ACZONE- dapsone gel
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1. Before You Use Aczone Gel, 7.5%, Tell Your Doctor About All Of Your Medical Conditions, Including If You:
2. How Do I Use Aczone Gel, 7.5%?
3. Aczone Gel, 7.5% May Cause Serious Side Effects, Including:
4. How Should I Store Aczone Gel, 7.5%?
5. Active Ingredient:
6. Inactive Ingredients:
7. Patient Information

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.

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. 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.

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

Exton, PA 19341

2019 Almirall, LLC. All rights reserved.

All trademarks are the property of their respective owners.

Patented.

For more information, call 1-866-665-2782

Patient 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 (5.2)].

Important Administration Instructions

• Advise patients to applyACZONEGel, 5%, twice daily to the acne affected area [see Dosage and Administration (2)].
  
• ACZONEGel, 5% is for topical use only.
  
• Do not applyACZONEGel, 5% to eyes, mouth, or mucous membranes.

Distributed by: Allergan USA, Inc.

Madison, NJ 07940

2018 Allergan. All rights reserved.

All trademarks are the property of their respective owners.

v1.0USPI3670

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1. No Title 1572546096
2. Highlights Of Prescribing Information
3. Indications And Usage
4. Dosage And Administration
5. Dosage Forms And Strengths
6. Contraindications
7. Warnings And Precautions
8. Adverse Reactions
9. Drug Interactions
10. 5 Warnings And Precautions
11. 6 Adverse Reactions
12. 7 Drug Interactions
13. 8 Use In Specific Populations
14. 12 Clinical Pharmacology
15. 13 Nonclinical Toxicology
16. 1 Indications And Usage
17. 2 Dosage And Administration
18. 3 Dosage Forms And Strengths
19. 4 Contraindications
20. 5 Warnings And Precautions
21. 6 Adverse Reactions
22. 7 Drug Interactions
23. 8 Use In Specific Populations
24. 11 Description
25. 12 Clinical Pharmacology
26. 13 Nonclinical Toxicology
27. 14 Clinical Studies
28. 16 How Supplied/storage And Handling
29. No Title 1572450214
30. Principal Display Panel
31. Recent Major Changes
32. 1 Indications And Usage
33. 2 Dosage And Administration
34. 3 Dosage Forms And Strengths
35. 4 Contraindications
36. 5 Warnings And Precautions
37. 6 Adverse Reactions
38. 7 Drug Interactions
39. 8 Use In Specific Populations
40. 11 Description
41. 12 Clinical Pharmacology
42. 13 Nonclinical Toxicology
43. 14 Clinical Studies
44. 16 How Supplied/storage And Handling
45. Principal Display Panel - Ndc: 16110-526-90 - 90 G Carton Label

No Title 1572546096 ⮝

PATIENT INFORMATION ACZONE (AK-z n) (dapsone) Gel, 5%
Important: For use on skin only (topical use). Do not use ACZONE Gel, 5% in or on your mouth, eyes, or vagina.
What is ACZONE Gel, 5%? ACZONE Gel, 5% is a prescription medicine used on your skin (topical) to treat acne vulgaris. ACZONE Gel has not been studied in children under 12 years of age.
Before using ACZONE 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 Gel, 5 % will harm your unborn baby. Are breastfeeding or plan to breastfeed. ACZONE Gel, 5% can pass into your breast milk and may harm your baby. You and your doctor should decide if you will use ACZONE 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 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 I use ACZONE Gel, 5%? Use ACZONE Gel, 5% exactly as your doctor tells you. Apply ACZONE Gel, 5% twice a day. Gently wash and pat dry the areas of your skin where you will apply ACZONE Gel, 5%. Apply a pea-sized amount of ACZONE Gel, 5% in a thin layer to the areas of your skin that have acne. Rub ACZONE 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 Gel tube. Close it tightly. Wash your hands after applying ACZONE Gel, 5%. If your acne does not get better after using ACZONE Gel, 5% for 12 weeks, talk to your doctor about continuing treatment.
What are the possible side effects of ACZONE Gel, 5%? ACZONE Gel, 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, 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, 5% have developed mild hemolytic anemia. Stop using ACZONE 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 skin
The most common side effects of ACZONE Gel, 5% include oiliness, peeling, dryness, and redness of the skin being treated. These are not all of the possible side effects of ACZONE 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 I store ACZONE Gel, 5%? Store ACZONE Gel, 5% at room temperature 68 F to 77 F (20 C to 25 C). Protect ACZONE Gel, 5% from freezing. Keep ACZONE Gel, 5% and all medicines out of the reach of children.
General information about the safe and effective use of ACZONE Gel, 5%? Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ACZONE Gel, 5% for a condition for which it was not prescribed. Do not give ACZONE 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 Gel, 5% that is written for health professionals.
What are the ingredients in ACZONE 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 2018 Allergan. All rights reserved. All trademarks are the property of their respective owners. v1.0PPI3670 For more information, call 1-800-678-1605

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 05/2018

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use ACZONE Gel, 7.5% safely and effectively. See full prescribing information for ACZONE Gel, 7.5%.

ACZONE (dapsone) Gel, 7.5%, for topical use
Initial U.S. Approval: 1955

Indications And Usage ⮝

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

Dosage And Administration ⮝

• 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).

Dosage Forms And Strengths ⮝

Gel, 7.5% (3).

Contraindications ⮝

None (4).

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).

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.

Drug Interactions ⮝

• 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).

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 9/2019

5 Warnings And Precautions ⮝

5.1 Methemoglobinemia

5.2 Hematologic Effects

5.3 Peripheral Neuropathy

5.4 Skin

6 Adverse Reactions ⮝

6.1 Clinical Studies Experience

6.2 Experience with Oral Use of Dapsone

6.3 Postmarketing Experience

7 Drug Interactions ⮝

7.1 Trimethoprim-Sulfamethoxazole

7.2 Topical Benzoyl Peroxide

7.3 Drug Interactions with Oral Dapsone

7.4 Concomitant Use with Drugs that Induce Methemoglobinemia

8 Use In Specific Populations ⮝

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 G6PD Deficiency

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4 Microbiology

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

1 Indications And Usage  ⮝

ACZONE Gel, 5%, is indicated for the topical treatment of acne vulgaris.

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, 5%, in a 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.

3 Dosage Forms And Strengths  ⮝

Gel, 5%. Each gram of ACZONE gel contains 50 mg of dapsone in a white to pale yellow gel.

4 Contraindications  ⮝

None.

5 Warnings And Precautions  ⮝

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 a 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.

6 Adverse Reactions  ⮝

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.

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 pharyngitis

In the clinical trials, a total of 12 out of 4032 subjects were reported to have depression (3 of 1660 treated with vehicle and 9 of 2372 treated with ACZONE Gel, 5%). Psychosis was reported in 2 of 2372 subjects treated with ACZONE Gel, 5%, and in 0 of 1660 subjects treated with vehicle.

Combined contact sensitization/irritation studies with ACZONE Gel, 5%, in 253 healthy subjects resulted in at least 3 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 1 below.

Table 1 Application Site Adverse Reactions by Maximum Severity

	ACZONE (N=1819)			Vehicle (N=1660)
Application Site Event	Mild	Moderate	Severe	Mild	Moderate	Severe
Erythema	9%	5%	<1%	9%	6%	<1%
Dryness	14%	3%	<1%	14%	4%	<1%
Oiliness/Peeling	13%	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 2 Adverse Reactions Occurring in at Least 1% of Subjects

	ACZONE N=1819	Vehicle N=1660
Application Site Reaction NOS	18%	20%
Application Site Dryness	16%	17%
Application Site Erythema	13%	14%
Application Site Burning	1%	2%
Application Site Pruritus	1%	1%
Pyrexia	1%	1%
Nasopharyngitis	5%	6%
Upper Respiratory Tract Inf. NOS	3%	3%
Sinusitis NOS	2%	1%
Influenza	1%	1%
Pharyngitis	2%	2%
Cough	2%	2%
Joint Sprain	1%	1%
Headache NOS	4%	4%

NOS = Not otherwise specified

One 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 a 12 month safety trial. The adverse event profile in this trial was consistent with that observed in the vehicle-controlled trials.

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 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)

7 Drug Interactions  ⮝

7.1 Trimethoprim-Sulfamethoxazole

A drug-drug interaction study evaluated the effect of the use of ACZONE Gel, 5%, in combination with double strength (160 mg/800 mg) trimethoprim-sulfamethoxazole (TMP/SMX). During co-administration, systemic levels of TMP and SMX were essentially unchanged. However, levels of dapsone and its metabolites increased in the presence of TMP/SMX. Systemic exposure (AUC0-12) of dapsone and N-acetyl-dapsone (NAD) were increased by about 40% and 20% respectively in 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 a temporary local yellow or orange discoloration of the skin and facial hair (reported by 7 out of 95 subjects in a clinical study) with resolution in 4 to 57 days.

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 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, 5%, use in pregnant women to inform a 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.

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 956 times [rats] and 289 times [rabbits] the systemic exposure observed in human females as a 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 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 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 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 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 a 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 a Week 2 blood draw and applied at least 50% of treatment applications. Table 3 contains results from testing of relevant hematology parameters for these two treatment periods. ACZONE Gel was associated with a 0.32 g/dL drop in hemoglobin after two weeks of treatment, but hemoglobin levels generally returned to baseline levels at Week 12.

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

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

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

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

11 Description  ⮝

ACZONE Gel, 5%, contains dapsone, a sulfone, in an aqueous gel base for topical dermatologic use. ACZONE Gel, 5% is a gritty translucent material with visible drug substance particles. Chemically, dapsone has an empirical formula of C12H12N2O2S. It is a white, odorless crystalline powder that has a molecular weight of 248. Dapsone s chemical name is 4,4 -diaminodiphenylsulfone and its structural formula is:

Each gram of ACZONE Gel, 5%, contains 50 mg of dapsone, USP, in a gel of carbomer homopolymer type C; diethylene glycol monoethyl ether, NF; methylparaben, NF; sodium hydroxide, NF; and purified water, USP.

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 a single 100 mg dose of oral dapsone administered to a subgroup of patients (n=10) in a crossover design. On Day 14 the mean dapsone AUC0-24h was 415 224 ng h/mL for ACZONE Gel, 5%, whereas following a single 100 mg dose of oral dapsone the AUC0-infinity was 52,641 36,223 ng h/mL. Exposure after the oral dose of 100 mg dapsone was approximately 100 times greater than after the topical ACZONE Gel, 5% dose, twice a day.

In a 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.

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 a result of use of the MRHD of ACZONE Gel, 5%, based on AUC comparisons).

No evidence of potential to induce carcinogenesis 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 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 a 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.

14 Clinical Studies  ⮝

Two randomized, double-blind, vehicle-controlled, clinical trials were conducted to evaluate ACZONE Gel, 5%, for the treatment of subjects with acne vulgaris (N=1475 and 1525). The trials were designed to enroll subjects 12 years of age and older with 20 to 50 inflammatory and 20 to 100 non-inflammatory lesions at baseline. In these trials, subjects applied either ACZONE Gel, 5%, or vehicle control twice daily for up to 12 weeks. Efficacy was evaluated in terms of success on the Global Acne Assessment Score (no or minimal acne) and in the percent reduction in inflammatory, non-inflammatory, and total lesions.

The Global Acne Assessment Score was a 5-point scale as follows:

0 None: no evidence of facial acne vulgaris

1 Minimal: few non-inflammatory lesions (comedones) are present; a few inflammatory lesions

(papules/pustules) may be present

2 Mild: several to many non-inflammatory lesions (comedones) are present; a few inflammatory lesions

(papules/pustules) are present

3 Moderate: many non-inflammatory (comedones) and inflammatory lesions (papules/pustules) are present; no

nodulo-cystic lesions are allowed

4 Severe: significant degree of inflammatory disease; papules/pustules are a predominant feature; a few

nodulo-cystic lesions may be present; comedones may be present.

The success rates on the Global Acne Assessment Score (no or minimal acne) at Week 12 are presented in Table 4.

Table 4 - Success (No or Minimal Acne) on the Global Acne Assessment Score at Week 12

	Study 1*		Study 2*
	ACZONE N=699	Vehicle N=687	ACZONE N=729	Vehicle N=738
Subjects with No or Minimal Acne	291 (42%)	223 (32%)	253 (35%)	206 (28%)

*Analysis excludes subjects classified with minimal acne at baseline

Table 5 presents the mean percent reduction in inflammatory, non-inflammatory, and total lesions from baseline to Week 12.

Table 5 - Percent Reduction in Lesions from Baseline to Week 12

	Study 1		Study 2
	ACZONE N=745	Vehicle N=740	ACZONE N=761	Vehicle N=764
Inflammatory	46%	42%	48%	40%
Non-Inflammatory	31%	24%	30%	21%
Total	38%	32%	37%	29%

The clinical trials enrolled about equal proportions of male and female subjects. Female subjects tended to have greater percent reductions in lesions and greater success on the Global Acne Assessment Score than males. The breakdown by race in the clinical trials was about 73% Caucasian, 14% Black, 9% Hispanic, and 2% Asian. Efficacy results were similar across the racial subgroups.

16 How Supplied/storage And Handling  ⮝

ACZONE (dapsone) Gel, 5%, is supplied in the following size tubes:

NDC 0023-3670-30

30 gram laminate tube

NDC 0023-3670-60

60 gram laminate tube

NDC 0023-3670-90

90 gram laminate tube

Store ACZONE gel at controlled room temperature, 20 -25 C (68 -77 F), excursions permitted to 15 -30 C (59 -86 F). Protect from freezing.

No Title 1572450214 ⮝

PATIENT INFORMATION ACZONE (AK-z n) (dapsone) Gel, 5%
Important: For use on skin only (topical use). Do not use ACZONE Gel, 5% in or on your mouth, eyes, or vagina.
What is ACZONE Gel, 5%? ACZONE Gel, 5% is a prescription medicine used on your skin (topical) to treat acne vulgaris. ACZONE Gel has not been studied in children under 12 years of age.
Before using ACZONE 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 Gel, 5 % will harm your unborn baby. Are breastfeeding or plan to breastfeed. ACZONE Gel, 5% can pass into your breast milk and may harm your baby. You and your doctor should decide if you will use ACZONE 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 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 I use ACZONE Gel, 5%? Use ACZONE Gel, 5% exactly as your doctor tells you. Apply ACZONE Gel, 5% twice a day. Gently wash and pat dry the areas of your skin where you will apply ACZONE Gel, 5%. Apply a pea-sized amount of ACZONE Gel, 5% in a thin layer to the areas of your skin that have acne. Rub ACZONE 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 Gel tube. Close it tightly. Wash your hands after applying ACZONE Gel, 5%. If your acne does not get better after using ACZONE Gel, 5% for 12 weeks, talk to your doctor about continuing treatment.
What are the possible side effects of ACZONE Gel, 5%? ACZONE Gel, 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, 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, 5% have developed mild hemolytic anemia. Stop using ACZONE 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 skin
The most common side effects of ACZONE Gel, 5% include oiliness, peeling, dryness, and redness of the skin being treated. These are not all of the possible side effects of ACZONE 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 I store ACZONE Gel, 5%? Store ACZONE Gel, 5% at room temperature 68 F to 77 F (20 C to 25 C). Protect ACZONE Gel, 5% from freezing. Keep ACZONE Gel, 5% and all medicines out of the reach of children.
General information about the safe and effective use of ACZONE Gel, 5%? Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ACZONE Gel, 5% for a condition for which it was not prescribed. Do not give ACZONE 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 Gel, 5% that is written for health professionals.
What are the ingredients in ACZONE 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 2018 Allergan. All rights reserved. All trademarks are the property of their respective owners. v1.0PPI3670 For more information, call 1-800-678-1605

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 05/2018

Principal Display Panel ⮝

NDC 0023-3670-90
Aczone
(dapsone)gel, 5%
90 g
Rx Only

ACZONE dapsone gel

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0023-3670 Route of Administration TOPICAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DAPSONE (UNII: 8W5C518302) (DAPSONE - UNII:8W5C518302) DAPSONE 50 mg in 1 g

Inactive Ingredients Ingredient Name Strength CARBOMER HOMOPOLYMER TYPE C (UNII: 4Q93RCW27E) DIETHYLENE GLYCOL MONOETHYL ETHER (UNII: A1A1I8X02B) METHYLPARABEN (UNII: A2I8C7HI9T) SODIUM HYDROXIDE (UNII: 55X04QC32I) WATER (UNII: 059QF0KO0R)

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0023-3670-03 15 in 1 CARTON 06/24/2009 1 3 g in 1 TUBE; Type 0: Not a Combination Product 2 NDC:0023-3670-30 1 in 1 CARTON 06/24/2009 2 30 g in 1 TUBE; Type 0: Not a Combination Product 3 NDC:0023-3670-60 1 in 1 CARTON 06/24/2009 3 60 g in 1 TUBE; Type 0: Not a Combination Product 4 NDC:0023-3670-90 1 in 1 CARTON 06/24/2009 4 90 g in 1 TUBE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021794 06/24/2009

Labeler - Allergan, Inc. (144796497)

Establishment
Name	Address	ID/FEI	Business Operations
Allergan Sales, LLC		362898611	MANUFACTURE(0023-3670)

Revised: 5/2018 Document Id: fb50ffe5-5ae2-4e70-ad5e-50a846943ad1 34391-3 Set id: b7d605cf-bf84-461b-939b-1f773a4cba65 Version: 12 Effective Time: 20180528 Allergan, Inc.

Recent Major Changes ⮝

Indications and Usage (1)

09/2019

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.

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.

3 Dosage Forms And Strengths ⮝

Gel, 7.5%. Each gram of ACZONE Gel, 7.5% contains 75 mg of dapsone in an off-white to yellow gel with suspended particles.

4 Contraindications ⮝

None.

5 Warnings And Precautions ⮝

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 ⮝

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).

7 Drug Interactions ⮝

No formal drug-drug interaction studies were conducted with ACZONE Gel, 7.5%.

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. 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)].

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 C12H12N2O2S. 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.

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 (AUC0-24h) 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.

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.

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%

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.

Principal Display Panel - Ndc: 16110-526-90 - 90 G Carton Label ⮝

ACZONE dapsone gel

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:16110-526 Route of Administration TOPICAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DAPSONE (UNII: 8W5C518302) (DAPSONE - UNII:8W5C518302) DAPSONE 75 mg in 1 g

Inactive Ingredients Ingredient Name Strength DIETHYLENE GLYCOL MONOETHYL ETHER (UNII: A1A1I8X02B) METHYLPARABEN (UNII: A2I8C7HI9T) SODIUM ACRYLOYLDIMETHYLTAURATE-ACRYLAMIDE COPOLYMER (1:1; 90000-150000 MPA.S) (UNII: 5F4963KLHS) ISOHEXADECANE (UNII: 918X1OUF1E) POLYSORBATE 80 (UNII: 6OZP39ZG8H) WATER (UNII: 059QF0KO0R)

Product Characteristics Color WHITE (off-white to yellow) Score Shape Size Flavor Imprint Code Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:16110-526-30 1 in 1 CARTON 09/10/2019 1 30 g in 1 BOTTLE, PUMP; Type 0: Not a Combination Product 2 NDC:16110-526-60 1 in 1 CARTON 09/10/2019 2 60 g in 1 BOTTLE, PUMP; Type 0: Not a Combination Product 3 NDC:16110-526-90 1 in 1 CARTON 09/10/2019 3 90 g in 1 BOTTLE, PUMP; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA207154 09/10/2019

Labeler - Almirall, LLC (605425912)

Establishment
Name	Address	ID/FEI	Business Operations
DPT Laboratories, Ltd.		832224526	MANUFACTURE(16110-526)

Revised: 9/2019 Document Id: fe7553ec-43ac-4528-81a9-1921282b0741 34391-3 Set id: 22058b7d-a578-4eaa-a476-ac982337f02a Version: 2 Effective Time: 20190927 Almirall, LLC