STORAGE AND HANDLING SECTION.

Storage and HandlingStore at 20C to 25C (68F to 77F) with excursions permitted to 15C to 30oC (59F to 86oF) [see USP Controlled Room Temperature]. Keep away from heat. Do not freeze. Discard unused cream 30 days after first use. Store at 20C to 25C (68F to 77F) with excursions permitted to 15C to 30oC (59F to 86oF) [see USP Controlled Room Temperature]. Keep away from heat. Do not freeze. Discard unused cream 30 days after first use.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (incidence >= 1%) are application site reactions: pain, erythema, pruritis and edema. (6.1)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.. Most common adverse reactions (incidence >= 1%) are application site reactions: pain, erythema, pruritis and edema. (6.1). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In two randomized, double-blind, vehicle-controlled trials, adult subjects with rosacea applied EPSOLAY (N 488) or vehicle (N 234) once daily for 12 weeks. The majority of subjects were Caucasian (93%) and female (73%) with mean age of 51 years.Table presents the most common adverse reactions occurring in >= 1% of subjects treated with EPSOLAY and more frequently than in subjects treated with vehicle.Table 1: Adverse Reactions Occurring in >= 1% of Subjects Treated with EPSOLAY and with Greater Frequency than Subjects Treated with Vehicle Application site edema includes: application site swelling and application site edemaEPSOLAY N=488Vehicle N=234Application site pain11 (2%)2 (1%)Application site erythema11 (2%)2 (1%)Application site pruritus6 (1%)1 (<1%)Application site edema4 (1%)0 (0%)During the clinical trials, local tolerability evaluations were conducted at baseline and at each study visit by assessment of dryness, itching, scaling and stinging/burning. Table presents the local tolerability assessments by severity grade at Week 12.Table 2: Facial Cutaneous Tolerability Assessment Of the 488 subjects treated with EPSOLAY, 455 subjects had local tolerability assessments at Week 12.Sign/SymptomEPSOLAY N=455Severity at Week 12MildModerateSevereDryness25%7%0%Itching24%6%0%Scaling13%4%0%Stinging/Burning20%3%1%In 40-week open-label extension safety study (for total of up to 52 weeks of treatment) the frequency and severity of local tolerability signs and symptoms at Week 52 were comparable to those reported at Week 12.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity, mutagenicity, and impairment of fertility studies were not conducted with EPSOLAY.The role of benzoyl peroxide as tumor promoter has been well established in several animal species. However, the significance of this finding in humans is unknown.No significant increase in tumor formation was observed in rats treated topically with 15 to 25% benzoyl peroxide carbopol gel (3 to times the concentration of benzoyl peroxide in EPSOLAY) for two years. Similar results were obtained in mice topically treated with 25% benzoyl peroxide gel for 56 weeks followed by intermittent treatment with 15% benzoyl peroxide gel for rest of the years study period and in mice topically treated with 5% benzoyl peroxide gel for two years.Bacterial mutagenicity assays (Ames test) conducted with benzoyl peroxide have provided mixed results; mutagenic potential was observed in few studies but not in majority of investigations. Benzoyl peroxide has been found to cause DNA strand breaks in variety of mammalian cell types and to cause sister chromatid exchanges in Chinese hamster ovary cells.Fertility studies were not conducted with benzoyl peroxide.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Benzoyl peroxide is an oxidizing agent with bactericidal and keratolytic effects but the precise mechanism of action in the treatment of rosacea is unknown.. 12.2 Pharmacodynamics. The pharmacodynamics of EPSOLAY in the treatment of rosacea are unknown.. 12.3 Pharmacokinetics. Benzoyl peroxide is absorbed by the skin where it is converted to benzoic acid, an endogenous substance, which is eliminated in the urine. The systemic exposure of benzoyl peroxide following the application of EPSOLAY was not assessed.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of EPSOLAY was evaluated in two multicenter, randomized, double-blind, vehicle-controlled trials (Trial [NCT03448939] and Trial [NCT03564119]) in subjects with moderate-to-severe papulopustular rosacea. The trials were conducted in 733 subjects, aged 18 years and older. Subjects were treated once daily for 12 weeks with either EPSOLAY or vehicle cream.Subjects were required to have minimum of 15 to 70 total inflammatory lesions (papules and/or pustules) and no more than nodules (where nodule was defined as papule or pustule greater than mm in diameter) and an Investigator Global Assessment (IGA) score of (moderate) or (severe) at baseline. Overall, 93% of subjects were Caucasian, 73% were female, and the mean age was 51 years (ranged from 18 to 85 years). At baseline, subjects had mean inflammatory lesion count of 27.5, 89% were scored as moderate (IGA=3), and 11% scored as severe (IGA=4).The co-primary efficacy endpoints in both trials were the proportion of subjects with treatment success at Week 12, defined as an IGA score of (clear) or (almost clear) with at least two-grade reduction from baseline, and the absolute change from baseline in inflammatory lesion counts at Week 12. The results at Week 12 are presented in Table 3. EPSOLAY was more effective than vehicle cream on the co-primary efficacy endpoints starting from weeks of treatment in both trials, see Figure through Figure 4.Table 3: Efficacy Results of EPSOLAY in Subjects with Moderate to Severe Papulopustular Rosacea at Week 12 Investigator Global Assessment (IGA) success was defined as an IGA score of (clear)or (almost clear) with at least two-grade reduction from baseline. Means presented in table are Least Square (LS) Means.Trial 1EPSOLAY Vehicle (N=243) (N=118)Trial 2EPSOLAY Vehicle (N=250) (N=122)IGA Treatment SuccessDifference from Vehicle(99% CI) 47.4% 20.7% 26.7% (16.7%, 36.8%) 49.2% 28.2% 21.0% (10.7%, 31.3%)Inflammatory LesionsMean+ Absolute Change Difference from Vehicle(95% CI) Mean+ Percent Change Difference from Vehicle(95% CI) -17.4 -9.5 -7.9(-10.0, -5.9) -68.2% -38.3% -29.9% (-37.8%, -22.0%) -20.3 -13.3 -6.9 (-9.0, -4.9) -69.4% -46.0% -23.4% (-30.5%, -16.3%)Figure 1: IGA Success Rate Over Time in Trial Figure 2: IGA Success Rate Over Time in Trial Figure 3: Mean Absolute Change in Inflammatory Lesion Counts from Baseline Over Time in Trial Figure 4: Mean Absolute Change in Inflammatory Lesion Counts from Baseline Over Time in Trial.

DESCRIPTION SECTION.

11 DESCRIPTION. EPSOLAY (benzoyl peroxide) cream is for topical use. Each gram of EPSOLAY contains 50 mg of benzoyl peroxide.The chemical name for benzoyl peroxide is benzoyl benzenecarboperoxoate. It has the following structural formula:Molecular Formula: C14H10O4 Molecular Weight: 242.23The benzoyl peroxide in EPSOLAY is in solid form that is incorporated into microcapsule composed of silicon dioxide, cetrimonium chloride and polyquaternium-7.EPSOLAY contains anhydrous citric acid, cetrimonium chloride, cetyl alcohol, cyclomethicone, edetate disodium, glycerin, hydrochloric acid, lactic acid, macrogol stearate Type I, mono and di-glycerides, phenoxyethanol, polyquaternium-7, purified water, silicon dioxide and sodium hydroxide as inactive ingredients.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Before initial use, prime the pump until the first drop of cream is released.Apply pea-sized amount of EPSOLAY once daily in thin layer to each area of the face (forehead, chin, nose, each cheek) on clean and dry skin. Avoid the eyes, lips and mouth.Wash hands after application.EPSOLAY may bleach hair or colored fabric.EPSOLAY is for topical use only. Not for oral, ophthalmic, or intravaginal use.Discard unused EPSOLAY 30 days after first use.. Before initial use, prime the pump until the first drop of cream is released.. Apply pea-sized amount of EPSOLAY once daily in thin layer to each area of the face (forehead, chin, nose, each cheek) on clean and dry skin. Avoid the eyes, lips and mouth.. Wash hands after application.. EPSOLAY may bleach hair or colored fabric.. EPSOLAY is for topical use only. Not for oral, ophthalmic, or intravaginal use.. Discard unused EPSOLAY 30 days after first use.. Apply to the affected areas once daily. (2)Wash hands after application. (2)Not for oral, ophthalmic, or intravaginal use. (2). Apply to the affected areas once daily. (2). Wash hands after application. (2). Not for oral, ophthalmic, or intravaginal use. (2).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedEPSOLAY is white to off-white cream supplied in an airless pump as follows: 30 gram pump: NDC 0299-5890-30. Storage and HandlingStore at 20C to 25C (68F to 77F) with excursions permitted to 15C to 30oC (59F to 86oF) [see USP Controlled Room Temperature]. Keep away from heat. Do not freeze. Discard unused cream 30 days after first use. Store at 20C to 25C (68F to 77F) with excursions permitted to 15C to 30oC (59F to 86oF) [see USP Controlled Room Temperature]. Keep away from heat. Do not freeze. Discard unused cream 30 days after first use.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information). HypersensitivityInform patients that serious hypersensitivity reactions occurred with the use of benzoyl peroxide products. If patient experiences serious hypersensitivity reaction, instruct patient to discontinue EPSOLAY immediately and seek medical help [see Warnings and Precautions (5.1)]. Skin Irritation/Contact DermatitisInform patients that EPSOLAY may cause irritation such as erythema, scaling, dryness, stinging or burning. Advise the patient to use moisturizer for irritation [see Warnings and Precautions (5.2)].Photosensitivity Advise patients to minimize or avoid exposure to natural or artificial light (tanning beds or UVA/B treatment) and to use sun protective measures, if patients need to be outdoors while using EPSOLAY [see Warnings and Precautions (5.3)]. Administration InstructionsAdvise patients to apply EPSOLAY exactly as directed in thin layer, avoiding the eyes, lips and mouth and to wash hands immediately after application. Inform patients that EPSOLAY may bleach hair or colored fabric [see Dosage and Administration (2)].

LABORATORY TESTS SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.In two randomized, double-blind, vehicle-controlled trials, adult subjects with rosacea applied EPSOLAY (N 488) or vehicle (N 234) once daily for 12 weeks. The majority of subjects were Caucasian (93%) and female (73%) with mean age of 51 years.Table presents the most common adverse reactions occurring in >= 1% of subjects treated with EPSOLAY and more frequently than in subjects treated with vehicle.Table 1: Adverse Reactions Occurring in >= 1% of Subjects Treated with EPSOLAY and with Greater Frequency than Subjects Treated with Vehicle Application site edema includes: application site swelling and application site edemaEPSOLAY N=488Vehicle N=234Application site pain11 (2%)2 (1%)Application site erythema11 (2%)2 (1%)Application site pruritus6 (1%)1 (<1%)Application site edema4 (1%)0 (0%)During the clinical trials, local tolerability evaluations were conducted at baseline and at each study visit by assessment of dryness, itching, scaling and stinging/burning. Table presents the local tolerability assessments by severity grade at Week 12.Table 2: Facial Cutaneous Tolerability Assessment Of the 488 subjects treated with EPSOLAY, 455 subjects had local tolerability assessments at Week 12.Sign/SymptomEPSOLAY N=455Severity at Week 12MildModerateSevereDryness25%7%0%Itching24%6%0%Scaling13%4%0%Stinging/Burning20%3%1%In 40-week open-label extension safety study (for total of up to 52 weeks of treatment) the frequency and severity of local tolerability signs and symptoms at Week 52 were comparable to those reported at Week 12.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 systemic exposure of benzoyl peroxide is unknown. Based on the published literature, benzoyl peroxide is metabolized to benzoic acid (an endogenous substance), which is eliminated in the urine. Any amount of benzoyl peroxide excreted into human milk by nursing mother would be expected to be metabolized by tissue and stomach esterases. Therefore, breastfeeding is not expected to result in exposure of the infant to EPSOLAY. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for EPSOLAY and any potential adverse effects on the breastfed child from EPSOLAY or from the underlying maternal condition.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenicity, mutagenicity, and impairment of fertility studies were not conducted with EPSOLAY.The role of benzoyl peroxide as tumor promoter has been well established in several animal species. However, the significance of this finding in humans is unknown.No significant increase in tumor formation was observed in rats treated topically with 15 to 25% benzoyl peroxide carbopol gel (3 to times the concentration of benzoyl peroxide in EPSOLAY) for two years. Similar results were obtained in mice topically treated with 25% benzoyl peroxide gel for 56 weeks followed by intermittent treatment with 15% benzoyl peroxide gel for rest of the years study period and in mice topically treated with 5% benzoyl peroxide gel for two years.Bacterial mutagenicity assays (Ames test) conducted with benzoyl peroxide have provided mixed results; mutagenic potential was observed in few studies but not in majority of investigations. Benzoyl peroxide has been found to cause DNA strand breaks in variety of mammalian cell types and to cause sister chromatid exchanges in Chinese hamster ovary cells.Fertility studies were not conducted with benzoyl peroxide.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe systemic exposure of benzoyl peroxide is unknown. Based on the published literature, benzoyl peroxide is metabolized to benzoic acid (an endogenous substance), which is eliminated in the urine. Hence, maternal use is not expected to result in fetal exposure to the drug. Animal reproductive studies have not been conducted with EPSOLAY or benzoyl peroxide.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThe systemic exposure of benzoyl peroxide is unknown. Based on the published literature, benzoyl peroxide is metabolized to benzoic acid (an endogenous substance), which is eliminated in the urine. Hence, maternal use is not expected to result in fetal exposure to the drug. Animal reproductive studies have not been conducted with EPSOLAY or benzoyl peroxide.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. 8.2 Lactation. Risk SummaryThere 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 systemic exposure of benzoyl peroxide is unknown. Based on the published literature, benzoyl peroxide is metabolized to benzoic acid (an endogenous substance), which is eliminated in the urine. Any amount of benzoyl peroxide excreted into human milk by nursing mother would be expected to be metabolized by tissue and stomach esterases. Therefore, breastfeeding is not expected to result in exposure of the infant to EPSOLAY. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for EPSOLAY and any potential adverse effects on the breastfed child from EPSOLAY or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness of EPSOLAY for the treatment of inflammatory lesions of rosacea have not been established in pediatric patients.. 8.5 Geriatric Use. Of the 733 subjects in the clinical trials of EPSOLAY, 127 (17%) subjects were 65 and over, while 37 (3%) subjects were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity: Severe hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with the use of benzoyl peroxide products. (5.1)Skin irritation/contact dermatitis: Erythema, scaling, dryness, stinging/burning, irritation and allergic contact dermatitis may occur with use of EPSOLAY and may necessitate discontinuation. (5.2)Photosensitivity: Avoid or minimize exposure to natural or artificial sunlight and use sun protection measures. (5.3) Hypersensitivity: Severe hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with the use of benzoyl peroxide products. (5.1). Skin irritation/contact dermatitis: Erythema, scaling, dryness, stinging/burning, irritation and allergic contact dermatitis may occur with use of EPSOLAY and may necessitate discontinuation. (5.2). Photosensitivity: Avoid or minimize exposure to natural or artificial sunlight and use sun protection measures. (5.3) 5.1 Hypersensitivity. Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, have been reported with the use of benzoyl peroxide products. If serious hypersensitivity reaction occurs, discontinue EPSOLAY immediately and initiate appropriate therapy.. 5.2 Skin Irritation/Contact Dermatitis. Erythema, scaling, dryness and stinging/burning may be experienced with use of EPSOLAY. Irritation and contact dermatitis may occur. Apply moisturizer and discontinue EPSOLAY if symptoms do not improve. Avoid application of EPSOLAY to cuts, abrasions, eczematous or sunburned skin.. 5.3 Photosensitivity. Benzoyl peroxide may increase sensitivity to sunlight. Minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using EPSOLAY. Instruct the patient to implement sun protection measures (e.g., sunscreen and loose-fitting clothes) when sun exposure cannot be avoided. Discontinue EPSOLAY at the first evidence of sunburn.