These Highlights Do Not Include All The Information Needed To Use Adapalene And Benzoyl Peroxide Topical Gel Safely And Effectively. See Full Prescribing Information For Adapalene And Benzoyl Peroxide Topical Gel.

Risk Summary

Available pharmacovigilance data with adapalene and benzoyl peroxide topical gel 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.

• 5235292 21

Adapalene and benzoyl peroxide topical gel, 0.3%/2.5% is a white to pale yellow, opaque gel for topical use containing adapalene 0.3% and benzoyl peroxide 2.5%.

Adapalene, a synthetic retinoid, is a naphthoic acid derivative with retinoid-like properties. The chemical name for adapalene is (6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid). It has the following structural formula:

Benzoyl peroxide is a highly lipophilic oxidizing agent that localizes in both bacterial and keratinocyte cell membranes. The chemical name for benzoyl peroxide is dibenzoyl peroxide. It has the following structural formula:

Adapalene and benzoyl peroxide topical gel contains the following inactive ingredients: docusate sodium, edetate disodium, glycerin, poloxamer 124, polyacrylamide & C13-14 isoparaffin & laureth 7 (sepigel 305), propylene glycol and purified water.

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:

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

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.

The safety and efficacy of adapalene and benzoyl peroxide topical gel, 0.3%/2.5% applied once daily for 12 weeks for the treatment of acne vulgaris were assessed in a multicenter, randomized, double-blind, vehicle-controlled trial, comparing adapalene and benzoyl peroxide topical gel, 0.3%/2.5% to vehicle gel in subjects with acne vulgaris. The trial also evaluated adapalene and benzoyl peroxide gel, 0.1%/2.5%, a lower strength product than adapalene and benzoyl peroxide topical gel, 0.3%/2.5%. In this trial, 217 subjects were treated with adapalene and benzoyl peroxide topical gel, 0.3%/2.5%, 217 subjects with adapalene and benzoyl peroxide gel, 0.1%/2.5% and 69 subjects with the vehicle gel.

Treatment response was defined as the percent of subjects who were rated "clear" or "almost clear" at Week 12 with at least a two-grade improvement based on the Investigator's Global Assessment (IGA), and mean absolute change from baseline at Week 12 in both inflammatory and non-inflammatory lesion counts. An IGA score of "Clear" corresponded to clear skin with no inflammatory or non-inflammatory lesions. An IGA score of "almost clear" corresponded to a few scattered comedones and a few small papules.

At baseline, 50% of subjects were graded as "moderate" (IGA Grade 3) and 50% were graded as "severe" (IGA Grade 4) on the IGA scale. Subjects had an average of 98 (range 51 to 226) total lesions of which the mean number of inflammatory lesions was 38 (range: 20 to 99) and the mean number of non-inflammatory lesions was 60 (range 30 to 149). Subjects ranged in age from 12 to 57 years, with 273 (54%) of subjects 12 to 17 years of age. Approximately equal number of males (48%) and females (52%) were enrolled.

The IGA success rate, mean reduction, and percent reduction in acne lesion counts from baseline after 12 weeks of treatment are presented in the following table.

In subjects graded as "severe" (IGA Grade 4), efficacy was observed in the adapalene and benzoyl peroxide topical gel, 0.3%/2.5% group.

Adapalene and benzoyl peroxide topical gel 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.

The most common adverse reactions (incidence ≥1%) are skin irritation, eczema, atopic dermatitis and skin burning sensation. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc. at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

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.

Pharmacodynamics of adapalene and benzoyl peroxide topical gel is unknown.

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.

Adapalene and benzoyl peroxide topical gel is indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older.

• 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: 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 adapalene and benzoyl peroxide topical gel and may necessitate discontinuation. ( 5.3)

• For topical use only. Adapalene and benzoyl peroxide topical gel is not for oral, ophthalmic, or intravaginal use.
• Apply a thin layer of adapalene and benzoyl peroxide topical gel 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 may bleach hair or colored fabrics.
• Avoid the eyes, lips and mucous membranes.

Each gram of adapalene and benzoyl peroxide topical gel contains 3 mg (0.3%) adapalene and 25 mg (2.5%) benzoyl peroxide in a white to pale yellow, opaque gel. Adapalene and benzoyl peroxide topical gel is available in pumps containing 45 g or 60 g.

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.

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.

Advise the patient to read the FDA approved patient labeling (Patient Information).

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).

NDC 51672-1384-9

45 g

Adapalene and

Benzoyl Peroxide

Topical Gel 0.3% / 2.5%

PUMP

FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL OR INTRAVAGINAL USE.

Rx only

Keep this and all medications out of the reach of children.

TARO

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.

Risk Summary

Available pharmacovigilance data with adapalene and benzoyl peroxide topical gel 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.

• 5235292 21

Adapalene and benzoyl peroxide topical gel, 0.3%/2.5% is a white to pale yellow, opaque gel for topical use containing adapalene 0.3% and benzoyl peroxide 2.5%.

Adapalene, a synthetic retinoid, is a naphthoic acid derivative with retinoid-like properties. The chemical name for adapalene is (6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid). It has the following structural formula:

Benzoyl peroxide is a highly lipophilic oxidizing agent that localizes in both bacterial and keratinocyte cell membranes. The chemical name for benzoyl peroxide is dibenzoyl peroxide. It has the following structural formula:

Adapalene and benzoyl peroxide topical gel contains the following inactive ingredients: docusate sodium, edetate disodium, glycerin, poloxamer 124, polyacrylamide & C13-14 isoparaffin & laureth 7 (sepigel 305), propylene glycol and purified water.

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:

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

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.

The safety and efficacy of adapalene and benzoyl peroxide topical gel, 0.3%/2.5% applied once daily for 12 weeks for the treatment of acne vulgaris were assessed in a multicenter, randomized, double-blind, vehicle-controlled trial, comparing adapalene and benzoyl peroxide topical gel, 0.3%/2.5% to vehicle gel in subjects with acne vulgaris. The trial also evaluated adapalene and benzoyl peroxide gel, 0.1%/2.5%, a lower strength product than adapalene and benzoyl peroxide topical gel, 0.3%/2.5%. In this trial, 217 subjects were treated with adapalene and benzoyl peroxide topical gel, 0.3%/2.5%, 217 subjects with adapalene and benzoyl peroxide gel, 0.1%/2.5% and 69 subjects with the vehicle gel.

Treatment response was defined as the percent of subjects who were rated "clear" or "almost clear" at Week 12 with at least a two-grade improvement based on the Investigator's Global Assessment (IGA), and mean absolute change from baseline at Week 12 in both inflammatory and non-inflammatory lesion counts. An IGA score of "Clear" corresponded to clear skin with no inflammatory or non-inflammatory lesions. An IGA score of "almost clear" corresponded to a few scattered comedones and a few small papules.

At baseline, 50% of subjects were graded as "moderate" (IGA Grade 3) and 50% were graded as "severe" (IGA Grade 4) on the IGA scale. Subjects had an average of 98 (range 51 to 226) total lesions of which the mean number of inflammatory lesions was 38 (range: 20 to 99) and the mean number of non-inflammatory lesions was 60 (range 30 to 149). Subjects ranged in age from 12 to 57 years, with 273 (54%) of subjects 12 to 17 years of age. Approximately equal number of males (48%) and females (52%) were enrolled.

The IGA success rate, mean reduction, and percent reduction in acne lesion counts from baseline after 12 weeks of treatment are presented in the following table.

In subjects graded as "severe" (IGA Grade 4), efficacy was observed in the adapalene and benzoyl peroxide topical gel, 0.3%/2.5% group.

Adapalene and benzoyl peroxide topical gel 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.

The most common adverse reactions (incidence ≥1%) are skin irritation, eczema, atopic dermatitis and skin burning sensation. ( 6)

To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc. at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

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.

Pharmacodynamics of adapalene and benzoyl peroxide topical gel is unknown.

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.

Adapalene and benzoyl peroxide topical gel is indicated for the topical treatment of acne vulgaris in adults and pediatric patients 12 years of age and older.

• 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: 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 adapalene and benzoyl peroxide topical gel and may necessitate discontinuation. ( 5.3)

• For topical use only. Adapalene and benzoyl peroxide topical gel is not for oral, ophthalmic, or intravaginal use.
• Apply a thin layer of adapalene and benzoyl peroxide topical gel 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 may bleach hair or colored fabrics.
• Avoid the eyes, lips and mucous membranes.

Each gram of adapalene and benzoyl peroxide topical gel contains 3 mg (0.3%) adapalene and 25 mg (2.5%) benzoyl peroxide in a white to pale yellow, opaque gel. Adapalene and benzoyl peroxide topical gel is available in pumps containing 45 g or 60 g.

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.

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.

Advise the patient to read the FDA approved patient labeling (Patient Information).

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).

NDC 51672-1384-9

45 g

Adapalene and

Benzoyl Peroxide

Topical Gel 0.3% / 2.5%

PUMP

FOR TOPICAL USE ONLY. NOT FOR OPHTHALMIC, ORAL OR INTRAVAGINAL USE.

Rx only

Keep this and all medications out of the reach of children.

TARO

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.