TWYNEO

1 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 )

2 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 )

4 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 )

5 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.

6 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

8.1 Pregnancy Risk Summary Available data from published observational studies of topical tretinoin in pregnant women have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Studies conducted with topical benzoyl peroxide have not demonstrated systemic absorption and maternal use is not expected to result in fetal exposure to benzoyl peroxide. There are no data on TWYNEO use in pregnant women. There are reports of major birth defects reported with maternal use of topical tretinoin similar to those seen in infants exposed to oral retinoids, but these case reports do not establish a pattern or association with tretinoin-related embryopathy ( see Data ). Animal reproductive studies have not been conducted with TWYNEO or benzoyl peroxide. Topical administration of tretinoin to pregnant rats during organogenesis was associated with malformations (craniofacial abnormalities [hydrocephaly], asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) at doses greater than 1 mg tretinoin/kg/day, approximately 5 times the maximum recommended human dose (MRHD) based on body surface area (BSA) comparison and assuming 100% absorption. Oral administration of tretinoin to pregnant cynomolgus monkeys during organogenesis was associated with malformations at 10 mg/kg/day (approximately 100 times the MRHD based on BSA comparison and assuming 100% absorption) ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss and other adverse outcomes. The background risk in the U.S. general population of major birth defects is 2 to 4% of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Human Data While available studies cannot definitively establish the absence of risk, published data from multiple prospective controlled observational studies on the use of topical tretinoin products during pregnancy have not identified an association with topical tretinoin and major birth defects or miscarriage. The available studies have methodologic limitations, including small sample size and in some cases, lack of physical exam by an expert in birth defects. There are published case reports of infants exposed to topical tretinoin during the first trimester that describe major birth defects similar to those seen in infants exposed to oral retinoids; however, no pattern of malformations has been identified and no causal association has been established in these cases. The significance of these spontaneous reports in terms of risk to the fetus is not known. Animal Data For purposes of comparison of the animal exposure to human exposure, the MRHD is defined as 1.5 g of TWYNEO (containing 0.1% tretinoin) applied daily to a 60-kg person (0.03 mg tretinoin/kg body weight). Topical tretinoin embryofetal development studies have generated equivocal results. There is evidence for malformations (shortened or kinked tail) after topical tretinoin administration in Wistar rats at doses greater than 1 mg/kg/day (approximately 5 times the MHRD based on BSA comparison and assuming 100% absorption). Anomalies (humerus: short 13%, bent 6%, or parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day (approximately 50 times the MRHD based on BSA comparison and assuming 100% absorption) was topically applied to pregnant rats during organogenesis. Increased incidence of domed head and hydrocephaly, typical of retinoid-induced fetal malformations were noted in New Zealand White rabbits administered topical doses greater than 0.2 mg/kg/day (2.2 times the MRHD based on BSA comparison and assuming 100% absorption). Oral tretinoin induced malformations in rats, mice, hamsters, and nonhuman primates when administered during the period of organogenesis. Fetal malformations were observed when tretinoin was orally administered to pregnant Wistar rats during organogenesis. It was teratogenic and fetotoxic in Wistar rats when given orally or topically in doses greater than 1 mg/kg/day (approximately 5 times the MRHD based on BSA comparison and assuming 100% absorption). In the cynomolgus monkey, fetal malformations were reported when an oral dose of 10 mg/kg/day was administered to pregnant monkeys during organogenesis (approximately 100 times the MRHD based on BSA comparison and assuming 100% absorption). No fetal malformations were observed at an oral dose of 5 mg/kg/day (approximately 50 times the MRHD based on BSA comparison and assuming 100% absorption). Increased skeletal variations were observed at all doses, and a dose-related increase in embryo lethality and abortion was reported in this study. Similar results have also been reported in pigtail macaques. Oral tretinoin has been shown to be fetotoxic in rats when administered at a dose of 2.5 mg/kg/day (13 times the MRHD based on BSA comparison and assuming 100% absorption). Topical tretinoin has been shown to be fetotoxic in rabbits when administered at a dose of 0.5 mg/kg/day (5 times the MRHD based on BSA comparison and assuming 100% absorption).