Duobrii

1 INDICATIONS AND USAGE DUOBRII ® (halobetasol propionate and tazarotene) Lotion, 0.01%/0.045% is indicated for the topical treatment of plaque psoriasis in adults. DUOBRII Lotion is a combination of halobetasol propionate and tazarotene indicated for the topical treatment of plaque psoriasis in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Apply a thin layer of DUOBRII Lotion once daily to cover only affected areas and rub in gently. If a bath or shower is taken prior to application, the skin should be dry before applying the lotion. The total dosage should not exceed approximately 50 g per week because of the potential for the drug to suppress the hypothalamic-pituitary-adrenal (HPA) axis [see Warnings and Precautions (5.2) ] . Do not use with occlusive dressings unless directed by a physician. Discontinue treatment when control is achieved. Avoid application of DUOBRII Lotion on the face, groin, or in the axillae. DUOBRII Lotion is not for oral, ophthalmic, or intravaginal use. • Apply a thin layer of DUOBRII Lotion to the affected areas once daily. ( 2 ) • Not for oral, ophthalmic, or intravaginal use. ( 2 )

4 CONTRAINDICATIONS DUOBRII Lotion is contraindicated in pregnancy ( 4.1 , 8.1 ) 4.1 Pregnancy DUOBRII Lotion is contraindicated in pregnancy [ see Warnings and Precautions (5.1) , Use in Specific Populations ( 8.1 , 8.3) ].

5 WARNINGS AND PRECAUTIONS • Embryofetal risk : DUOBRII Lotion contains tazarotene, which is a teratogenic substance. In females of reproductive potential, obtain a negative pregnancy test within 2 weeks prior to initiating treatment and advise patients to use an effective method of contraception during treatment. (5.1) • Reversible hypothalamic-pituitary-adrenal (HPA) axis suppression may occur, with the potential for glucocorticosteroid insufficiency during or after treatment. (5.2) • Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. (5.2) • Systemic absorption may require evaluation for HPA axis suppression. (5.2) • Use of potent corticosteroids on large areas, for prolonged durations, under occlusive dressings, or on an altered skin barrier may increase systemic exposure. (5.2) • Local Adverse Reactions : Local adverse reactions may include atrophy, striae, telangiectasias, and folliculitis. If these effects occur, discontinue at least until the integrity of the skin has been restored. DUOBRII Lotion should not be used on eczematous skin, as it may cause severe irritation. (5.3) • Photosensitivity and Risk for Sunburn : Avoid exposure to sunlight, sunlamps, and weather extremes. DUOBRII Lotion should be administered with caution if the patient is also taking drugs known to be photosensitizers. (5.4) • Ophthalmic Adverse Reactions : Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. If visual symptoms occur, consider referral to an ophthalmologist (5.5) . 5.1 Embryofetal Risk Based on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, DUOBRII Lotion may cause fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Tazarotene is teratogenic, and it is not known what level of exposure is required for teratogenicity in humans [see Contraindications (4) , Clinical Pharmacology (12.3) ]. Tazarotene elicits teratogenic and developmental effects associated with retinoids after topical or systemic administration in rats and rabbits [see Use in Specific Populations (8.1 )]. Advise pregnant females of the potential risk to a fetus. Obtain a pregnancy test within 2 weeks prior to DUOBRII Lotion therapy. Initiate DUOBRII Lotion therapy during a menstrual period. Advise females of reproductive potential to use effective contraception during treatment with DUOBRII Lotion therapy [see Use in Specific Populations ( 8.1 and 8.3 )] . 5.2 Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression and Other Unwanted Systemic Glucocorticoid Effects DUOBRII Lotion contains halobetasol propionate, a corticosteroid, and has been shown to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Systemic effects of topical corticosteroids may include reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of treatment of the topical corticosteroid. The potential for hypothalamic-pituitary-adrenal (HPA) axis suppression with DUOBRII Lotion was evaluated in a study of 20 adult subjects with moderate to severe plaque psoriasis involving ≥20% of their body surface area. The subjects were treated once daily for 8 weeks and assessed for HPA axis suppression at Weeks 4 and 8. HPA axis suppression occurred in 3 out of 20 (15%) subjects at Week 4 and none (0%) of these 20 subjects had HPA axis suppression at Week 8 [see Clinical Pharmacology (12.2) ] . Because of the potential for systemic absorption, use of topical corticosteroids, including DUOBRII Lotion, may require that patients be evaluated periodically for evidence of HPA axis suppression. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of more potent corticosteroids, use over large surface areas, occlusive use, use on an altered skin barrier, concomitant use of multiple corticosteroid-containing products, liver failure, and young age. An adrenocorticotropic hormone (ACTH) stimulation test may be helpful in evaluating patients for HPA axis suppression. If HPA axis suppression is documented, attempt to gradually withdraw the drug or reduce the frequency of application. Manifestations of adrenal insufficiency may require supplemental systemic corticosteroids. Recovery of HPA axis function is generally prompt and complete upon discontinuation of topical corticosteroids. Systemic effects of topical corticosteroids may also include Cushing’s syndrome, hyperglycemia, and glucosuria. Use of more than one corticosteroid-containing product at the same time may increase the total systemic exposure to topical corticosteroids. Pediatric patients may be more susceptible than adults to systemic toxicity from the use of topical corticosteroids because of their larger surface-to-body-mass ratio [see Use in Specific Populations (8.4) ] . 5.3 Local Adverse Reactions Local adverse reactions may include atrophy, striae, telangiectasias, folliculitis and contact dermatitis. Some local adverse reactions may be irreversible. If these adverse reactions occur, discontinue the medication at least until the integrity of the skin is restored; do not resume treatment if allergic contact dermatitis is identified. Avoid use of DUOBRII Lotion on eczematous skin, as it may cause severe irritation. 5.4 Photosensitivity and Risk for Sunburn Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be avoided unless deemed medically necessary, and in such cases, exposure should be minimized during the use of DUOBRII Lotion. Patients must be instructed to use sunscreens and protective clothing when using DUOBRII Lotion. Patients with sunburn should be advised not to use DUOBRII Lotion until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using DUOBRII Lotion. DUOBRII Lotion should be administered with caution if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity. 5.5 Ophthalmic Adverse Reactions Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported postmarketing with the use of topical corticosteroid products. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation. 5.6 Concomitant Skin Infections Use an appropriate antimicrobial agent if a skin infection is present or develops. If a favorable response does not occur promptly, discontinue use of DUOBRII Lotion until the infection has been adequately treated.

6 ADVERSE REACTIONS • The most common adverse reactions are contact dermatitis (7%), application site pain (3%), folliculitis (2%), skin atrophy (2%), and excoriation (2%). ( 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 widely varying 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 clinical practice. In randomized, double-blind, multicenter, vehicle-controlled clinical trials, 410 adults with plaque psoriasis were treated with DUOBRII Lotion or vehicle lotion and had post-baseline safety data. Subjects applied DUOBRII Lotion or vehicle lotion once daily for up to 8 weeks. Table 1 presents adverse reactions that occurred in at least 1% of subjects treated with DUOBRII Lotion and more frequently than in vehicle-treated subjects. Table 1: Adverse Reactions Occurring in ≥1% of the Subjects Treated with DUOBRII Lotion through Week 8 Adverse Reaction DUOBRII Lotion (N=270) Vehicle Lotion (N=140) Contact Dermatitis 20 (7%) 0 Application Site Pain 7 (3%) 1 (1%) Folliculitis 5 (2%) 0 Skin Atrophy 5 (2%) 0 Excoriation 5 (2%) 0 Rash 4 (1%) 0 Skin Abrasion 3 (1%) 0 Skin Exfoliation 2 (1%) 0

8.1 Pregnancy Risk Summary Based on data from animal reproduction studies, retinoid pharmacology, and the potential for systemic absorption, DUOBRII Lotion may cause fetal harm when administered to a pregnant female and is contraindicated during pregnancy. Safety in pregnant females has not been established. The potential risk to the fetus outweighs the potential benefit to the mother from DUOBRII Lotion during pregnancy; therefore, DUOBRII Lotion should be discontinued as soon as pregnancy is recognized [see Contraindications (4) , Warnings and Precautions (5.1) , Clinical Pharmacology (12.3) ] . Observational studies suggest an increased risk of low birthweight in infants with the maternal use of potent or very potent topical corticosteroids ( see Data ). In animal reproduction studies with pregnant rats, reduced fetal body weights and reduced skeletal ossification were observed after topical administration of a tazarotene gel formulation during the period of organogenesis at a dose 11 times the maximum recommended human dose (MRHD) (based on AUC comparison). In animal reproduction studies with pregnant rabbits, single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies were observed after topical administration of a tazarotene gel formulation at 116 times the MRHD (based on AUC comparison) (see Data) . In animal reproduction studies with pregnant rats and rabbits, malformations, fetal toxicity, developmental delays, and/or behavioral delays were observed after oral administration of tazarotene during the period of organogenesis at doses 9 and 228 times, respectively, the MRHD (based on AUC comparison). In pregnant rats, decreased litter size, decreased numbers of live fetuses, decreased fetal body weights, and increased malformations were observed after oral administration of tazarotene prior to mating through early gestation at doses 9 times the MRHD (based on AUC comparison) (see Data) . In animal reproduction studies, increased malformations, including cleft palate and omphalocele, were observed after oral administration of halobetasol propionate during the period of organogenesis to pregnant rats and rabbits (see Data) . The available data do not support relevant comparisons of systemic halobetasol propionate exposures achieved in the animal studies to exposures observed in humans after topical use of DUOBRII Lotion. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. Data Human Data Available observational studies in pregnant women did not identify a drug-associated risk of major birth defects, preterm delivery, or fetal mortality with the use of topical corticosteroids of any potency. However, when the dispensed amount of potent or very potent topical corticosteroids exceeded 300 g during the entire pregnancy, maternal use was associated with an increased risk of low birth weight in infants. Animal Data Halobetasol propionate has been shown to cause malformations in rats and rabbits when given orally during organogenesis at doses of 0.04 to 0.1 mg/kg/day in rats and 0.01 mg/kg/day in rabbits. Halobetasol propionate was embryotoxic in rabbits but not in rats. Cleft palate was observed in both rats and rabbits. Omphalocele was seen in rats but not in rabbits. In an embryofetal development study in rats, a tazarotene gel formulation, 0.5% (0.25 mg/kg/day tazarotene) was topically administered to pregnant rats during gestation days 6 through 17. Reduced fetal body weights and reduced skeletal ossification occurred at this dose (11 times the MRHD based on AUC comparison). In an embryofetal development study in rabbits, a tazarotene gel formulation (0.5%, 0.25 mg/kg/day tazarotene) was topically administered to pregnant rabbits during gestation days 6 through 18. Single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies were noted at this dose (116 times the MRHD based on AUC comparison). When tazarotene was given orally to animals, developmental delays were seen in rats; malformations and post-implantation loss were observed in rats and rabbits at doses producing 9 and 228 times, respectively, the MRHD (based on AUC comparisons). In female rats orally administered 2 mg/kg/day of tazarotene from 15 days before mating through gestation day 7, classic developmental effects of retinoids including decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights were observed at this dose (16 times the MRHD based on AUC comparison). A low incidence of retinoid-related malformations was observed at that dose. In a pre- and postnatal development toxicity study, topical administration of a tazarotene gel formulation (0.125 mg/kg/day) to pregnant female rats from gestation day 16 through lactation day 20 reduced pup survival but did not affect the reproductive capacity of the offspring. Based on data from another study, the systemic drug exposure in the rat at this dose would be equivalent to 5 times the MRHD (based on AUC comparison).