ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Dry skin of mild to moderate severity was the most frequently reported (>= 1%) treatment related adverse vent. Erythema, scaling, dryness, burning/stinging were also seen during treatment. (6) To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.A total of 2141 subjects with acne vulgaris, 12 years and older, were treated once daily for 12 weeks. Of these, 1068 were exposed to DIFFERIN Lotion during the clinical trials. total of 1057 subjects completed at least one post treatment evaluation.Related adverse reactions that were reported in at least 1% of patients treated with DIFFERIN Lotion or with the Vehicle Lotion are presented in Table 1.The majority of cases was transient, mild to moderate in severity and was managed with moisturizers.Table 1: Adverse Reactions Reported in Clinical Trials by At Least 1% of PatientsSystemTermOrganClass/Preferred Adapalene Lotion 0.1% = 1068 Vehicle Lotion = 1073 Subjects with Related AR(s)10.2%4.6% Dry Skin7.7%3.0% Skin Irriitation1.5%0.7% Skin burning/skin discomfort0.9%0.0% Sunburn0.6%0.6%Local tolerability evaluations, presented in Table 2, were conducted at each study visit in clinical trials. Erythema, scaling, dryness, burning/stinging were assessed:Table 2: Incidence of Local Cutaneous Irritation, for Subjects Whose Irritation Score was Higher than at Baseline, in Controlled Clinical Studies Adverse Reactions (DIFFERIN Lotion Group = 1057 )Combined Study 1and Study 2Maximum SeverityDuring Treatment (N 1057)Week 12 Treatment Severity(N 950)Local CutaneousIrritation (skin irritation)MildModerateSevereMildModerateSevereErythema21.8%8.0%0.2%7.9%2.6%0.2%Scaling25.3%6.5%0.1%5.3%1.1%0Dryness36.1%7.3%0.3%7.6%2.0%0Stinging/burning22.1%7.0%0.9%4.6%1.0%0.4%Local tolerability scores for erythema, scaling, dryness, burning/stinging rose during the first two weeks of treatment and generally decreased thereafter.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity, mutagenicity and impairment of fertility studies were conducted with DIFFERIN Lotion.Carcinogenicity studies with adapalene have been conducted in mice at topical doses of 0.4, 1.3, and 4.0 mg/kg/day (1.2, 3.9, and 12 mg/m2/day), and in rats at oral doses of 0.15, 0.5, and 1.5 mg/kg/day (0.9, 3.0, and 9.0 mg/m2/day). In terms of body surface area, the highest dose levels are 9.8 (mice) and 7.4 times (rats) the MRHD of grams of DIFFERIN Lotion. In the rat study, an increased incidence of benign and malignant pheochromocytomas in the adrenal medulla of male rats was observed.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, mouse lymphoma TK assay) or in vivo (mouse micronucleus test).In rat oral studies, 20 mg adapalene/kg/day (120 mg/m2/day; 98 times the MRHD based on mg/m2/day comparison) did not affect the reproductive performance and fertility of F0 males and females, or growth, development and reproductive function of F1 offspring.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Adapalene binds to specific retinoic acid nuclear receptors but does not bind to cytosolic receptor protein. Biochemical and pharmacological profile studies have demonstrated that adapalene is modulator of cellular differentiation, keratinization and inflammatory processes. However, the significance of these findings with regard to the mechanism of action of adapalene for the treatment of acne is unknown.. 12.2 Pharmacodynamics. Pharmacodynamics of DIFFERIN Lotion is unknown.. 12.3 Pharmacokinetics. Systemic exposure of adapalene following topical application of DIFFERIN Lotion was studied in one clinical study. Fourteen subjects at 18-29 years of age with severe acne were treated with g of DIFFERIN Lotion once daily for 30 days to approximately 1000 cm2 of acne involved skin. Serial plasma samples were collected for 24 or 72 hours following application on days 1, 15 and 30. All plasma concentrations for 12 out of 14 patients were below the limit of quantification (LOQ=0.1 ng/mL). One patient had one sample above LOQ at day 30 and the other patient had four plasma samples above LOQ on both days and 15, which ranged from 0.102 and 0.131 ng/mL. Due to the limited number of available data points, PK analysis was not undertaken.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of DIFFERIN Lotion applied once daily for the treatment of acne vulgaris were assessed in two 12-week, multicenter, controlled clinical studies of similar design, comparing DIFFERIN Lotion to the Lotion vehicle in acne subjects.In Study 1, 1075 subjects were randomized to DIFFERIN Lotion or vehicle. The median age of these subjects was 16.7 years old and 53.1% were females. At baseline subjects had between 20 to 50 inflammatory lesions and 30 to 100 non-inflammatory lesions. The majority of subjects (91.0%) had baseline IGA score of Moderate.In Study 2, 1066 subjects were randomized to DIFFERIN Lotion or vehicle. The median age of subjects was 16.7 years old and 53.7% were females. At baseline subjects had the same inclusion criteria as in Study and 95.7% of subjects had baseline IGA score of Moderate.The outcome of the two studies is presented in Table 3.Table 3: Clinical Study Primary Efficacy Results at Week 12Study DIFFERINLotion(N 533)VehicleLotion(N 542)IGA Success140(26.3%)94(17.3%)Total Lesions: Mean Absolute(Percent) Change37.9(51.5%)26.7(37.1%)Inflammatory Lesions: Mean Absolute(Percent) Change14.7(54.9%)10.6(40.3%)Non-inflammatory Lesions: Mean Absolute(Percent) Change23.2(49.6%)16.1(35.7%)Study DIFFERINLotion(N 535)VehicleLotion(N 531)IGA Success129(24.1%)87(16.4%)Total Lesions: Mean Absolute(Percent) Change32.4(44.6%)23.4(32.8%)Inflammatory Lesions: Mean Absolute(Percent) Change12.7(46.0%)10.2(36.9%)Non-inflammatory Lesions: Mean Absolute(Percent) Change19.6(43.1%)13.1(30.2%).

DESCRIPTION SECTION.

11 DESCRIPTION. DIFFERIN (adapalene) Lotion, 0.1% for topical use, is an adapalene-based product.Adapalene is naphthoic acid derivative with retinoid-like properties. The chemical name for adapalene is (6-[3-(1-adamantyl)-4-meghoxyphenyl]-2-naphthoic acid). Adapalene has the following structural formula:Adapalene:Molecular formula: C28H28O3 Molecular weight: 412.5DIFFERIN Lotion contains the following inactive ingredients: carbomer 941, disodium edetate, medium chain triglycerides, methylparaben, phenoxyethanol, poloxamer 124, polyoxyl-6-polyoxyl-32 palmitostearate, PPG-12/SMDI copolymer, propylene glycol, propylparaben, sodium hydroxide, stearyl alcohol, and purified water.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Apply thin film of DIFFERIN Lotion to the entire face and other affected areas of the skin once daily, after washing gently with mild soapless cleanser. Dispense nickel size amount of DIFFERIN Lotion (3-4 actuations of the pump) to cover the entire face. Avoid application to the areas of skin around eyes, lips and mucous membranes.DIFFERIN Lotion is for topical use only and not for oral, ophthalmic, or intravaginal use.. Apply thin film of DIFFERIN Lotion to the entire face and other affected areas of the skin once daily, after washing gently with mild soapless cleanser. Dispense nickel size amount of DIFFERIN Lotion (3-4 actuations of the pump) to cover the entire face. Avoid application to the areas of skin around eyes, lips and mucous membranes. (2) DIFFERIN Lotion is for topical use only and not for oral, ophthalmic, or intravaginal use. (2).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Concomitant use of topical products with strong drying effect can increase skin irritation. Use with caution, especially in using preparations containing sulfur, resorcinol, or salicylic acid in combination with DIFFERIN Lotion. (7.1) 7.1 Concomitant Topical Medications. Concomitant topical acne therapy should be used with caution because possible cumulative irritancy effect may occur, especially with the use of peeling, desquamating, or abrasive agents. Caution should be exercised in using preparation containing sulfur, resorcinol or salicylic acid in combination with DIFFERIN Lotion.No formal drug-drug interaction studies were conducted with DIFFERIN Lotion.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. DIFFERIN (adapalene) Lotion, 0.1%, is packaged in 2 oz (59 mL) bottle which is equipped with Lotion dispensing pump.The DIFFERIN Lotion is supplied as follows: oz bottle pump (59 mL) NDC 54868-6114-0 Storage and handlingStore at controlled room temperature, 20 25C (68 77F); excursions permitted to 15 30C (59 86F).Do not freeze.Do not refrigerate.Protect from light.Keep out of reach of children.Keep away from heat.Keep bottle tightly closed.. Store at controlled room temperature, 20 25C (68 77F); excursions permitted to 15 30C (59 86F).. Do not freeze.. Do not refrigerate.. Protect from light.. Keep out of reach of children.. Keep away from heat.. Keep bottle tightly closed.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Apply thin film of DIFFERIN Lotion to the affected areas of the skin once daily, after washing gently with mild soapless cleanser. Dispense nickel size amount of DIFFERIN Lotion (3-4 actuations of the pump) to cover the entire face. Avoid application to the areas of skin around eyes, lips and mucous membranes. DIFFERIN Lotion may cause irritation such as erythema, scaling, dryness, stinging or burning.Advise patients to cleanse the area to be treated with mild or soapless cleanser; pat dry. Apply DIFFERIN Lotion to the entire face or other acne affected areas as thin layer, avoiding the eyes, lips and mucous membranes.Exposure of the eye to this medication may result in reactions such as swelling, conjunctivitis and eye irritation.Patients should be advised 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.Advise patients to minimize exposure to sunlight including sunlamps. Recommend the use of sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided.Moisturizers may be used if necessary; however, products containing alpha hydroxy or glycolic acids should be avoided.This medication should not be applied to cuts, abrasions, eczematous, or sunburned skin.Wax depilation should not be performed on treated skin due to the potential for skin erosions.This product is for external use only.Marketed by:GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USAManufactured by:Galderma Production Canada Inc., Baie dUrfe, QC, H9X 3S4 CanadaMade in Canada.GALDERMA is registered trademark.P51503-0. Apply thin film of DIFFERIN Lotion to the affected areas of the skin once daily, after washing gently with mild soapless cleanser. Dispense nickel size amount of DIFFERIN Lotion (3-4 actuations of the pump) to cover the entire face. Avoid application to the areas of skin around eyes, lips and mucous membranes. DIFFERIN Lotion may cause irritation such as erythema, scaling, dryness, stinging or burning.. Advise patients to cleanse the area to be treated with mild or soapless cleanser; pat dry. Apply DIFFERIN Lotion to the entire face or other acne affected areas as thin layer, avoiding the eyes, lips and mucous membranes.. Exposure of the eye to this medication may result in reactions such as swelling, conjunctivitis and eye irritation.. Patients should be advised 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.. Advise patients to minimize exposure to sunlight including sunlamps. Recommend the use of sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided.. Moisturizers may be used if necessary; however, products containing alpha hydroxy or glycolic acids should be avoided.. This medication should not be applied to cuts, abrasions, eczematous, or sunburned skin.. Wax depilation should not be performed on treated skin due to the potential for skin erosions.. This product is for external use only.. Additional barcode labeling by:Physicians Total Care, Inc.Tulsa, Oklahoma 74146.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity, mutagenicity and impairment of fertility studies were conducted with DIFFERIN Lotion.Carcinogenicity studies with adapalene have been conducted in mice at topical doses of 0.4, 1.3, and 4.0 mg/kg/day (1.2, 3.9, and 12 mg/m2/day), and in rats at oral doses of 0.15, 0.5, and 1.5 mg/kg/day (0.9, 3.0, and 9.0 mg/m2/day). In terms of body surface area, the highest dose levels are 9.8 (mice) and 7.4 times (rats) the MRHD of grams of DIFFERIN Lotion. In the rat study, an increased incidence of benign and malignant pheochromocytomas in the adrenal medulla of male rats was observed.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, mouse lymphoma TK assay) or in vivo (mouse micronucleus test).In rat oral studies, 20 mg adapalene/kg/day (120 mg/m2/day; 98 times the MRHD based on mg/m2/day comparison) did not affect the reproductive performance and fertility of F0 males and females, or growth, development and reproductive function of F1 offspring.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL. Rx OnlyNDC 54868-6114-0Differin(R) (adapalene) Lotion 0.1%For ExternalUse Only2 FL OZ(59 mL)For external use only.Not for ophthalmic oral or intravaginal use.Usual dosage: Apply thin film on the entire face and other affected areas of the skin once daily. See package insert for complete prescribing information.Each gram contains: adapalene mg (0.1%) in an aqueous based lotion consisting of the following inactive ingredients:carbomer 941, disodium edetate, medium chain triglycerides, methylparaben, phenoxyethanol, poloxamer 124, polyoxyl-6-polyoxyl-32 palmitostearate, PPG-12/SMDI copolymer, propylene glycol, propylparaben, sodium hydroxide, stearyl alcohol, and purified water.Storage: Store at controlled room temperature 68 77F (20 25C) with excursions permitted between 59 86F (15 30C). Do not freeze or refrigerate.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Systemic exposure of adapalene following topical application of DIFFERIN Lotion was studied in one clinical study. Fourteen subjects at 18-29 years of age with severe acne were treated with g of DIFFERIN Lotion once daily for 30 days to approximately 1000 cm2 of acne involved skin. Serial plasma samples were collected for 24 or 72 hours following application on days 1, 15 and 30. All plasma concentrations for 12 out of 14 patients were below the limit of quantification (LOQ=0.1 ng/mL). One patient had one sample above LOQ at day 30 and the other patient had four plasma samples above LOQ on both days and 15, which ranged from 0.102 and 0.131 ng/mL. Due to the limited number of available data points, PK analysis was not undertaken.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category C. There are no well-controlled trials in pregnant women treated with DIFFERIN Lotion. Therefore, DIFFERIN Lotion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with DIFFERIN Lotion. Furthermore, such studies are not always predictive of human response.Human DataIn clinical trials involving DIFFERIN Lotion, 0.1% in the treatment of acne vulgaris, women of childbearing potential initiated treatment only after negative pregnancy test. Two women became pregnant while using DIFFERIN Lotion, 0.1%. One patient delivered healthy full term baby and the other patient electively terminated her pregnancy.Animal DataNo 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 grams of DIFFERIN Lotion. 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 0.6-6.0 mg adapalene/kg/day [25-59 times (mg/m2) the MRHD] exhibited no fetotoxicity and only minimal increases in supernumerary ribs in both species and delayed ossification in rabbits.Systemic exposure (AUC 0-24h) to adapalene at topical doses (6.0 mg/kg/day) in rats represented 101 times the exposure to adapalene in patients with acne treated with DIFFERIN Lotion applied to the face, chest and back (2 grams applied to 1000 cm2 of acne-involved skin).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Category C. There are no well-controlled trials in pregnant women treated with DIFFERIN Lotion. Therefore, DIFFERIN Lotion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies have not been conducted with DIFFERIN Lotion. Furthermore, such studies are not always predictive of human response.Human DataIn clinical trials involving DIFFERIN Lotion, 0.1% in the treatment of acne vulgaris, women of childbearing potential initiated treatment only after negative pregnancy test. Two women became pregnant while using DIFFERIN Lotion, 0.1%. One patient delivered healthy full term baby and the other patient electively terminated her pregnancy.Animal DataNo 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 grams of DIFFERIN Lotion. 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 0.6-6.0 mg adapalene/kg/day [25-59 times (mg/m2) the MRHD] exhibited no fetotoxicity and only minimal increases in supernumerary ribs in both species and delayed ossification in rabbits.Systemic exposure (AUC 0-24h) to adapalene at topical doses (6.0 mg/kg/day) in rats represented 101 times the exposure to adapalene in patients with acne treated with DIFFERIN Lotion applied to the face, chest and back (2 grams applied to 1000 cm2 of acne-involved skin).. 8.3 Nursing Mothers. It is not known whether adapalene is excreted in human milk following use of DIFFERIN Lotion. Because many drugs are excreted in human milk, caution should be exercised when DIFFERIN Lotion is administered to nursing woman.. 8.4 Pediatric Use. Safety and effectiveness of DIFFERIN Lotion in pediatric patients under the age of 12 have not been established.. 8.5 Geriatric Use. Clinical studies of DIFFERIN Lotion did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

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, and stinging/ burning may occur with use of DIFFERIN Lotion. (5.2) 5.1 Ultraviolet Light and Environmental Exposure. Exposure to sunlight, including sunlamps, should be avoided during the use of DIFFERIN Lotion. Patients with high levels of sun exposure and those with inherent sensitivity to sun should be warned to exercise 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 DIFFERIN Lotion.. 5.2 Local Cutaneous Reactions. Signs and symptoms of local skin irritation (such as erythema, scaling, dryness, stinging/burning) may be experienced with use of DIFFERIN Lotion. These are most likely to occur during the first weeks of treatment, are mostly mild to moderate in severity, and usually lessen with continued use of DIFFERIN Lotion. Depending upon the severity of these side effects, patients should be instructed to use moisturizer, reduce the frequency of the application of DIFFERIN Lotion 0.1%, or discontinue use.DIFFERIN Lotion should not be applied to cuts, abrasions, eczematous or sunburned skin. As with other retinoids, use of waxing as depilatory method should be avoided on skin treated with DIFFERIN Lotion.Avoid concomitant use of other potentially irritating topical products (abrasive soaps and cleansers, soaps and cosmetics that have strong skin-drying effect and products with high concentrations of alcohol, astringents, spices, or limes).