Atralin

1 INDICATIONS AND USAGE Atralin Gel is indicated for topical treatment of acne vulgaris. Atralin Gel is a retinoid indicated for topical treatment of acne vulgaris. ( 1 )

2 DOSAGE AND ADMINISTRATION For topical use only. Not for oral, ophthalmic, or intravaginal use. Atralin Gel should be applied once daily, before bedtime, to the skin where acne lesions appear, using a thin layer to cover the entire affected area. Atralin Gel should be kept away from the eyes, the mouth, paranasal creases, and mucous membranes. Application of excessive amounts of gel will not provide incremental efficacy. Patients treated with Atralin Gel may use cosmetics, but the areas to be treated should be cleansed thoroughly before the medication is applied. When treating with Atralin Gel, caution should be exercised with the use of concomitant topical over-the-counter preparations, topical medications, medicated or abrasive soaps and cleansers, products that have strong drying effect, and products with high concentrations of alcohol, astringents, spices, or lime. Particular caution should be exercised with acne preparations containing benzoyl peroxide, sulfur, resorcinol, or salicylic acid. Allow the effects of such preparations to subside before use of Atralin Gel has begun. • Apply a thin layer of Atralin Gel once daily, before bedtime, to skin where lesions occur. Keep away from eyes, mouth, nasal creases, and mucous membranes. ( 2 ) • Atralin Gel is not for oral, ophthalmic, or intravaginal use. ( 2 )

4 CONTRAINDICATIONS None. None ( 4 )

5 WARNINGS AND PRECAUTIONS • Atralin Gel should not be used on eczematous or sunburned skin due to potential for severe irritation. ( 5.1 ) • Topical over-the-counter acne preparations, concomitant topical medications, medicated cleansers, topical products with alcohol or astringents: Use with caution, irritation may occur. ( 5.1 ) • Avoid unprotected exposure to sunlight including sunlamps (UV light) when using Atralin Gel due to potential for increased photosensitization. Use sunscreen of at least SPF 15 and protective clothing during exposure. ( 5.2 ) • Avoid use of Atralin Gel with weather extremes, such as wind or cold due to potential for increased irritation. ( 5.2 ) • Use Atralin Gel with caution if allergic to fish due to potential for allergenicity to fish protein. Patients who develop pruritus or urticaria should contact their healthcare provider. ( 5.3 ) 5.1 Skin Irritation The skin of certain individuals may become dry, red, or exfoliated while using Atralin Gel. If the degree of irritation warrants, patients should be directed to temporarily reduce the amount or frequency of application of the medication, discontinue use temporarily, or discontinue use all together. Efficacy at reduced frequencies of application has not been established. If a reaction suggesting sensitivity occurs, use of the medication should be discontinued. Mild to moderate skin dryness may also be experienced; if so, use of an appropriate moisturizer during the day may be helpful. Tretinoin has been reported to cause severe irritation on eczematous or sunburned skin and should be used with caution in patients with these conditions. To help limit skin irritation, patients must: • wash the treated skin gently, using a mild, non-medicated soap, and pat it dry, • avoid washing the treated skin too often and scrubbing the affected skin area, and • avoid contact with the peels of limes. 5.2 Ultraviolet Light and Environmental Exposure Unprotected exposure to sunlight, including sunlamps, should be minimized during the use of Atralin Gel. Patients who normally experience high levels of sun exposure, and those with inherent sensitivity to sun, should be warned to exercise caution. Use of sunscreen products of at least SPF 15 and protective clothing over treated areas is recommended when exposure cannot be avoided. Weather extremes, such as wind or cold, also may be irritating to tretinoin-treated skin. 5.3 Fish Allergies Atralin Gel contains soluble fish proteins and should be used with caution in patients with known sensitivity or allergy to fish. Patients who develop pruritus or urticaria should contact their healthcare provider.

6 ADVERSE REACTIONS The most common adverse reactions (incidence ≥5%) with Atralin Gel are dry skin, peeling/scaling/flaking skin, skin burning sensation, and erythema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch Health US, LLC at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under prescribing conditions, adverse reaction 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 two randomized, controlled trials, 674 subjects received treatment for up to 12 weeks with Atralin Gel [see Clinical Studies (14) ]. In these studies, 50% of the subjects who were treated with Atralin Gel reported one or more adverse reactions; 30% of the subjects reported treatment-related adverse reactions. In the vehicle group, 29% of the 487 randomized subjects reported at least one adverse reaction; 5% of the subjects reported events that were treatment-related. There were no serious, treatment-related adverse reactions reported by subjects in any of the treatment groups. Selected adverse reactions that occurred in at least 1% of subjects in the two trials combined are shown in Table 1 (below). Most skin-related adverse reactions first appear during the first two weeks of treatment with Atralin Gel, and the incidence rate for skin-related reactions peaks around the second and third week of treatment. In some subjects, the skin-related adverse reactions persist throughout the treatment period. Table 1: Number of Subjects with Selected Adverse Reactions (Occurring in at Least 1% of Subjects) Event Atralin Gel (N = 674) Vehicle (N = 487) Dry Skin 109 (16%) 8 (2%) Peeling/Scaling/Flaking Skin 78 (12%) 7 (1%) Skin Burning Sensation 53 (8%) 8 (2%) Erythema 47 (7%) 1 (<1%) Pruritus 11 (2%) 3 (1%) Pain of Skin 7 (1%) 0 (0%) Sunburn 7 (1%) 3 (1%) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Atralin Gel. 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. Temporary hyper- or hypopigmentation has been reported with repeated application of tretinoin.

8.1 Pregnancy There are no well-controlled trials in pregnant women treated with Atralin Gel. Atralin Gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Atralin Gel at doses of 0.1, 0.3 and 1 g/kg/day was tested for maternal and developmental toxicity in pregnant Sprague-Dawley rats by dermal application. The dose of 1 g/kg/day was approximately four times the clinical dose assuming 100% absorption and based on body surface area comparison. Possible tretinoin-associated teratogenic effects (craniofacial abnormalities [hydrocephaly], asymmetrical thyroids, variations in ossification, and increased supernumerary ribs) were noted in the fetuses of Atralin Gel-treated animals. These findings were not observed in control animals. Other maternal and reproductive parameters in the Atralin Gel-treated animals were not different from control. For purposes of comparison of the animal exposure to human exposure, the clinical dose is defined as 2 g of Atralin Gel applied daily to a 50 kg person. Oral tretinoin has been shown to be teratogenic in rats, mice, rabbits, hamsters and nonhuman primates. Tretinoin was teratogenic in Wistar rats when given orally in doses greater than 1 mg/kg/day (approximately eight times the clinical dose based on body surface area comparison). In the cynomolgus monkey, fetal malformations were reported for doses of 10 mg/kg/day, but none were observed at 5 mg/kg/day (approximately 80 times the clinical dose based on body surface area comparison), although increased skeletal variations were observed at all doses. Dose-related increases in embryolethality and abortion also were reported. Similar results have also been reported in pigtail macaques. Topical tretinoin in a different formulation has generated equivocal results in animal teratogenicity tests. There is evidence for teratogenicity (shortened or kinked tail) of topical tretinoin in Wistar rats at doses greater than 1 mg/kg/day (approximately eight times the clinical dose assuming 100% absorption and based on body surface area comparison). Anomalies (humerus: short 13%, bent 6%, os parietal incompletely ossified 14%) have also been reported when 10 mg/kg/day (approximately 160 times the clinical dose assuming 100% absorption and based on body surface area comparison) was topically applied. Supernumerary ribs have been a consistent finding in rats when dams were treated topically or orally with retinoids. With widespread use of any drug, a small number of birth defect reports associated temporally with the administration of the drug would be expected by chance alone. Cases of temporally associated congenital malformations have been reported with use of other topical tretinoin products. The significance of these spontaneous reports in terms of risk to the fetus is not known. Nonteratogenic Effects on Fetuses: Oral tretinoin has been shown to be fetotoxic in rats when administered in doses 20 times the clinical dose based on body surface area comparison. Topical tretinoin has been shown to be fetotoxic in rabbits when administered in doses eight times the clinical dose based on body surface area comparison.