Adapalene and Benzoyl Peroxide

EPIDUO FORTE is indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older. EPIDUO FORTE, 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 )

Each gram of EPIDUO FORTE topical gel contains 3 mg (0.3%) adapalene and 25 mg (2.5%) benzoyl peroxide in a white to very pale yellow, opaque gel. EPIDUO FORTE is available in pumps containing 15 g, 30 g, 45 g, 60 g or 70 g. Topical Gel, 0.3%/2.5% ( 3 )

EPIDUO FORTE is contraindicated in patients with a history of hypersensitivity reactions to benzoyl peroxide or any components of the formulation in EPIDUO FORTE. EPIDUO FORTE is contraindicated in patients with a history of hypersensitivity reactions to benzoyl peroxide or any components of the formulation in EPIDUO FORTE. ( 4 )

Hypersensitivity: Severe hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with the use of benzoyl peroxide products. ( 5.1 ) Photosensitivity: Avoid exposure to sunlight and sunlamps. Wear broad spectrum sunscreen and protective clothing when sun exposure cannot be avoided. ( 5.2 ) Skin Irritation: Erythema, scaling, dryness, stinging/burning, irritant and allergic contact dermatitis may occur with use of EPIDUO FORTE and may necessitate discontinuation. ( 5.3 )

5.1 Hypersensitivity Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, have been reported with the use of benzoyl peroxide products. If a serious hypersensitivity reaction occurs, discontinue EPIDUO FORTE immediately and initiate appropriate therapy.

5.2 Photosensitivity Avoid exposure to sunlight, including sunlamps, during the use of EPIDUO FORTE. Patients with high levels of sun exposure and those with inherent sensitivity to sun should exercise particular caution. Use of broad spectrum sunscreen products and protective apparel (e.g., hat) are recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, may be irritating to patients under treatment with EPIDUO FORTE.

5.3 Skin Irritation/Contact Dermatitis Erythema, scaling, dryness, and stinging/burning may be experienced with use of EPIDUO FORTE. These are most likely to occur during the first four weeks of treatment, are mostly mild to moderate in intensity, and usually lessen with continued use of the medication. Irritant and allergic contact dermatitis may occur. Depending upon the severity of these adverse reactions, patients should be instructed to use a moisturizer, reduce the frequency of the application of EPIDUO FORTE, or discontinue use. The product should not be applied to cuts, abrasions, eczematous or sunburned skin. As with other retinoids, use of “waxing” as a depilatory method should be avoided on skin treated with EPIDUO FORTE. Avoid concomitant use of other potentially irritating topical products (medicated or abrasive soaps and cleansers, soaps and cosmetics that have strong skin-drying effect and products with high concentrations of alcohol, astringents, spices or limes).

The most common adverse reactions (incidence ≥1%) are skin irritation, eczema, atopic dermatitis and skin burning sensation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience The following adverse reactions are discussed in greater detail elsewhere in the labeling: Hypersensitivity [ see Warnings and Precautions ( 5.1 ) ] Skin Irritation/Contact Dermatitis [ see Warnings and Precautions ( 5.3 ) ] 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 the randomized, double-blind, vehicle- and active-controlled clinical trial, 217 subjects were exposed to EPIDUO FORTE. A total of 197 subjects with acne vulgaris, 12 years and older, were treated once daily for 12 weeks. Adverse reactions reported within 12 weeks of treatment in at least 1% of subjects treated with EPIDUO FORTE and for which the rate with EPIDUO FORTE exceeded the rate for the vehicle are presented in Table 1: Table 1. Adverse Reactions Occurring in ≥ 1% of Subjects with Acne Vulgaris in a 12-week Clinical Trial EPIDUO FORTE (N=217) Adapalene and Benzoyl Peroxide Gel, 0.1%/2.5% (N=217) Vehicle (N=69) Skin irritation 4% <1% 0% Eczema 1% 0% 0% Dermatitis atopic 1% 0% 0% Skin burning sensation 1% 0% 0% Local tolerability evaluations presented in Table 2, were conducted at each trial visit in the clinical trial by assessment of erythema, scaling, dryness, and stinging/burning, which peaked at Week 1 of therapy and decreased thereafter. Table 2. Incidence of Local Cutaneous Irritation in 12-week Clinical Trial in Subjects with Acne Vulgaris Maximum Severity During Treatment End of Treatment Severity (Final Score) Moderate Severe Moderate Severe EPIDUO FORTE (N=213) Erythema 20% 1% 4% <1% Scaling 17% 1% 1% <1% Dryness 15% 2% 3% <1% Stinging/Burning 19% 6% 1% 1% Adapalene and Benzoyl Peroxide Gel, 0.1%/2.5% (N=212) Erythema 15% 1% 2% <1% Scaling 12% <1% 2% 0% Dryness 13% 1% 2% 0% Stinging/Burning 14% 9% 3% 0% Vehicle (N=68) Erythema 6% 1% 1% 0% Scaling 6% 0% 1% 0% Dryness 4% 1% 1% 0% Stinging/Burning 3% 1% 0% 0%

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of EPIDUO FORTE. 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. Skin and subcutaneous tissue disorders : sunburn, blister (including vesicles and bullae), pruritus, hyperpigmentation and hypopigmentation..

8.1 Pregnancy Risk Summary Available pharmacovigilance data with EPIDUO FORTE 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 EPIDUO FORTE based on a mg/m2 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/m2 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/m2 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 EPIDUO FORTE and any potential adverse effects on the breastfed child from EPIDUO FORTE or from the underlying maternal condition. Clinical Considerations To minimize potential exposure to the breastfed infant via breastmilk, use EPIDUO FORTE on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply EPIDUO FORTE directly to the nipple and areola to avoid direct infant exposure.

8.4 Pediatric Use Safety and effectiveness of EPIDUO FORTE in pediatric patients under the age of 12 have not been established.

8.5 Geriatric Use Clinical studies of EPIDUO FORTE did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

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.