but with correspondingly smaller doses. Dapsone is generally not considered to have an effect on the later growth, development and functional development of the pediatric patient.

ADVERSE REACTIONS In addition to the warnings listed above, the following syndromes and serious reactions have been reported in patients on Dapsone. Hematologic Effects Dose-related hemolysis is the most common adverse effect and is seen in patients with or without G6PD deficiency. Almost all patients demonstrate the inter-related changes of a loss of 1 to 2g of hemoglobin, an increase in the reticulocytes (2 to 12%), a shortened red cell life span and a rise in methemoglobin. G6PD deficient patients have greater responses. Nervous System Effects Peripheral neuropathy is a definite but unusual complication of Dapsone therapy in non-leprosy patients. Motor loss is predominant. If muscle weakness appears, Dapsone should be withdrawn. Recovery on withdrawal is usually substantially complete. The mechanism of recovery is reported by axonal regeneration. Some recovered patients have tolerated retreatment at reduced dosage. In leprosy this complication may be difficult to distinguish from a leprosy reactional state. Body As A Whole In addition to the warnings and adverse effects reported above, additional adverse reactions include: nausea, vomiting, abdominal pains, pancreatitis, vertigo, blurred vision, tinnitus, insomnia, fever, headache, psychosis, phototoxicity, pulmonary eosinophilia, tachycardia, albuminuria, the nephrotic syndrome, hypoalbuminemia without proteinuria, renal papillary necrosis, male infertility, drug-induced Lupus erythematosus and an infectious mononucleosis-like syndrome. In general, with the exception of the complications of severe anoxia from overdosage (retinal and optic nerve damage, etc.) these adverse reactions have regressed off drug. To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DOSAGE AND ADMINISTRATION Dermatitis herpetiformis The dosage should be individually titrated starting in adults with 50 mg daily and correspondingly smaller doses in children. If full control is not achieved within the range of 50 to 300 mg daily, higher doses may be tried. Dosage should be reduced to a minimum maintenance level as soon as possible. In responsive patients there is a prompt reduction in pruritus followed by clearance of skin lesions. There is no effect on the gastrointestinal component of the disease. Dapsone levels are influenced by acetylation rates. Patients with high acetylation rates, or who are receiving treatment affecting acetylation may require an adjustment in dosage. A strict gluten free diet is an option for the patient to elect, permitting many to reduce or eliminate the need for Dapsone; the average time for dosage reduction is 8 months with a range of 4 months to 2 1/2 years and for dosage elimination 29 months with a range of 6 months to 9 years. Leprosy In order to reduce secondary Dapsone resistance, the WHO Expert Committee on Leprosy and the USPHS at Carville, LA, recommended that Dapsone should be commenced in combination with one or more anti-leprosy drugs. In the multidrug program Dapsone should be maintained at the full dosage of 100 mg daily without interruption (with corresponding smaller doses for children) and provided to all patients who have sensitive organisms with new or recrudescent disease or who have not yet completed a two year course of Dapsone monotherapy. For advice and other drugs, the USPHS at Carville, LA (1-800-642-2477) should be contacted. Before using other drugs consult appropriate product labeling. In bacteriologically negative tuberculoid and indeterminate disease, the recommendation is the coadministration of Dapsone 100 mg daily with six months of Rifampin 600 mg daily. Under WHO, daily Rifampin may be replaced by 600 mg Rifampin monthly, if supervised. The Dapsone is continued until all signs of clinical activity are controlled - usually after an additional six months. Then Dapsone should be continued for an additional three years for tuberculoid and indeterminate patients and for five years for borderline tuberculoid patients. In lepromatous and borderline lepromatous patients, the recommendation is the coadministration of Dapsone 100 mg daily with two years of Rifampin 600 mg daily. Under WHO daily Rifampin may be replaced by 600 mg Rifampin monthly, if supervised. One may elect the concurrent administration of a third anti-leprosy drug, usually either Clofazamine 50 to 100 mg daily or Ethionamide 250 to 500 mg daily. Dapsone 100 mg daily is continued 3 to 10 years until all signs of clinical activity are controlled with skin scrapings and biopsies negative for one year. Dapsone should then be continued for an additional 10 years for borderline patients and for life for lepromatous patients. Secondary Dapsone resistance should be suspected whenever a lepromatous or borderline lepromatous patient receiving Dapsone treatment relapses clinically and bacteriologically, solid staining bacilli being found in the smears taken from the new active lesions. If such cases show no response to regular and supervised Dapsone therapy within three to six months or good compliance for the past 3 to 6 months can be assured, Dapsone resistance should be considered confirmed clinically.

iologically, solid staining bacilli being found in the smears taken from the new active lesions. If such cases show no response to regular and supervised Dapsone therapy within three to six months or good compliance for the past 3 to 6 months can be assured, Dapsone resistance should be considered confirmed clinically. Determination of drug sensitivity using the mouse footpad method is recommended and, after prior arrangement, is available without charge from the USPHS, Carville, LA. Patients with proven Dapsone resistance should be treated with other drugs. LEPROSY REACTIONAL STATES Abrupt changes in clinical activity occur in leprosy with any effective treatment and are known as reactional states. The majority can be classified into two groups. The "Reversal" reaction (Type 1) may occur in borderline or tuberculoid leprosy patients often soon after chemotherapy is started. The mechanism is presumed to result from a reduction in the antigenic load: the patient is able to mount an enhanced delayed hypersensitivity response to residual infection leading to swelling ("Reversal") of existing skin and nerve lesions. If severe, or if neuritis is present, large doses of steroids should always be used. If severe, the patient should be hospitalized. In general anti-leprosy treatment is continued and therapy to suppress the reaction is indicated such as analgesics, steroids, or surgical decompression of swollen nerve trunks. USPHS at Carville, LA should be contacted for advice in management. Erythema nodosum leprosum (ENL) (lepromatous reaction) (Type 2 reaction) occurs mainly in lepromatous patients and small numbers of borderline patients. Approximately 50% of treated patients show this reaction in the first year. The principal clinical features are fever and tender erythematous skin nodules sometimes associated with malaise, neuritis, orchitis, albuminuria, joint swelling, iritis, epistaxis or depression. Skin lesions can become pustular and/or ulcerate. Histologically there is a vasculitis with an intense polymorphonuclear infiltrate. Elevated circulating immune complexes are considered to be the mechanism of reaction. If severe, patients should be hospitalized. In general, anti-leprosy treatment is continued. Analgesics, steroids, and other agents available from USPHS, Carville, LA, are used to suppress the reaction.

HOW SUPPLIED Dapsone Tablets USP, 25 mg are available as round white scored tablets, debossed "25" above and "102" below the score and on the obverse "JACOBUS" in light and child-resistant bottles. Bottle of 100: NDC 42291-008-01 Dapsone Tablets USP, 100 mg are available as round white scored tablets, debossed "100" above and "101" below the score and on the obverse "JACOBUS" in light and child-resistant bottles.

REFERENCES Lee, B., et al., Zidovudine, Trimethoprim, and Dapsone Pharmacokinetic Interactions in Patients with HIV Infection. Antimicrobial Agents and Chemotherapy, May 1996; 1231-1236. Lee, B., et al., Dapsone, Trimethoprim, and Sulfamethoxazole Plasma Levels During Treatment of Pneumocystis Carinii Pneumonia in Patients with AIDS, Annals of Internal Medicine, 1989; 110:606-611.

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light. Rx only. Keep this and all drugs out of the reach of children.