adapalene and benzoyl peroxide

1 INDICATIONS AND USAGE Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% is indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older. Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% is a combination of adapalene, a retinoid, and benzoyl peroxide, and is indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION • For topical use only. Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% is not for oral, ophthalmic, or intravaginal use. • Apply a thin layer of Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% to affected areas of the face and/or trunk once daily after washing. • Use a pea-sized amount for each area of the face (e.g., forehead, chin, each cheek). • Wash hands after application as Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% may bleach hair or colored fabrics. • Avoid the eyes, lips and mucous membranes. • For topical use only • Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% is not for oral, ophthalmic, or intravaginal use. ( 2 ) • Apply a thin layer of Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% to affected areas of the face and/or trunk once daily after washing. ( 2 ) • Use a pea-sized amount for each area of the face (e.g., forehead, chin, each cheek). ( 2 ) • Avoid the eyes, lips, and mucous membranes. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Each gram of Adapalene and Benzoyl Peroxide Gel, 0.1%/2.5% contains 1 mg (0.1%) adapalene and 25 mg (2.5%) benzoyl peroxide in a white to very pale yellow, opaque, aqueous based gel. Each gram of Adapalene and Benzoyl Peroxide Gel, 0.1%/2.5% contains 1 mg (0.1%) adapalene and 25 mg (2.5%) benzoyl peroxide. ( 3 )

4 CONTRAINDICATIONS Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% is contraindicated in patients with a history of hypersensitivity reactions to benzoyl peroxide or any components of the formulation in Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5%. • Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% is contraindicated in patients with a history of hypersensitivity reactions to benzoyl peroxide or any components of the formulation in Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5%. ( 4 )

6 ADVERSE REACTIONS Most commonly reported adverse events (≥1%) in patients treated with Adapalene and Benzoyl Peroxide Gel, 0.1%/2.5% were dry skin, contact dermatitis, application site burning, application site irritation and skin irritation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Padagis ® at 1-866-634-9120 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. During clinical trials, 1401 subjects were exposed to adapalene and benzoyl peroxide gel, 0.1%/2.5%. A total of 1036 subjects with acne vulgaris, 12 years and older, were treated once daily for 12 weeks to 12 months. Related adverse events reported within 12 weeks of treatment and in at least 1% of subjects treated with adapalene and benzoyl peroxide gel, 0.1%/2.5% and those reported in subjects treated with the vehicle gel are presented in Table 1: Table 1 Drug Related Adverse Events Reported in Clinical Trials by At Least 1% of Patients Treated For 12 Weeks System Organ Class/Preferred Term Adapalene and Benzoyl Peroxide Gel, 0.1%/2.5% N=564 Vehicle gel N=489 Subjects with AE (s) 14% 4% Dry Skin 7% 2% Contact dermatitis 3% <1% Application site burning 2% <1% Application site irritation 1% <1% Skin irritation 1% 0% Local tolerability evaluations, presented in Table 2, were conducted at each study visit in clinical trials by assessment of erythema, scaling, dryness, burning, and stinging. Table 2 Incidence of Local Cutaneous Irritation in Controlled Clinical Trials (N=553) Treatment Emergent Signs and Symptoms Maximum Severity During Treatment End of Treatment Severity (12 Weeks) Mild Moderate Severe Mild Moderate Severe Erythema 27% 13% 1% 8% 2% 1% Scaling 35% 11% 1% 9% 1% <1% Dryness 41% 13% 1% 10% 2% <1% Stinging/burning 41% 15% 3% 7% 2% 1% Analysis over the 12-week period showed that local tolerability scores for erythema, scaling, dryness, and stinging/burning peaked at Week 1 of therapy and decreased thereafter. During a pediatric clinical trial, 285 children with acne vulgaris, 9 to 11 years of age were treated with adapalene and benzoyl peroxide gel, 0.1%/2.5% or with the vehicle gel once daily for 12 weeks. Overall, the safety profile of adapalene and benzoyl peroxide gel, 0.1%/2.5% in these subjects is comparable to the safety profile observed in older subjects 12 years of age and above, both in the nature and frequency of the observed events. Analysis of local tolerability evaluations shows similar incidence of treatment emergent signs and symptoms as in subjects 12 years of age and above, with local tolerability signs and symptoms peaking during the first week and decreasing over time. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of adapalene and benzoyl peroxide gel, 0.1%/2.5%: eyelid edema, sunburn, blister, pain of skin, pruritus, swelling face, conjunctivitis, skin discoloration, rash, eczema, throat tightness and allergic contact dermatitis. 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.

7 DRUG INTERACTIONS Concomitant topical acne therapy should be used with caution because a possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents. No formal drug-drug interaction studies were conducted with Adapalene and Benzoyl Peroxide Gel, 0.1%/2.5%.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available pharmacovigilance data with Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with the combination gel. Adapalene gel, 0.3% Available data from clinical trials with adapalene gel 0.3% use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of adapalene to pregnant rats and rabbits during organogenesis at dose exposures 41 and 81 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 2 g resulted in fetal skeletal and visceral malformations (see Data) . Benzoyl peroxide gel, 2.5% The systemic exposure of benzoyl peroxide is unknown. Based on published literature, benzoyl peroxide is rapidly metabolized to benzoic acid (an endogenous substance), which is eliminated in the urine. Hence, maternal use is not expected to result in fetal exposure of the drug. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data No malformations were observed in rats treated with oral adapalene doses of 0.15 to 5.0 mg/kg/day, up to 8 times the MRHD of 2 grams of Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% based on a mg/m 2 comparison. However, malformations were observed in rats and rabbits when treated with oral doses of ≥ 25 mg/kg/day adapalene (41 and 81 times the MRHD, respectively, based on a mg/m 2 comparison). Findings included cleft palate, microphthalmia, encephalocele, and skeletal abnormalities in rats and umbilical hernia, exophthalmos, and kidney and skeletal abnormalities in rabbits. Dermal adapalene embryofetal development studies in rats and rabbits at doses up to 6.0 mg/kg/day (9.7 and 19.5 times the MRHD, respectively, based on a mg/m 2 comparison) exhibited no fetotoxicity and only minimal increases in skeletal variations (supernumerary ribs in both species and delayed ossification in rabbits). 8.2 Lactation Risk Summary Adapalene gel, 0.3% There are no data on the presence of adapalene topical gel or its metabolite in human milk, the effects on the breastfed infant, or the effects on milk production. In animal studies, adapalene is present in rat milk with oral administration of the drug. When a drug is present in animal milk, it is likely that the drug will be present in human milk. It is possible that topical administration of large amounts of adapalene could result in sufficient systemic absorption to produce detectable quantities in human milk (see Clinical Considerations) . Benzoyl peroxide gel, 2.5% The systemic exposure of benzoyl peroxide is unknown. Based on the published literature, benzoyl peroxide is rapidly metabolized to benzoic acid (an endogenous substance), which is eliminated in the urine. Any amount of benzoyl peroxide excreted into human milk by a nursing mother would be expected to be rapidly metabolized by tissue and stomach esterases. There are no data on the presence of benzoyl peroxide in human milk, its effects on the breastfed infant or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% and any potential adverse effects on the breastfed child from Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% or from the underlying maternal condition. Clinical Considerations To minimiz …

12.1 Mechanism of Action Adapalene Adapalene binds to specific retinoic acid nuclear receptors but does not bind to cytosolic receptor protein. Biochemical and pharmacological profile studies have demonstrated that adapalene is a modulator of cellular differentiation, keratinization and inflammatory processes. However, the significance of these findings with regard to the mechanism of action of adapalene for the treatment of acne is unknown. Benzoyl peroxide Benzoyl peroxide is an oxidizing agent with bactericidal and keratolytic effects.

11 DESCRIPTION Adapalene and Benzoyl Peroxide Gel, 0.1%/2.5% is a white to pale yellow, opaque gel for topical use containing adapalene, USP, 0.1%, and benzoyl peroxide, USP, 2.5%. Adapalene, USP a synthetic retinoid, is a naphthoic acid derivative with retinoid-like properties. The chemical name for adapalene, USP is 6-(4-Methoxy-3-(tricyclo [3.3.1.13,7 ]dec-1-ylphenyl)-2-naphthalene carboxylic acid . It has the following structural formula: Adapalene, USP: Molecular formula: C 28 H 28 O 3 Molecular weight: 412.52 g/mol Benzoyl peroxide, USP is a highly lipophilic oxidizing agent that localizes in both bacterial and keratinocyte cell membranes. The chemical name for benzoyl peroxide, USP is dibenzoyl peroxide. It has the following structural formula: Benzoyl Peroxide, USP: Molecular formula: C 14 H 10 O 4 Molecular weight: 242.23 g/mol Adapalene and Benzoyl Peroxide Gel contains the following inactive ingredients: carbomer homopolymer type C, cyclomethicone, docusate sodium, edetate disodium, glycerin, propylene glycol, poloxamer 124, purified water, sorbitan oleate and sodium hydroxide. adapalenestructure benzoylperoxidestructure

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Adapalene and Benzoyl Peroxide Topical Gel, 0.3%/2.5% is white to very pale yellow in color and opaque in appearance, and is supplied as a 45 gram pump NDC: 72162-1432-2: 45 g in a BOTTLE, PUMP 16.2 Storage and handling Store at controlled room temperature 20° – 25°C (68° – 77°F) with excursions permitted to 15° – 30°C (59° – 86°F) [see USP controlled room temperature]. Keep away from heat. Protect from light. Keep out of reach of children. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504