ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (incidence >= 10%) are oiliness/peeling, dryness and erythema at the application site (6).To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-678-1605 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Serious adverse reactions reported in subjects treated with ACZONE Gel, 5%, during clinical trials included but were not limited to the following:Nervous system/Psychiatric Suicide attempt, tonic clonic movements. Gastrointestinal Abdominal pain, severe vomiting, pancreatitis. Other Severe pharyngitisIn the clinical trials, total of 12 out of 4032 subjects were reported to have depression (3 of 1660 treated with vehicle and of 2372 treated with ACZONE Gel, 5%). Psychosis was reported in of 2372 subjects treated with ACZONE Gel, 5%, and in of 1660 subjects treated with vehicle.Combined contact sensitization/irritation studies with ACZONE Gel, 5%, in 253 healthy subjects resulted in at least subjects with moderate erythema. ACZONE Gel, 5%, did not induce phototoxicity or photoallergy in human dermal safety studies.ACZONE Gel, 5%, was evaluated for 12 weeks in four controlled trials for local cutaneous events in 1819 subjects. The most common events reported from these studies include oiliness/peeling, dryness, and erythema. These data are shown by severity in Table below.Table - Application Site Adverse Reactions by Maximum SeverityACZONE(R)(N=1819)Vehicle(N=1660)Application Site EventMildModerateSevereMildModerateSevereErythema9%5%<1%9%6%<1%Dryness14%3%<1%14%4%<1%Oiliness/Peeling13%6%<1%15%6%<1%The adverse reactions occurring in at least 1% of subjects in either arm in the four vehicle controlled trials are presented in Table 2.Table - Adverse Reactions Occurring in at Least 1% of SubjectsACZONE(R)N=1819VehicleN=1660Application Site Reaction NOS18%20%Application Site Dryness16%17%Application Site Erythema13%14%Application Site Burning1%2%Application Site Pruritus1%1%Pyrexia1%1%Nasopharyngitis5%6%Upper Respiratory Tract Inf. NOS3%3%Sinusitis NOS2%1%Influenza1%1%Pharyngitis2%2%Cough2%2%Joint Sprain1%1%Headache NOS4%4% NOS Not otherwise specifiedOne subjects treated with ACZONE Gel in the clinical trials had facial swelling which led to discontinuation of medication.In addition, 486 subjects were evaluated in 12 month safety trial. The adverse event profile in this trial was consistent with that observed in the vehicle-controlled trials.. Nervous system/Psychiatric Suicide attempt, tonic clonic movements. Gastrointestinal Abdominal pain, severe vomiting, pancreatitis. Other Severe pharyngitis. 6.2 Experience with Oral Use of Dapsone. Although not observed in the clinical trials with ACZONE Gel (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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 231 times the systemic exposure observed in humans as result of use of the MRHD of ACZONE Gel, 5%, based on AUC comparisons).No evidence of potential to induce carcinogenesis was observed in 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 bacterial reverse mutation assay (Ames test), and was negative in micronucleus assay conducted in mice. Dapsone was positive (clastogenic) in 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 mg/kg/day or greater (approximately 15 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 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 127 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 5%, based on AUC comparisons), presumably due to reduced numbers or effectiveness of sperm, indicating impairment of fertility. When administered to female rats at dosage of 75 mg/kg/day (approximately 956 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 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.

CLINICAL PHARMACOLOGY SECTION.

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 An open-label study compared the pharmacokinetics of dapsone after ACZONE Gel, 5%, (110 +- 60 mg/day) was applied twice daily (~BSA 22.5%) for 14 days (n=18) with single 100 mg dose of oral dapsone administered to subgroup of patients (n=10) in crossover design. On Day 14 the mean dapsone AUC0-24h was 415 +- 224 ngoh/mL for ACZONE Gel, 5%, whereas following single 100 mg dose of oral dapsone the AUC0-infinity was 52,641 +- 36,223 ngoh/mL. Exposure after the oral dose of 100 mg dapsone was approximately 100 times greater than after the topical ACZONE Gel, 5% dose, twice day.In long-term safety study of ACZONE Gel, 5% treatment, periodic blood samples were collected up to 12 months to determine systemic exposure of dapsone and its metabolites in approximately 500 patients. Based on the measurable dapsone concentrations from 408 patients (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 patients.. 12.4 Microbiology In Vivo Activity: No microbiology or immunology studies were conducted during dapsone gel clinical trials.Drug Resistance: No dapsone resistance studies were conducted during dapsone gel clinical trials. Because no microbiology studies were done, there are no data available as to whether dapsone treatment may have resulted in decreased susceptibility of Propionibacterium acnes, an organism associated with acne, 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.

CLINICAL STUDIES SECTION.

6.1 Clinical Studies Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Serious adverse reactions reported in subjects treated with ACZONE Gel, 5%, during clinical trials included but were not limited to the following:Nervous system/Psychiatric Suicide attempt, tonic clonic movements. Gastrointestinal Abdominal pain, severe vomiting, pancreatitis. Other Severe pharyngitisIn the clinical trials, total of 12 out of 4032 subjects were reported to have depression (3 of 1660 treated with vehicle and of 2372 treated with ACZONE Gel, 5%). Psychosis was reported in of 2372 subjects treated with ACZONE Gel, 5%, and in of 1660 subjects treated with vehicle.Combined contact sensitization/irritation studies with ACZONE Gel, 5%, in 253 healthy subjects resulted in at least subjects with moderate erythema. ACZONE Gel, 5%, did not induce phototoxicity or photoallergy in human dermal safety studies.ACZONE Gel, 5%, was evaluated for 12 weeks in four controlled trials for local cutaneous events in 1819 subjects. The most common events reported from these studies include oiliness/peeling, dryness, and erythema. These data are shown by severity in Table below.Table - Application Site Adverse Reactions by Maximum SeverityACZONE(R)(N=1819)Vehicle(N=1660)Application Site EventMildModerateSevereMildModerateSevereErythema9%5%<1%9%6%<1%Dryness14%3%<1%14%4%<1%Oiliness/Peeling13%6%<1%15%6%<1%The adverse reactions occurring in at least 1% of subjects in either arm in the four vehicle controlled trials are presented in Table 2.Table - Adverse Reactions Occurring in at Least 1% of SubjectsACZONE(R)N=1819VehicleN=1660Application Site Reaction NOS18%20%Application Site Dryness16%17%Application Site Erythema13%14%Application Site Burning1%2%Application Site Pruritus1%1%Pyrexia1%1%Nasopharyngitis5%6%Upper Respiratory Tract Inf. NOS3%3%Sinusitis NOS2%1%Influenza1%1%Pharyngitis2%2%Cough2%2%Joint Sprain1%1%Headache NOS4%4% NOS Not otherwise specifiedOne subjects treated with ACZONE Gel in the clinical trials had facial swelling which led to discontinuation of medication.In addition, 486 subjects were evaluated in 12 month safety trial. The adverse event profile in this trial was consistent with that observed in the vehicle-controlled trials.. Nervous system/Psychiatric Suicide attempt, tonic clonic movements. Gastrointestinal Abdominal pain, severe vomiting, pancreatitis. Other Severe pharyngitis.

DOSAGE & ADMINISTRATION SECTION.

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 pea-sized amount of ACZONE Gel, 5%, in thin layer to the acne affected areas twice daily. Rub in ACZONE Gel, 5%, gently and completely. ACZONE Gel, 5%, is gritty with visible drug substance particles. Wash hands after application of ACZONE Gel, 5%.If there is no improvement after 12 weeks, treatment with ACZONE Gel, 5%, should be reassessed.. Apply twice daily (2). Apply approximately pea-sized amount of ACZONE Gel, 5%, in thin layer to the acne affected area (2). If there is no improvement after 12 weeks, treatment with ACZONE Gel, 5%, should be reassessed (2). For topical use only. Not for oral, ophthalmic, or intravaginal use (2).. Apply twice daily (2). Apply approximately pea-sized amount of ACZONE Gel, 5%, in thin layer to the acne affected area (2). If there is no improvement after 12 weeks, treatment with ACZONE Gel, 5%, should be reassessed (2). For topical use only. Not for oral, ophthalmic, or intravaginal use (2).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Trimethoprim/sulfamethoxazole (TMP/SMX) increases the level of dapsone and its metabolites (7.1). Topical benzoyl peroxide used at the same time as ACZONE may result in temporary local yellow or orange skin discoloration (7.2).. Trimethoprim/sulfamethoxazole (TMP/SMX) increases the level of dapsone and its metabolites (7.1). Topical benzoyl peroxide used at the same time as ACZONE may result in temporary local yellow or orange skin discoloration (7.2).. 7.1 Trimethoprim-Sulfamethoxazole. 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 the 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.. 7.2 Topical Benzoyl Peroxide. Topical application of ACZONE Gel followed by benzoyl peroxide in subjects with acne vulgaris resulted in temporary local yellow or orange discoloration of the skin and facial hair (reported by out of 95 subjects in clinical study) with resolution in to 57 days.. 7.3 Drug Interactions with Oral Dapsone. Certain concomitant medications (such as rifampin, anticonvulsants, St. Johns wort) may increase the formation of dapsone hydroxylamine, 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 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 )].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Hematological EffectsInform 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 5.2 )].Important Administration InstructionsAdvise patients to apply ACZONE Gel, 5%, twice daily to the acne affected area [see Dosage and Administration (2)]. ACZONE Gel, 5% is for topical use only. Do not apply ACZONE Gel, 5% to eyes, mouth, or mucous membranes.Distributed by: Allergan USA, Inc.Madison, NJ 07940(C) 2018 Allergan. All rights reserved. All trademarks are the property of their respective owners. v1.0USPI3670-------Cut Here ----------------------------------------------------------------------------------------------------------------. 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 5.2 )].. Advise patients to apply ACZONE Gel, 5%, twice daily to the acne affected area [see Dosage and Administration (2)]. ACZONE Gel, 5% is for topical use only. Do not apply ACZONE Gel, 5% to eyes, mouth, or mucous membranes.. Allergan. CUT.

NONCLINICAL TOXICOLOGY SECTION.

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 231 times the systemic exposure observed in humans as result of use of the MRHD of ACZONE Gel, 5%, based on AUC comparisons).No evidence of potential to induce carcinogenesis was observed in 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 bacterial reverse mutation assay (Ames test), and was negative in micronucleus assay conducted in mice. Dapsone was positive (clastogenic) in 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 mg/kg/day or greater (approximately 15 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 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 127 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 5%, based on AUC comparisons), presumably due to reduced numbers or effectiveness of sperm, indicating impairment of fertility. When administered to female rats at dosage of 75 mg/kg/day (approximately 956 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics An open-label study compared the pharmacokinetics of dapsone after ACZONE Gel, 5%, (110 +- 60 mg/day) was applied twice daily (~BSA 22.5%) for 14 days (n=18) with single 100 mg dose of oral dapsone administered to subgroup of patients (n=10) in crossover design. On Day 14 the mean dapsone AUC0-24h was 415 +- 224 ngoh/mL for ACZONE Gel, 5%, whereas following single 100 mg dose of oral dapsone the AUC0-infinity was 52,641 +- 36,223 ngoh/mL. Exposure after the oral dose of 100 mg dapsone was approximately 100 times greater than after the topical ACZONE Gel, 5% dose, twice day.In long-term safety study of ACZONE Gel, 5% treatment, periodic blood samples were collected up to 12 months to determine systemic exposure of dapsone and its metabolites in approximately 500 patients. Based on the measurable dapsone concentrations from 408 patients (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 patients.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data on ACZONE Gel, 5%, use in pregnant women to inform drug-associated risk for adverse developmental outcomes. In animal reproduction studies, oral doses of dapsone administered to pregnant rats and rabbits during organogenesis that resulted in systemic exposures more than 250 times the systemic exposure at the maximum recommended human dose (MRHD) of ACZONE Gel, 5%, resulted in embryocidal effects. When orally administered to rats from the onset of organogenesis through the end of lactation at systemic exposures approximately 400 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.DataAnimal 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 956 times [rats] and 289 times [rabbits] the systemic exposure observed in human females as result of use of the MRHD of ACZONE Gel, 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 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 dapsone dose of 30 mg/kg/day (approximately 382 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 5%, based on AUC comparisons). No effects were observed on the viability, physical development, behavior, learning ability, or reproductive function of surviving pups.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONACZONE(R) AK-zon (dapsone) Gel, 5%Important: For use on skin only (topical use). Do not use ACZONE(R) Gel, 5% in or on your mouth, eyes, or vagina.What is ACZONE(R) Gel, 5%ACZONE(R) Gel, 5% is prescription medicine used on your skin (topical) to treat acne vulgaris.ACZONE(R) Gel has not been studied in children under 12 years of age.Before using ACZONE(R) Gel, 5%, tell your doctor about all of your medical conditions, including if you:Have 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(R) Gel, % will harm your unborn baby. Are breastfeeding or plan to breastfeed. ACZONE(R) Gel, 5% can pass into your breast milk and may harm your baby. You and your doctor should decide if you will use ACZONE(R) Gel, 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(R) Gel, 5% at the same time may cause your skin or facial hair to temporarily turn yellow or orange at the site of application. How should use ACZONE(R) Gel, 5%Use ACZONE(R) Gel, 5% exactly as your doctor tells you. Apply ACZONE(R) Gel, 5% twice day. Gently wash and pat dry the areas of your skin where you will apply ACZONE(R) Gel, 5%. Apply pea-sized amount of ACZONE(R) Gel, 5% in thin layer to the areas of your skin that have acne. Rub ACZONE(R) Gel, 5% in gently and completely. It may feel gritty and you may see particles in the gel. Make sure to put the cap back on the ACZONE(R) Gel tube. Close it tightly. Wash your hands after applying ACZONE(R) Gel, 5%. If your acne does not get better after using ACZONE(R) Gel, 5% for 12 weeks, talk to your doctor about continuing treatment.What are the possible side effects of ACZONE(R) Gel, 5%ACZONE(R) Gel, 5% may cause serious side effects, including:Decrease of oxygen in your blood caused by certain type of abnormal red blood cell (methemoglobinemia). Stop using ACZONE(R) Gel, 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(R) Gel, 5% have developed mild hemolytic anemia. Stop using ACZONE(R) Gel, 5% and tell your doctor right away if you get any of the following signs and symptoms: back pain shortness of breath tiredness or weakness dark brown urine fever yellow or pale skinThe most common side effects of ACZONE(R) Gel, 5% include oiliness, peeling, dryness, and redness of the skin being treated.These are not all of the possible side effects of ACZONE(R) Gel, 5%. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ACZONE(R) Gel, 5%Store ACZONE(R) Gel, 5% at room temperature 68oF to 77oF (20oC to 25oC). Protect ACZONE(R) Gel, 5% from freezing.Keep ACZONE(R) Gel, 5% and all medicines out of the reach of children.General information about the safe and effective use of ACZONE(R) Gel, 5%Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ACZONE(R) Gel, 5% for condition for which it was not prescribed. Do not give ACZONE(R) Gel, 5% to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for information about ACZONE(R) Gel, 5% that is written for health professionals. What are the ingredients in ACZONE (R) Gel 5% Active ingredient: dapsone Inactive ingredients: carbomer homopolymer type C, diethylene glycol monoethyl ether, methylparaben, sodium hydroxide, and purified water, USP.Distributed by: Allergan USA, Inc.Madison, NJ 07940(C) 2018 Allergan. All rights reserved. All trademarks are the property of their respective owners. v1.0PPI3670For more information, call 1-800-678-1605This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 05/2018. Have 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(R) Gel, % will harm your unborn baby. Are breastfeeding or plan to breastfeed. ACZONE(R) Gel, 5% can pass into your breast milk and may harm your baby. You and your doctor should decide if you will use ACZONE(R) Gel, 5% or breastfeed. You should not do both.. Use ACZONE(R) Gel, 5% exactly as your doctor tells you. Apply ACZONE(R) Gel, 5% twice day. Gently wash and pat dry the areas of your skin where you will apply ACZONE(R) Gel, 5%. Apply pea-sized amount of ACZONE(R) Gel, 5% in thin layer to the areas of your skin that have acne. Rub ACZONE(R) Gel, 5% in gently and completely. It may feel gritty and you may see particles in the gel. Make sure to put the cap back on the ACZONE(R) Gel tube. Close it tightly. Wash your hands after applying ACZONE(R) Gel, 5%. If your acne does not get better after using ACZONE(R) Gel, 5% for 12 weeks, talk to your doctor about continuing treatment.. Decrease of oxygen in your blood caused by certain type of abnormal red blood cell (methemoglobinemia). Stop using ACZONE(R) Gel, 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(R) Gel, 5% have developed mild hemolytic anemia. Stop using ACZONE(R) Gel, 5% and tell your doctor right away if you get any of the following signs and symptoms:. Store ACZONE(R) Gel, 5% at room temperature 68oF to 77oF (20oC to 25oC). Protect ACZONE(R) Gel, 5% from freezing.. allergan.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data on ACZONE Gel, 5%, use in pregnant women to inform drug-associated risk for adverse developmental outcomes. In animal reproduction studies, oral doses of dapsone administered to pregnant rats and rabbits during organogenesis that resulted in systemic exposures more than 250 times the systemic exposure at the maximum recommended human dose (MRHD) of ACZONE Gel, 5%, resulted in embryocidal effects. When orally administered to rats from the onset of organogenesis through the end of lactation at systemic exposures approximately 400 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.DataAnimal 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 956 times [rats] and 289 times [rabbits] the systemic exposure observed in human females as result of use of the MRHD of ACZONE Gel, 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 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 dapsone dose of 30 mg/kg/day (approximately 382 times the systemic exposure that is associated with the MRHD of ACZONE Gel, 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 SummaryThere 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 minimal relative to oral dapsone administration; however, it is known that dapsone is present in human milk following administration of oral dapsone. 8.4 Pediatric Use. Safety and efficacy was evaluated in 1169 children aged 12-17 years old treated with ACZONE Gel, 5%, in the clinical trials. 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.. 8.5 Geriatric Use. Clinical trials of ACZONE Gel, 5%, did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 G6PD Deficiency. ACZONE Gel, 5% and vehicle were evaluated in randomized, double-blind, cross-over design clinical trial 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. There were 56 out of 64 subjects who had Week blood draw and applied at least 50% of treatment applications. Table contains results from testing of relevant hematology parameters for these two treatment periods. ACZONE Gel was associated with 0.32 g/dL drop in hemoglobin after two weeks of treatment, but hemoglobin levels generally returned to baseline levels at Week 12.Table - Mean Hemoglobin, Bilirubin, and Reticulocyte Levels in Acne Subjects with G6PD Deficiency in ACZONE/Vehicle Cross-Over StudyACZONE(R)VehicleNMeanNMeanHemoglobin (g/dL) Pre-treatment5313.445613.362 weeks5313.125513.3412 weeks5013.425013.37Bilirubin (mg/dL) Pre-treatment540.58560.552 weeks530.65550.5612 weeks500.61500.62Reticulocytes (%) Pre-treatment531.30551.342 weeks531.51551.3412 weeks501.48501.41There 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, 5% and vehicle treatment (8 of 58 subjects had such decreases during ACZONE treatment compared to 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 hemolysis.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS Methemoglobinemia: Cases of methemoglobinemia have been reported. Discontinue ACZONE gel if signs of methemoglobinemia occur (5.1). Hematologic Effects: Some subjects with G6PD deficiency using ACZONE Gel developed laboratory changes suggestive of hemolysis. (5.2)(8.6).. Methemoglobinemia: Cases of methemoglobinemia have been reported. Discontinue ACZONE gel if signs of methemoglobinemia occur (5.1). Hematologic Effects: Some subjects with G6PD deficiency using ACZONE Gel developed laboratory changes suggestive of hemolysis. (5.2)(8.6).. 5.1 Methemoglobinemia. Cases of methemoglobinemia, with resultant hospitalization, have been reported postmarketing in association with ACZONE 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, 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 slate grey cyanosis seen in, e.g., buccal mucous membranes, lips and nail beds. Advise patients to discontinue ACZONE Gel, 5% and seek immediate medical attention in the event of cyanosis. Dapsone can cause elevated methemoglobin levels particularly in conjunction with methemoglobin-inducing agents.. 5.2 Hematologic 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.Some subjects with G6PD deficiency using ACZONE Gel developed laboratory changes suggestive of hemolysis. There was no evidence of clinically relevant hemolysis or anemia in patients treated with ACZONE Gel, 5%, including patients who were G6PD deficient.Discontinue ACZONE Gel, 5%, if signs and symptoms suggestive of hemolytic anemia occur. Avoid use of ACZONE Gel, 5% in patients who are taking oral dapsone or antimalarial medications because of the potential for hemolytic reactions. Combination of ACZONE Gel, 5%, with trimethoprim/sulfamethoxazole (TMP/SMX) may increase the likelihood of hemolysis in patients with G6PD deficiency.. 5.3 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, 5% treatment.. 5.4 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, 5% treatment.