Adapalene Gel USP, 0.3%

6 ADVERSE REACTIONS The most frequently reported (≥1%) adverse reactions were dry skin, skin discomfort, pruritus, desquamation, and sunburn. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Encube Ethicals Private Limited at 1-833-285-4151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the multi-center, controlled clinical trial, signs and symptoms of local cutaneous irritation were monitored in 258 acne subjects who used Adapalene gel, 0.3% once daily for 12 weeks. Of the subjects who experienced cutaneous irritation (erythema, scaling, dryness, and/or burning/stinging), the majority of cases were mild to moderate in severity, occurred early in treatment and decreased thereafter. The incidence of local cutaneous irritation with Adapalene gel, 0.3% from the controlled clinical trial is provided in the following table: Table 1: Physician assessed local cutaneous irritation with Adapalene gel Incidence of Local Cutaneous Irritation with Adapalene gel, 0.3% (N = 253*) Maximum Severity Scores Higher Than Baseline Mild Moderate Severe Erythema 66 (26.1%) 33 (13.0%) 1 (0.4%) Scaling 110 (43.5%) 47 (18.6%) 3 (1.2%) Dryness 113 (44.7%) 43 (17.0%) 2 (0.8%) Burning / Stinging 72 (28.5%) 36 (14.2%) 9 (3.6%) * Total number of subjects with local cutaneous data for at least one post-Baseline evaluation. Table 2: Patient reported local cutaneous adverse reactions with Adapalene Gel Adapalene Gel, 0.3% Vehicle Gel N = 258 N = 134 Related* Adverse Reactions Dry Skin Skin Discomfort 57 (22.1%) 36 (14%) 15 (5.8%) 4 (1.6%) 6 (4.5%) 2 (1.5%) 0 (0.0%) 0 (0.0%) * Selected adverse reactions defined by investigator as Possibly, Probably or Definitely Related The following adverse reactions occurred in less than 1 % of subjects: acne flare, contact dermatitis, eyelid edema, conjunctivitis, erythema, pruritus, skin discoloration, rash, and eczema. In a one-year, open-label safety trial of 551 subjects with acne who received Adapalene gel, 0.3%, the pattern of adverse reactions was similar to the 12-week controlled study. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of adapalene: Immune system disorders: angioedema, face edema, lip swelling Skin disorders: application site pain Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

4 CONTRAINDICATIONS Adapalene gel, 0.3% is contraindicated in patients who have known hypersensitivity to adapalene or any excipient of adapalene gel, 0.3% [see WARNINGS AND PRECAUTIONS (5.1) ]. Contraindicated in patients who have known hypersensitivity to adapalene or any excipient of adapalene gel,0.3%

11 DESCRIPTION Adapalene Gel USP, 0.3% contains adapalene 0.3% (3 mg/g) in a topical aqueous gel for use in the treatment of acne vulgaris, consisting of carbomer 980, edetate disodium, methylparaben, poloxamer 182, propylene glycol, purified water, and sodium hydroxide. May contain hydrochloric acid for pH adjustment. The chemical name of adapalene is 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid. It is a white to off-white powder, which is soluble in tetrahydrofuran, very slightly soluble in ethanol, and practically insoluble in water. The molecular formula is C 28 H 28 O 3 and molecular weight is 412.53. Adapalene is represented by the following structural formula. adap-str

2 DOSAGE AND ADMINISTRATION Wash affected areas gently with a non-medicated soap. Apply a thin film of adapalene gel, 0.3% to the entire face and any other affected areas of the skin once daily in the evening. Avoid application to the areas of skin around eyes, lips, and mucous membranes. A mild transitory sensation of warmth or slight stinging may occur shortly after the application of adapalene gel,0.3%. Instruct patients to minimize sun exposure and to use moisturizers for relief of dry skin or irritation. If therapeutic results are not noticed after 12 weeks of treatment, therapy should be reevaluated. For topical use only. Not for ophthalmic, oral or intravaginal use. • Wash affected areas gently with a non-medicated soap. ( 2 ) • Apply a thin film of adapalene gel, to the entire face and other affected areas of the skin once daily in the evening. ( 2 ) For topical use only. Not for ophthalmic, oral or intravaginal use. ( 2 )

1 INDICATIONS AND USAGE ADAPALENE Gel, 0.3% is indicated for the topical treatment of acne vulgaris in patients 12 years of age and older. ADAPALENE Gel, 0.3% is a retinoid, indicated for the topical treatment of acne vulgaris in patients 12 years of age and older.

10 OVERDOSAGE Chronic ingestion of the drug may lead to the same side effects as those associated with excessive oral intake of vitamin A.

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 a 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 Clinical pharmacodynamic studies have not been conducted for Adapalene Gel,0.3%. 12.3 Pharmacokinetics Systemic exposure of adapalene following topical application of adapalene gel was evaluated in a clinical trial. Sixteen acne subjects were treated once daily for 10 days with 2 grams of adapalene gel, 0.3% applied to the face, chest and back, corresponding to approximately 2 mg/cm 2 . Fifteen subjects had quantifiable (LOQ = 0.1 ng/mL) adapalene levels resulting in a mean C max , of 0.553 ± 0.466 ng/mL on Day 10 of treatment. The mean AUC 0-24hr was 8.37 ± 8.46 ng.h/mL as determined in 15 of the 16 subjects on Day 10. The terminal apparent half-life, determined in 15 of 16 subjects, ranged from 7 to 51 hours, with a mean of 17.2 ± 10.2 hours. Adapalene was rapidly cleared from plasma and was not detected 72 hours after the last application for all but one subject. Exposure of potential circulating metabolites of adapalene was not measured. Excretion of adapalene appears to be primarily by the biliary route. In another clinical trial in subjects with moderate to moderately severe acne, Adapalene gel, 0.3% or Adapalene Gel, 0.1% was applied to the face and optionally to the trunk, once daily for 12 weeks. Seventy-eight (78) subjects had plasma adapalene levels evaluated at Weeks 2, 8, and 12. Of the 209 plasma samples analyzed, adapalene concentrations were below the limit of detection (LOD = 0.15 ng/mL) of the method in all samples but three. For the three samples, traces of adapalene below the limit of quantification (LOQ= 0.25 ng/mL) of the method were found. One of these samples was taken at Week 12 from a male subject treated with adapalene gel, 0.3% who treated the face and the trunk for eight weeks (thereafter, only the face was treated). The second and third samples were from the Week 2 and 12 visits of a female subject treated with Adapalene Gel, 0.1% who treated only the face for 12 weeks. In this study, the average daily usage of product was 1 g/day.

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 a 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 Clinical pharmacodynamic studies have not been conducted for Adapalene Gel,0.3%.

12.3 Pharmacokinetics Systemic exposure of adapalene following topical application of adapalene gel was evaluated in a clinical trial. Sixteen acne subjects were treated once daily for 10 days with 2 grams of adapalene gel, 0.3% applied to the face, chest and back, corresponding to approximately 2 mg/cm 2 . Fifteen subjects had quantifiable (LOQ = 0.1 ng/mL) adapalene levels resulting in a mean C max , of 0.553 ± 0.466 ng/mL on Day 10 of treatment. The mean AUC 0-24hr was 8.37 ± 8.46 ng.h/mL as determined in 15 of the 16 subjects on Day 10. The terminal apparent half-life, determined in 15 of 16 subjects, ranged from 7 to 51 hours, with a mean of 17.2 ± 10.2 hours. Adapalene was rapidly cleared from plasma and was not detected 72 hours after the last application for all but one subject. Exposure of potential circulating metabolites of adapalene was not measured. Excretion of adapalene appears to be primarily by the biliary route. In another clinical trial in subjects with moderate to moderately severe acne, Adapalene gel, 0.3% or Adapalene Gel, 0.1% was applied to the face and optionally to the trunk, once daily for 12 weeks. Seventy-eight (78) subjects had plasma adapalene levels evaluated at Weeks 2, 8, and 12. Of the 209 plasma samples analyzed, adapalene concentrations were below the limit of detection (LOD = 0.15 ng/mL) of the method in all samples but three. For the three samples, traces of adapalene below the limit of quantification (LOQ= 0.25 ng/mL) of the method were found. One of these samples was taken at Week 12 from a male subject treated with adapalene gel, 0.3% who treated the face and the trunk for eight weeks (thereafter, only the face was treated). The second and third samples were from the Week 2 and 12 visits of a female subject treated with Adapalene Gel, 0.1% who treated only the face for 12 weeks. In this study, the average daily usage of product was 1 g/day.

20230524

3

3 DOSAGE FORMS AND STRENGTHS Each gram of adapalene gel, 0.3% contains 3 mg adapalene in an off-white aqueous gel. Gel, 0.3%

Adapalene Gel USP, 0.3% Adapalene Gel USP, 0.3% CARBOMER HOMOPOLYMER TYPE C EDETATE DISODIUM METHYLPARABEN PROPYLENE GLYCOL WATER SODIUM HYDROXIDE HYDROCHLORIC ACID POLOXAMER 182 ADAPALENE ADAPALENE

13.1 Carcinogenesis, Mutagenesis , Impairment of Fertility No carcinogenicity, genotoxicity, or impairment of fertility studies were conducted with Adapalene gel, 0.3%. Carcinogenicity studies with adapalene were conducted in mice at topical doses of 0.4, 1.3, and 4.0 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, 3.0, and 9.0 mg/m 2 /day). The highest dose levels are 3.2 (mice) and 2.4 (rats) times the MRHD based on a mg/m 2 comparison. In the rat study, an increased incidence of benign and malignant pheochromocytomas reported in the adrenal medulla of male rats was observed. 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). 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.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis , Impairment of Fertility No carcinogenicity, genotoxicity, or impairment of fertility studies were conducted with Adapalene gel, 0.3%. Carcinogenicity studies with adapalene were conducted in mice at topical doses of 0.4, 1.3, and 4.0 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, 3.0, and 9.0 mg/m 2 /day). The highest dose levels are 3.2 (mice) and 2.4 (rats) times the MRHD based on a mg/m 2 comparison. In the rat study, an increased incidence of benign and malignant pheochromocytomas reported in the adrenal medulla of male rats was observed. 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). 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.

ANDA200298

Adapalene Gel USP, 0.3%

Adapalene Gel USP, 0.3%

21922-051

HUMAN PRESCRIPTION DRUG

TOPICAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Carton Label NDC 21922- 051 -50 Adapalene Gel, USP 0.3% PUMP FOR TOPICAL USE ONLY Net Wt. 45g Rx only Container Label NDC 21922- 051 -50 Adapalene Gel, USP 0.3% PUMP FOR TOPICAL USE ONLY Net Wt. 45g Rx only Carton Label NDC 21922- 051 -06 Adapalene Gel, 0.3% For topical use only. Not for ophthalmic, oral or intravaginal use. Net Wt. 45g Rx only Container Label NDC 21922- 051 -06 Adapalene Gel, USP 0.3% For topical use only. Not for ophthalmic, oral or intravaginal use. Net Wt. 45g Rx only crt-45g cont-45g crt-tube-45g cont-tube-45g

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) Information for Patients Patients using Adapalene gel, 0.3% should receive the following information and instructions. 1. Apply a thin film of adapalene gel, 0.3% to the entire face and any other affected areas of the skin once daily in the evening, after washing gently with a non- medicated soap. 2. Avoid contact with the eyes, lips, angles of the nose, and mucous membranes 3. Moisturizers may be used if necessary; however, products containing alpha hydroxy or glycolic acids should be avoided. 4. This medication should not be applied to cuts, abrasions, eczematous, or sunburned skin. 5. Wax depilation should not be performed on treated skin due to the potential for skin erosions 6. Minimize exposure to sunlight including sunlamps Recommend the use of sunscreen products and protective apparel (e.g., hat) when exposure cannot be avoided. 7. Contact the doctor if skin rash, pruritus, hives, chest pain, edema, and shortness of breath occurs, as these may be signs of allergy or hypersensitivity. 8. This product is for external use only. 9. Lactation: Use Adapalene gel. 0.3% on the smallest area of skin and for the shortest duration possible while breastfeeding. Avoid application of Adapalene gel, 0.3% to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child. [See Use in Specific Populations, Lactation (8.2) ]

14 CLINICAL STUDIES The safety and efficacy of once daily use of adapalene gel, 0.3% for treatment of acne vulgaris were assessed in one 12 week, multi­ center, controlled, clinical trial, conducted in a total of 653 subjects 12 to 52 years of age with acne vulgaris of mild to moderate severity. All female subjects of child-bearing potential enrolled in the trial were required to have a negative urine pregnancy test at the beginning of the trial and were required to practice a highly effective method of contraception during the trial. Female subjects who were pregnant, nursing or planning to become pregnant were excluded from the trial. Subjects enrolled in the trial were Caucasian (72%), Hispanic (12%), African-American (10%), Asian (3%), and other (2%). An equal number of males (49.5%) and females (50.5%) enrolled. Success was defined as "Clear'" or "Almost Clear" in the Investigator's Global Assessment (IGA). The 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 study primary efficacy results at Week 12 Adapalene Gel, 0.3% Adapalene Gel, 0.1% Vehicle Gel N = 258 N = 261 N = 134 IGA Success Rate 53 (21%) 41 (16%) 12 (9%) Inflammatory Lesions Mean Baseline Count Mean Absolute (%) Reduction 27.7 14.4 (51.6%) 28.1 13.9 (49.7%) 27.2 11.2 (40.7%) Non-inflammatory Lesions Mean Baseline Count Mean Absolute(%) Reduction 39.4 16.3 (39.7%) 41.0 15.2 (35.2%) 40.0 10.3 (27.2%) Total Lesions Mean Baseline Count Mean Absolute(%) Reduction 67.1 30.6 (45.3) 69.1 29.0 (41.8%) 67.2 21.4 (33.7%)

8.5 Geriatric Use Clinical studies of adapalene gel, 0.3% did not include subjects 65 years of age and older to determine whether they respond differently than younger subjects. Safety and effectiveness in geriatric patients age 65 and above have not been established.

8.2 Lactation Risk Summary There are no data on the presence of topical adapalene 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 ). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for adapalene gel, 0.3% and any potential adverse effects on the breastfed child from adapalene gel, 0.3% or from the underlying maternal condition. Clinical Considerations To minimize potential exposure to the breastfed infant via breastmilk, use adapalene gel, 0.3% on the smallest area of skin and for the shortest duration possible while breastfeeding. Avoid application of adapalene gel, 0.3% to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child.

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients below the age of 12.

8.1 Pregnancy Risk Summary Available data from clinical trials with Adapalene 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. In animal reproduction studies, oral administration of adapalene to pregnant rats and rabbits_ during organogenesis at dose exposures 40 and 81 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 2 g resulted in fetal skeletal and visceral malformations ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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 are 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 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 (40 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from clinical trials with Adapalene 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. In animal reproduction studies, oral administration of adapalene to pregnant rats and rabbits_ during organogenesis at dose exposures 40 and 81 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 2 g resulted in fetal skeletal and visceral malformations ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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 are 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 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 (40 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 There are no data on the presence of topical adapalene 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 ). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for adapalene gel, 0.3% and any potential adverse effects on the breastfed child from adapalene gel, 0.3% or from the underlying maternal condition. Clinical Considerations To minimize potential exposure to the breastfed infant via breastmilk, use adapalene gel, 0.3% on the smallest area of skin and for the shortest duration possible while breastfeeding. Avoid application of adapalene gel, 0.3% to areas with increased risk for potential ingestion by or ocular exposure to the breastfeeding child. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients below the age of 12. 8.5 Geriatric Use Clinical studies of adapalene gel, 0.3% did not include subjects 65 years of age and older to determine whether they respond differently than younger subjects. Safety and effectiveness in geriatric patients age 65 and above have not been established.

16 HOW SUPPLIED/STORAGE AND HANDLING Adapalene Gel, USP,0.3% is supplied in the following size. 45g tube- NDC 21922-051-06 45g pump- NDC 21922-051-50 Storage: Store at controlled room temperature 68° to 77°F (20° to 25°C) with excursions permitted between 59° to 86°F (15° to 30°C). Protect from freezing. Keep out of reach of children.