th use of adapalene and benzoyl peroxide 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 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 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).

which the rate with adapalene and benzoyl peroxide gel exceeded the rate for the vehicle gel are presented in table 1: table 1. adverse reactions occurring in ≥ 1% of subjects with acne vulgaris in a 12-week clinical trial adapalene and benzoyl peroxide gel 0.3%/2.5% (n=217) adapalene and benzoyl peroxide gel, 0.1%/2.5% (n=217) vehicle gel (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 study 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 adapalene and benzoyl peroxide gel 0.3%/2.5% (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 gel (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 post-marketing experience there is no post-marketing experience with adapalene and benzoyl peroxide gel. the following adverse reactions have been identified during post-approval use of adapalene and benzoyl peroxide gel, a similar drug containing 0.1% adapalene and 2.5% benzoyl peroxide as the active ingredients: 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.

ney and skeletal abnormalities in rabbits. dermal teratology studies conducted in rats and rabbits at doses of 0.6-6.0 mg adapalene/kg/day (9.7-19.5 times mrhd) exhibited no fetotoxicity and only minimal increases in supernumerary ribs in both species and delayed ossification in rabbits. 8.3 nursing mothers it is not known whether adapalene or benzoyl peroxide is excreted in human milk following use of adapalene and benzoyl peroxide gel. because many drugs are excreted in human milk, caution should be exercised when adapalene and benzoyl peroxide gel is administered to a nursing woman. 8.4 pediatric use safety and effectiveness of adapalene and benzoyl peroxide gel in pediatric patients under the age of 12 have not been established. 8.5 geriatric use clinical studies of adapalene and benzoyl peroxide gel did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

in rabbits. dermal teratology studies conducted in rats and rabbits at doses of 0.6-6.0 mg adapalene/kg/day (9.7-19.5 times mrhd) exhibited no fetotoxicity and only minimal increases in supernumerary ribs in both species and delayed ossification in rabbits.

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 max of 0.16 ± 0.08 ng/ml and a mean auc 0-24hr of 2.49 ± 1.21 ng.h/ml. the most exposed subject had adapalene c max and auc 0-24hr of 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.

lications of 138 (males) and 205 (females) mg benzoyl peroxide/kg. in terms of body surface area, these levels are 27-40 times the mrhd. 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. the role of benzoyl peroxide as a tumor promoter has been well established in several animal species. the significance of this finding in humans is unknown. in a photocarcinogenicity study conducted with 5% benzoyl peroxide carbopol gel, no increase in uv-induced tumor formation was observed in hairless mice topically treated for 40 weeks. no photocarcinogenicity studies were conducted with adapalene. however, animal studies have shown an increased tumorigenic risk with the use of pharmacologically similar drugs (e.g., retinoids) when exposed to uv irradiation in the laboratory or sunlight. although the significance of these findings to humans is not clear, patients should be advised to avoid or minimize exposure to either sunlight or artificial irradiation sources. adapalene did not exhibit mutagenic or genotoxic effects in vitro (ames test, chinese hamster ovary cell assay, or mouse lymphoma tk assay) or in vivo (mouse micronucleus test). bacterial mutagenicity assays (ames test) with benzoyl peroxide has provided mixed results; mutagenic potential was observed in a few but not in a majority of investigations. it has been shown to produce single-strand dna breaks in human bronchial epithelial and mouse epidermal cells, caused dna-protein cross-links in the human cells, and also induced a dose-dependent increase in sister chromatid exchanges in chinese hamster ovary cells. in rat oral studies, 20 mg adapalene/kg/day did not affect the reproductive performance and fertility of f 0 males and females, or the growth, development and reproductive function of f 1 offspring. no fertility studies were conducted with benzoyl peroxide.

d 205 (females) mg benzoyl peroxide/kg. in terms of body surface area, these levels are 27-40 times the mrhd. 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. the role of benzoyl peroxide as a tumor promoter has been well established in several animal species. the significance of this finding in humans is unknown. in a photocarcinogenicity study conducted with 5% benzoyl peroxide carbopol gel, no increase in uv-induced tumor formation was observed in hairless mice topically treated for 40 weeks. no photocarcinogenicity studies were conducted with adapalene. however, animal studies have shown an increased tumorigenic risk with the use of pharmacologically similar drugs (e.g., retinoids) when exposed to uv irradiation in the laboratory or sunlight. although the significance of these findings to humans is not clear, patients should be advised to avoid or minimize exposure to either sunlight or artificial irradiation sources. adapalene did not exhibit mutagenic or genotoxic effects in vitro (ames test, chinese hamster ovary cell assay, or mouse lymphoma tk assay) or in vivo (mouse micronucleus test). bacterial mutagenicity assays (ames test) with benzoyl peroxide has provided mixed results; mutagenic potential was observed in a few but not in a majority of investigations. it has been shown to produce single-strand dna breaks in human bronchial epithelial and mouse epidermal cells, caused dna-protein cross-links in the human cells, and also induced a dose-dependent increase in sister chromatid exchanges in chinese hamster ovary cells. in rat oral studies, 20 mg adapalene/kg/day did not affect the reproductive performance and fertility of f 0 males and females, or the growth, development and reproductive function of f 1 offspring. no fertility studies were conducted with benzoyl peroxide.

rritation 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 study 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 adapalene and benzoyl peroxide gel 0.3%/2.5% (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 gel (n=68) erythema 6% 1% 1% 0% scaling 6% 0% 1% 0% dryness 4% 1% 1% 0% stinging/burning 3% 1% 0% 0%

. 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 51-226) total lesions of which the mean number of inflammatory lesions was 38 (range: 20-99) and the mean number of non-inflammatory lesions was 60 (range 30-149). 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. table 3. clinical efficacy of adapalene and benzoyl peroxide gel at week 12 in subjects with acne vulgaris adapalene and benzoyl peroxide gel 0.3%/2.5% (n=217) adapalene and benzoyl peroxide gel, 0.1%/2.5% (n=217) * vehicle gel (n=69) iga: two-grade improvement and "clear" or "almost clear" 33.7% 27.3% 11.0% inflammatory lesions: mean absolute (percent) reduction 27.8 (68.7%) 26.5 (69.3%) 13.2 (39.2%) non-inflammatory lesions: mean absolute (percent) reduction 40.5 (68.3%) 40.0 (68.0%) 19.7 (37.4%) * this study was not designed or powered to compare the efficacy of adapalene and benzoyl peroxide gel to the lower strength adapalene and benzoyl peroxide gel, 0.1%/2.5%, nor to compare the lower strength adapalene and benzoyl peroxide gel, 0.1%/2.5% to the vehicle control. in subjects graded as “severe” (iga grade 4), efficacy was observed in the adapalene and benzoyl peroxide group.

sses into your breast milk and if it can harm your baby. talk to your doctor about the best way to feed your baby if you use adapalene and benzoyl peroxide gel. tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. using other topical acne products may increase the irritation of your skin when used with adapalene and benzoyl peroxide gel. how should i use adapalene and benzoyl peroxide gel? • use adapalene and benzoyl peroxide gel exactly as your doctor tells you to use it. • apply adapalene and benzoyl peroxide gel 1 time a day. • do not use more adapalene and benzoyl peroxide gel than you need to cover the treatment area. using too much adapalene and benzoyl peroxide gel or using it more than 1 time a day may increase your chance of skin irritation. applying adapalene and benzoyl peroxide gel: • wash the area where the gel will be applied with a mild or soapless cleanser and pat dry. • adapalene and benzoyl peroxide gel comes in a pump. depress the pump to dispense a small amount (about the size of a pea) of adapalene and benzoyl peroxide gel and spread a thin layer over the affected area. • wash your hands after applying the gel. what should i avoid while using adapalene and benzoyl peroxide gel? • avoid spending time in sunlight or artificial sunlight, such as tanning beds or sunlamps. adapalene and benzoyl peroxide gel can make your skin sensitive to sun and the light from tanning beds and sunlamps. use sunscreen and wear a hat and clothes that cover the areas treated with adapalene and benzoyl peroxide gel if you have to be in sunlight. • cold weather and wind may irritate skin treated with adapalene and benzoyl peroxide gel. • avoid applying adapalene and benzoyl peroxide gel to cuts, abrasions, and sunburned skin. • avoid skin products that may dry or irritate your skin such as medicated or harsh soaps, astringents, cosmetics that make your skin dry, and products containing high levels of alcohol, spices, or limes. • avoid the use of “waxing” as a hair removal method on skin treated with adapalene and benzoyl peroxide gel. • adapalene and benzoyl peroxide gel may bleach your clothes or hair. allow adapalene and benzoyl peroxide gel to dry completely before dressing to prevent bleaching of your clothes. what are the possible side effects of adapalene and benzoyl peroxide gel? adapalene and benzoyl peroxide gel may cause serious side effects including: local skin reactions. local skin reactions are most likely to happen during the first 4 weeks of treatment and usually lessen with continued use of adapalene and benzoyl peroxide gel. signs and symptoms of local skin reactions include redness, scaling, dryness, stinging, or burning. tell your doctor right away if these side effects continue for longer than 4 weeks or get worse, you may have to stop using adapalene and benzoyl peroxide gel. these are not all the possible side effects of adapalene and benzoyl peroxide gel. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. you may also report side effects to teva pharmaceuticals usa, inc. at 1-888-838-2872 how should i store adapalene and benzoyl peroxide gel? • store adapalene and benzoyl peroxide gel at room temperature between 68°f to 77°f (20°c to 25°c). • keep adapalene and benzoyl peroxide gel out of light and away from heat. keep adapalene and benzoyl peroxide gel and all medicines out of the reach of children. general information about the safe and effective use of adapalene and benzoyl peroxide gel medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use adapalene and benzoyl peroxide gel for a condition for which it was not prescribed. do not give adapalene and benzoyl peroxide gel to other people, even if they have the same symptoms you have. it may harm them. you can ask your doctor or pharmacist for information about adapalene and benzoyl peroxide gel that is written for health professionals. what are the ingredients in adapalene and benzoyl peroxide gel? active ingredient: adapalene and benzoyl peroxide inactive ingredients: acrylamide/sodium acryloydimethyltaurate copolymer, docusate sodium, edetate disodium, glycerin, isohexadecane, polaxamer 124, polysorbate 80, propylene glycol, purified water and sorbitan oleate manufactured for: teva pharmaceuticals, inc., parsippany, nj 07054 this patient information has been approved by the u.s. food and drug administration. issued: 07/2015