Adapalene

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. ( 1 )

Purpose Acne treatment

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 re-evaluated. 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, 0.3% 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 )

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

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%. ( 4 )

Do not use on damaged skin (cuts, abrasions, eczema, sunburn) if you are allergic to adapalene or any of the ingredients in this product.

Stop use and ask doctor if you become pregnant, or are planning to become pregnant, while using the product you have symptoms of an allergic reaction (such as itching, rash, hives, swelling of the lips, eyelids, and shortness of breath) irritation becomes severe you see no improvement after 3 months of once daily use

6 ADVERSE REACTIONS The most frequently reported (≥ 1%) adverse reactions were erythema, scaling, dryness, and/or burning/stinging. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc. at 1-866-923-4914 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, 0.3% Incidence of Local Cutaneous Irritation with Adapalene Gel, 0.3% (N = 253 Total number of subjects with local cutaneous data for at least one post-Baseline evaluation. ) Maximum Severity Scores Higher Than Baseline Mild Moderate Severe Erythema 66 (26.1%) 33 (13%) 1 (0.4%) Scaling 110 (43.5%) 47 (18.6%) 3 (1.2%) Dryness 113 (44.7%) 43 (17%) 2 (0.8%) Burning/Stinging 72 (28.5%) 36 (14.2%) 9 (3.6%) Table 2: Patient reported local cutaneous adverse reactions with Adapalene Gel, 0.3% Adapalene Gel, 0.3% Vehicle Gel N=258 N=134 Related Selected adverse reactions defined by investigator as Possibly, Probably or Definitely Related Adverse Reactions 57 (22.1%) 6 (4.5%) Dry Skin 36 (14%) 2 (1.5%) Skin Discomfort 15 (5.8%) 0 (0%) Desquamation 4 (1.6%) 0 (0%) 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 Post-Marketing 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from clinical trials with Adapalene Gel, 0.3% 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 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 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.

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.

11 DESCRIPTION Adapalene Gel USP, 0.3% contains adapalene USP, 0.3% (3 mg/g) in a topical aqueous gel for use in the treatment of acne vulgaris, consisting of carbopol 980, edetate disodium, methylparaben, poloxamer 124, propylene glycol, purified water, and sodium hydroxide. May contain hydrochloric acid for pH adjustment. The chemical name of adapalene, USP 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, USP is represented by the following structural formula. Image

Active ingredient Adapalene, USP 0.1% (retinoid)* *read consumer Information leaflet

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

16 HOW SUPPLIED/STORAGE AND HANDLING Adapalene gel USP, 0.3% is supplied in the following size. 15 g tube – NDC 62332-549-15 45 g tube – NDC 62332-549-45 45 g pump – NDC 62332-549-46 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) [See USP Controlled Room Temperature]. Protect from freezing. Keep out of reach of children.