dapalene and benzoyl peroxide topical gel, 0.3%/2.5%. 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, 0.3%/2.5%. 5.3 skin irritation/contact dermatitis erythema, scaling, dryness, and stinging/burning may be experienced with use of adapalene and benzoyl peroxide topical gel, 0.3%/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 topical gel, 0.3%/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 topical gel, 0.3%/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).

e eyes, lips, and mucous membranes. ( 2 )

cts 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, 0.3%/2.5% and for which the rate with adapalene and benzoyl peroxide topical gel, 0.3%/2.5% 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 adapalene and benzoyl peroxide topical 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 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 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 postmarketing experience the following adverse reactions have been identified during postapproval use of adapalene and benzoyl peroxide topical gel, 0.3%/2.5%. 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.

. 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 adapalene and benzoyl peroxide topical gel, 0.3%/2.5% based on a mg/m 2 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/m 2 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/m 2 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 adapalene and benzoyl peroxide topical gel, 0.3%/2.5% and any potential adverse effects on the breastfed child from adapalene and benzoyl peroxide topical gel, 0.3%/2.5% or from the underlying maternal condition. clinical considerations to minimize potential exposure to the breastfed infant via breastmilk, use adapalene and benzoyl peroxide topical gel, 0.3%/2.5% on the smallest area of skin and for the shortest duration possible while breastfeeding. advise breastfeeding women not to apply adapalene and benzoyl peroxide topical gel, 0.3%/2.5% directly to the nipple and areola to avoid direct infant exposure. 8.4 pediatric use safety and effectiveness of adapalene and benzoyl peroxide topical gel, 0.3%/2.5% 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, 0.3%/2.5% did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

e, 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 adapalene and benzoyl peroxide topical gel, 0.3%/2.5% based on a mg/m 2 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/m 2 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/m 2 comparison) exhibited no fetotoxicity and only minimal increases in skeletal variations (supernumerary ribs in both species and delayed ossification in rabbits).

0.3%/2.5% 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 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. drug interactions no formal drug-drug interaction studies were conducted with adapalene and benzoyl peroxide topical gel, 0.3%/2.5%.

h adapalene and benzoyl peroxide topical gel, 0.3%/2.5%.

ived maximum daily applications of 138 (males) and 205 (females) mg/kg benzoyl peroxide (27-40 times the mrhd based on a mg/m 2 comparison). 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 vitro bacterial mutagenicity assays (ames tests) conducted. in rat oral studies, 20 mg/kg/day adapalene (32 times the mrhd based on a mg/m 2 comparison) did not affect the reproductive performance and fertility of f 0 males and females or the growth, development or reproductive function of f 1 offspring. no fertility studies were conducted with benzoyl peroxide.

tions of 138 (males) and 205 (females) mg/kg benzoyl peroxide (27-40 times the mrhd based on a mg/m 2 comparison). 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 vitro bacterial mutagenicity assays (ames tests) conducted. in rat oral studies, 20 mg/kg/day adapalene (32 times the mrhd based on a mg/m 2 comparison) did not affect the reproductive performance and fertility of f 0 males and females or the growth, development or reproductive function of f 1 offspring. no fertility studies were conducted with benzoyl peroxide.

n 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 51-226) 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 topical gel, 0.3%/2.5% at week 12 in subjects with acne vulgaris adapalene and benzoyl peroxide topical 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 trial was not designed or powered to compare the efficacy of adapalene and benzoyl peroxide topical gel, 0.3%/2.5% 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 topical gel, 0.3%/2.5% group.

tion use adapalene and benzoyl peroxide topical gel, 0.3%/2.5% 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, 0.3%/2.5% 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, 0.3%/2.5% 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, 0.3%/2.5% may bleach hair and colored fabric.

5%. before using adapalene and benzoyl peroxide topical gel, 0.3%/2.5%, tell your doctor about all of your medical conditions, including if you: • have other skin problems, including cuts, abrasions, sunburn or eczema. • are pregnant or plan to become pregnant. it is not known if adapalene and benzoyl peroxide topical gel, 0.3%/2.5% can harm your unborn baby. • are breastfeeding or plan to breastfeed. it is not known if adapalene and benzoyl peroxide topical gel, 0.3%/2.5% passes 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 topical gel, 0.3%/2.5%. if you use adapalene and benzoyl peroxide topical gel, 0.3%/2.5% while breastfeeding, use adapalene and benzoyl peroxide topical gel, 0.3%/2.5% on the smallest area of the skin and for the shortest time needed. do not apply adapalene and benzoyl peroxide topical gel, 0.3%/2.5% directly to the nipple and the areola to minimize contact with your baby. tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. how should i use adapalene and benzoyl peroxide topical gel, 0.3%/2.5%? • use adapalene and benzoyl peroxide topical gel, 0.3%/2.5% exactly as your doctor tells you to use it. • apply adapalene and benzoyl peroxide topical gel, 0.3%/2.5% 1 time a day. • do not use more adapalene and benzoyl peroxide topical gel, 0.3%/2.5% than you need to cover the treatment area. using too much adapalene and benzoyl peroxide topical gel, 0.3%/2.5% or using it more than 1 time a day may increase your chance of skin irritation. applying adapalene and benzoyl peroxide topical gel, 0.3%/2.5%: • wash the area where the gel will be applied with a mild or soapless cleanser and pat dry. • adapalene and benzoyl peroxide topical gel, 0.3%/2.5% comes in a pump. depress the pump to dispense a small amount (about the size of a pea) of adapalene and benzoyl peroxide topical gel, 0.3%/2.5% and spread a thin layer over the treatment area. use a pea-sized amount for each area of the face (forehead, chin, and each cheek). • wash your hands right away after applying the gel. adapalene and benzoyl peroxide topical gel, 0.3%/2.5% may bleach your hair or colored fabrics. allow adapalene and benzoyl peroxide topical gel, 0.3%/2.5% to dry completely before dressing to prevent bleaching of your clothes. what should i avoid while using adapalene and benzoyl peroxide topical gel, 0.3%/2.5%? • avoid spending time in sunlight or artificial sunlight, such as tanning beds or sunlamps. adapalene and benzoyl peroxide topical gel, 0.3%/2.5% 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, 0.3%/2.5% if you have to be in sunlight. • cold weather and wind may irritate skin treated with adapalene and benzoyl peroxide topical gel, 0.3%/2.5%. • avoid applying adapalene and benzoyl peroxide topical gel, 0.3%/2.5% 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 topical gel, 0.3%/2.5%. what are the possible side effects of adapalene and benzoyl peroxide topical gel, 0.3%/2.5%? adapalene and benzoyl peroxide topical gel, 0.3%/2.5% may cause serious side effects including: • allergic reactions. stop using adapalene and benzoyl peroxide topical gel, 0.3%/2.5% and get medical help right away if you have any of the following symptoms during treatment with adapalene and benzoyl peroxide topical gel 0.3%/2.5%: o hives, rash or severe itching o swelling of your face, eyes, lips, tongue, or throat o trouble breathing or throat tightness o feeling faint, dizzy, or lightheaded • skin irritation. skin irritation is common with adapalene and benzoyl peroxide topical gel, 0.3%/2.5% and is most likely to happen during the first 4 weeks of treatment, and usually lessen with continued use of adapalene and benzoyl peroxide topical gel, 0.3%/2.5%. skin reactions at the treatment area include redness, scaling, dryness, stinging, burning, itching and swelling. tell your doctor if you get any skin reactions. • sensitivity to sunlight. see “what should i avoid while using adapalene and benzoyl peroxide topical gel, 0.3%/2.5%?” these are not all the possible side effects of adapalene and benzoyl peroxide topical gel, 0.3%/2.5%. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store adapalene and benzoyl peroxide topical gel, 0.3%/2.5%? • store adapalene and benzoyl peroxide topical gel, 0.3%/2.5% at room temperature between 68°f to 77°f (20°c to 25°c). • keep adapalene and benzoyl peroxide topical gel, 0.3%/2.5% out of light and away from heat. keep adapalene and benzoyl peroxide topical gel, 0.3%/2.5% and all medicines out of the reach of children. general information about the safe and effective use of adapalene and benzoyl peroxide topical gel, 0.3%/2.5% medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use adapalene and benzoyl peroxide topical gel, 0.3%/2.5% for a condition for which it was not prescribed. do not give adapalene and benzoyl peroxide topical gel, 0.3%/2.5% 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 topical gel, 0.3%/2.5% that is written for health professionals. what are the ingredients in adapalene and benzoyl peroxide topical gel, 0.3%/2.5%? active ingredients: adapalene and benzoyl peroxide inactive ingredients: acrylamide/sodium acryloyldimethyltaurate copolymer, docusate sodium, edetate disodium, glycerin, isohexadecane, poloxamer 124, polysorbate 80, propylene glycol, purified water and sorbitan oleate manufactured by padagis, yeruham, israel distributed by padagis allegan, mi 49010 www.padagis.com for more information, contact padagis at 1-866-634-9120 this patient information has been approved by the u.s. food and drug administration. rev 05-22