Adapalene and Benzoyl Peroxide Gel, 0.1%/2.5%

1 INDICATIONS AND USAGE Adapalene and benzoyl peroxide gel 0.1% / 2.5% is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. Adapalene and benzoyl peroxide gel 0.1% / 2.5% is a combination of adapalene, a retinoid, and benzoyl peroxide, and is indicated for the topical treatment of acne vulgaris in patients 9 years of age and older. (1)

2 DOSAGE AND ADMINISTRATION For topical use only; adapalene and benzoyl peroxide gel 0.1% / 2.5% is not for oral, ophthalmic, or intravaginal use. Apply a thin film of adapalene and benzoyl peroxide gel 0.1% / 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). Avoid the eyes, lips and mucous membranes. Adapalene and benzoyl peroxide gel 0.1% / 2.5% is not for oral, ophthalmic, or intravaginal use. (2) Apply a thin film of adapalene and benzoyl peroxide gel 0.1% / 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). Avoid the eyes, lips and mucous membranes. (2)

4 CONTRAINDICATIONS None None. (4)

5 WARNINGS AND PRECAUTIONS Ultraviolet Light and Environmental Exposure: Avoid exposure to sunlight and sunlamps. Wear sunscreen when sun exposure cannot be avoided. (5.1) Erythema, scaling, dryness, stinging/burning, irritant and allergic contact dermatitis may occur with use of adapalene and benzoyl peroxide gel 0.1% / 2.5% and may necessitate discontinuation. (5.2) 5.1 Ultraviolet Light and Environmental Exposure Exposure to sunlight, including sunlamps, should be minimized during the use of adapalene and benzoyl peroxide gel 0.1% / 2.5%. Patients with high levels of sun exposure and those with inherent sensitivity to sun should exercise particular caution. Use of 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 adapalene and benzoyl peroxide gel 0.1% / 2.5%. 5.2 Local Cutaneous Reactions Erythema, scaling, dryness, and stinging/burning may be experienced with use of adapalene and benzoyl peroxide gel 0.1% / 2.5%. 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 adapalene and benzoyl peroxide gel 0.1% / 2.5%, 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 adapalene and benzoyl peroxide gel 0.1% / 2.5%. 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).

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%.

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 Encube Ethicals Private Limited, at 1-833-285-4151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. 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 adverse 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 post-approval 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.

8.1 Pregnancy Pregnancy Category C. There are no well-controlled trials in pregnant women treated with adapalene and benzoyl peroxide gel 0.1% / 2.5%. Animal reproduction studies have not been conducted with the combination gel or benzoyl peroxide. Furthermore, such studies are not always predictive of human response; therefore, adapalene and benzoyl peroxide gel 0.1% / 2.5% should be used during pregnancy only if the potential benefit justifies the risk to the fetus. No teratogenic effects were observed in rats treated with oral doses of 0.15 to 5.0 mg adapalene/kg/day, up to 25 times (mg/m2/day) the maximum recommended human dose (MRHD) of 2 grams of adapalene and benzoyl peroxide gel 0.1% / 2.5%. However, teratogenic changes were observed in rats and rabbits when treated with oral doses of ≥ 25 mg adapalene/kg/day representing 123 and 246 times MRHD, respectively. Findings included cleft palate, microphthalmia, encephalocele and skeletal abnormalities in rats; and umbilical hernia, exophthalmos and kidney and skeletal abnormalities in rabbits. Dermal teratology studies conducted in rats and rabbits at doses of 0.6 to 6.0 mg adapalene/kg/day [25 to 59 times (mg/m2) the MRHD] exhibited no fetotoxicity and only minimal increases in supernumerary ribs in both species and delayed ossification in rabbits.