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 adapalene and benzoyl peroxide topical gel immediately and initiate appropriate therapy.

5.2 Photosensitivity

Avoid exposure to sunlight, including sunlamps, during the use of adapalene and benzoyl peroxide topical gel. 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 adapalene and benzoyl peroxide topical gel.

5.3 Skin Irritation/Contact Dermatitis

Erythema, scaling, dryness, and stinging/burning may be experienced with use of adapalene and benzoyl peroxide topical gel. 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 topical gel, 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 topical gel.

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).

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 adapalene and benzoyl peroxide topical gel. 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 adapalene and benzoyl peroxide topical gel and for which the rate with adapalene and benzoyl peroxide topical gel exceeded the rate for the vehicle are presented in Table 1:

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of adapalene and benzoyl peroxide topical gel. 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

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of adapalene and benzoyl peroxide topical gel in pediatric patients under the age of 12 have not been established.

8.5 Geriatric Use

Clinical studies of adapalene and benzoyl peroxide topical gel did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

12.1 Mechanism of Action

12.2 Pharmacodynamics

Pharmacodynamics of adapalene and benzoyl peroxide topical gel is unknown.

12.3 Pharmacokinetics

A pharmacokinetic trial was conducted in 26 adult and adolescent subjects (12 to 33 years of age) with severe acne vulgaris who were treated with once-daily applications during a 4-week period with, on average, 2.3 grams/day (range 1.6 to 3.1 grams/day) of adapalene and benzoyl peroxide topical gel applied as a thin layer to the face, shoulders, upper chest and upper back. After a 4-week treatment, 16 subjects (62%) had quantifiable adapalene plasma concentrations above the limit of quantification of 0.1 ng/mL, with a mean C maxof 0.16 ± 0.08 ng/mL and a mean AUC 0-24hrof 2.49 ± 1.21 ng.h/mL. The most exposed subject had adapalene C maxand AUC 0-24hrof 0.35 ng/mL and 6.41 ng.h/mL, respectively. Excretion of adapalene appears to be primarily by the biliary route. Benzoyl peroxide is absorbed by the skin where it is converted to benzoic acid and eliminated in the urine.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity, genotoxicity, or fertility studies were conducted with adapalene and benzoyl peroxide topical gel.

Carcinogenicity studies with adapalene were conducted in mice at topical doses of 0.4, 1.3, and 4 mg/kg/day (1.2, 3.9, and 12 mg/m 2/day) and in rats at oral doses of 0.15, 0.5, and 1.5 mg/kg/day (0.9, 3, and 9 mg/m 2/day). The highest dose levels are 3.2 (mice) and 2.4 (rats) times the MRHD of adapalene and benzoyl peroxide topical gel based on a mg/m 2comparison. In the rat study, an increased incidence of benign and malignant pheochromocytomas reported in the adrenal medulla of male rats was observed.

No significant increase in tumor formation was observed in rodents topically treated with 15 to 25% benzoyl peroxide carbopol gel (6 to 10 times the concentration of benzoyl peroxide in adapalene and benzoyl peroxide topical gel) for two years. Rats received maximum daily applications of 138 (males) and 205 (females) mg/kg benzoyl peroxide (27 to 40 times the MRHD based on a mg/m 2comparison). Similar results were obtained in mice topically treated with 25% benzoyl peroxide carbopol gel for 56 weeks followed by intermittent treatment with 15% benzoyl peroxide carbopol gel for rest of the 2 year study period, and in mice topically treated with 5% benzoyl peroxide carbopol gel for two years.

Benzoyl peroxide is a tumor promoter in several animal species. The significance of this finding in humans is unknown.

Adapalene was not mutagenic or genotoxic in vitro(Ames test, Chinese hamster ovary cell assay, or mouse lymphoma TK assay) or in vivo(mouse micronucleus test).

Benzoyl peroxide caused DNA strand breaks and DNA-protein cross-links in mammalian cells, increased sister chromatid exchanges in Chinese hamster ovary cells, and was mutagenic in a few, but not all, in vitrobacterial mutagenicity assays (Ames tests) conducted.

In rat oral studies, 20 mg/kg/day adapalene (32 times the MRHD based on a mg/m 2comparison) did not affect the reproductive performance and fertility of F 0males and females or the growth, development, or reproductive function of F 1offspring.

No fertility studies were conducted with benzoyl peroxide.

16.1 How Supplied

Adapalene and benzoyl peroxide topical gel 0.3% / 2.5% is white to pale yellow in color and opaque in appearance, and is supplied as follows:

16.2 Storage and Handling

• Store at 20° to 25°C (68° to 77°F)[see USP Controlled Room Temperature].
• Keep away from heat.
• Protect from light.
• Keep out of reach of children.

Hypersensitivity

Inform patients that serious hypersensitivity reactions occurred with the use of benzoyl peroxide products. If a patient experiences a serious hypersensitivity reaction, instruct patient to discontinue adapalene and benzoyl peroxide topical gel immediately and seek medical help [see Warnings and Precautions (5.1)].

Photosensitivity

Advise patients to minimize or avoid exposure to natural or artificial light, including tanning beds or UVA/B treatment. Recommend the use of broad spectrum sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided [see Warnings and Precautions (5.2)].

Skin Irritation/Contact Dermatitis

Inform patients that adapalene and benzoyl peroxide topical gel may cause irritation such as erythema, scaling, dryness, stinging or burning [see Warnings and Precautions (5.3)].

Lactation

Use adapalene and benzoyl peroxide topical gel on the smallest part of the skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply adapalene and benzoyl peroxide topical gel directly to the nipple and areola to avoid direct infant exposure [see Use in Specific Populations (8.2)].

Administration Instructions

• Advise patients to cleanse the area to be treated with a mild or soapless cleanser; pat dry. Apply adapalene and benzoyl peroxide topical gel as a thin layer, avoiding the eyes, lips and mucous membranes.
• Advise patients not to use more than the recommended amount and not to apply more than once daily as this will not produce faster results, but may increase irritation.
• Wash hands after application as adapalene and benzoyl peroxide topical gel may bleach hair and colored fabric.