Benzoyl Peroxide and Tretinoin

INDICATIONS AND USAGE TWYNEO is indicated for the topical treatment of acne vulgaris in adults and pediatric patients 9 years of age and older. TWYNEO is a combination tretinoin, a retinoid, and benzoyl peroxide indicated for the topical treatment of acne vulgaris in adults and pediatric patients 9 years of age and older. ( 1 )

DOSAGE AND ADMINISTRATION Apply a thin layer of TWYNEO to the affected areas once daily on clean and dry skin. Avoid contact with the eyes, lips, paranasal creases, and mucous membranes. Wash hands after application. TWYNEO is for topical use only. TWYNEO is not for oral, ophthalmic, or intravaginal use. Apply a thin layer of TWYNEO to the affected areas once daily. ( 2 ) Avoid contact with eyes, lips, paranasal creases, and mucous membranes. ( 2 ) Wash hands after application. ( 2 ) Not for oral, ophthalmic, or intravaginal use. ( 2 )

WARNINGS AND PRECAUTIONS Hypersensitivity: Severe hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with use of benzoyl peroxide products. ( 4 , 5.1 ) Skin Irritation: Pain, dryness, exfoliation, erythema, and irritation may occur with use of TWYNEO. Avoid application of TWYNEO to cuts abrasions, eczematous or sunburned skin. ( 5.2 ) Photosensitivity : Minimize unprotected exposure to sunlight and sunlamps. Use sunscreen and protective clothing when sun exposure cannot be avoided. ( 5.3 ) 5.1 Hypersensitivity Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria, have been reported with the use of benzoyl peroxide products. If a serious hypersensitivity reaction occurs, discontinue TWYNEO immediately and initiate appropriate therapy. 5.2 Skin Irritation Patients using TWYNEO may experience application site dryness, pain, exfoliation, erythema, dermatitis, pruritis, and irritation [ see Adverse Reactions (6.1) ]. Depending upon the severity of these adverse reactions, instruct patients to use a moisturizer, reduce the frequency of the application of TWYNEO, or discontinue use. Avoid application of TWYNEO to cuts, abrasions, eczematous, or sunburned skin. 5.3 Photosensitivity TWYNEO may increase sensitivity to ultraviolet light. Minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while using TWYNEO. Instruct patients to implement sun protection measures (e.g., sunscreen and loose- fitting clothes) when sun exposure cannot be avoided. Discontinue TWYNEO at the first evidence of sunburn.

CONTRAINDICATIONS TWYNEO is contraindicated in patients with a history of hypersensitivity reaction to benzoyl peroxide or any components of TWYNEO [see Warnings and Precautions (5.1) ] . History of serious hypersensitivity reaction to benzoyl peroxide or any component of TWYNEO. ( 4 )

ADVERSE REACTIONS The most common adverse reactions (incidence ≥ 1%) are pain, dryness, exfoliation erythema, dermatitis, pruritus and irritation (all at the application site). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mayne Pharma. at 1-844-825-8500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical trials experience The following adverse reactions are discussed in greater detail elsewhere in the labeling: Hypersensitivity [see Warnings and Precautions (5.1) ] Skin Irritation [see Warnings and Precautions (5.2) ] Because clinical trials are conducted under widely varying conditions, adverse reaction rates are 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 two multicenter, randomized, double-blind, vehicle-controlled trials (Trial 1 and 2), 832 subjects 9 years of age and older with facial acne vulgaris applied TWYNEO (N=555) or vehicle (N=277) daily for 12 weeks. The majority of subjects were White (73%) and female (59%). Approximately 33% were Hispanic/Latino, and 46% were younger than 18 years of age. Adverse reactions reported in ≥ 1.0% of subjects treated with TWYNEO (and for which the rate exceeded the rate for vehicle), as well as the corresponding rates reported in subjects treated with vehicle are presented in Table 1. Table 1: Adverse Reactions Reported by ≥ 1% of Subjects with Facial Acne Vulgaris Treated with TWYNEO and More Frequently than Vehicle in Trials 1 and 2 TWYNEO Cream (N = 555) n (%) Vehicle Cream (N = 277) n (%) Application Site Pain Application site pain defined as application site stinging, burning or pain. 59 (10.6) 1 (0.4) Application Site Dryness 27 (4.9) 1 (0.4) Application Site Exfoliation 23 (4.1) 0 Application Site Erythema 22 (4.0) 0 Application Site Dermatitis 7 (1.3) 1 (0.4) Application Site Pruritus 7 (1.3) 0 Application Site Irritation 6 (1.1) 1 (0.4) Local tolerability evaluations were conducted at each study visit in the clinical trial by assessment of erythema, scaling, pigmentation, dryness, itching, burning, and stinging. Table 2 presents the active assessment of the signs and symptoms of local facial tolerability at Week 12 in subjects treated with TWYNEO. Table 2. Facial Cutaneous Tolerability Assessment at Week 12 in Subjects with Acne Vulgaris Treated with TWYNEO TWYNEO (N=494 The denominators for calculating the percentages were 494 of 555 subjects treated with TWYNEO and 264 of 277 subjects treated with vehicle in these trials who had cutaneous signs and local tolerability results reported at Week 12. ) (%) Vehicle (N = 264 ) (%) Mild Moderate Severe Mild Moderate Severe Erythema 33.0 6.9 0.2 26.9 8.0 0 Pigmentation 27.3 6.3 0.4 26.5 4.5 0 Dryness 22.3 5.3 0.4 16.7 2.3 0 Scaling 16.4 2.6 0 12.9 0.8 0 Burning 5.9 2.2 0 3.4 0.8 0 Itching 11.1 1.8 0 8.7 2.7 0 Stinging 5.3 0.2 0 1.9 1.1 0 Local tolerability scores for erythema, scaling, dryness, itching, burning, and stinging rose during the first two weeks of treatment and decreased thereafter. 6.2 Postmarketing Experience The following adverse reactions have been identified during use of benzoyl peroxide. 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. Immune System Disorders: Anaphylaxis, angioedema and urticaria

Mechanism of Action Benzoyl peroxide is an oxidizing agent with bactericidal and keratolytic effects, but the precise mechanism of action is unknown. Tretinoin is a metabolite of vitamin A that binds with high affinity to specific retinoic acid receptors located in both the cytosol and nucleus. Tretinoin activates three members of the retinoic acid (RAR) nuclear receptors (RARα , RARβ, RARγ) which act to modify gene expression, subsequent protein synthesis, and epithelial cell growth and differentiation. It has not been established whether the clinical effects of tretinoin are mediated through activation of retinoic acid receptors, and/or other mechanisms. Although the exact mode of action of tretinoin in acne treatment is unknown, current evidence suggests that topical tretinoin decreases cohesiveness of follicular epithelial cells with decreased microcomedo formation. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells causing extrusion of the comedones.