TACLONEX

1 INDICATIONS AND USAGE Taclonex ® Topical Suspension is indicated for the topical treatment of plaque psoriasis of the scalp and body in patients 12 years and older. Taclonex Topical Suspension is a combination of calcipotriene, a vitamin D analog, and betamethasone dipropionate, a corticosteroid, indicated for the topical treatment of plaque psoriasis of the scalp and body in patients 12 years and older. ( 1 )

2 DOSAGE AND ADMINISTRATION Instruct patients to shake bottle prior to using Taclonex Topical Suspension. Apply Taclonex Topical Suspension to affected areas on the scalp and body once daily for up to 8 weeks. Taclonex Topical Suspension should be discontinued when control is achieved. Instruct patients to wash their hands after applying the product. Inform patients that they should not take a bath or shower or wash their hair right after application of Taclonex Topical Suspension. Patients 12 to 17 years should not use more than 60 grams per week and patients 18 years and older should not use more than 100 grams per week. Taclonex Topical Suspension should not be: Used with occlusive dressings unless directed by a healthcare provider. Used on the face, groin, or axillae, or if skin atrophy is present at the treatment site. Applied to the scalp in the 12 hours before or after any chemical treatments to the hair. Taclonex Topical Suspension is not for oral, ophthalmic, or intravaginal use. Shake bottle before use. ( 2 ) Apply Taclonex Topical Suspension to affected areas on the scalp and body once daily for up to 8 weeks. Discontinue therapy when control is achieved. ( 2 ) Patients age 12 to 17 years should not use more than 60 grams per week.( 2 ) Adult patients should not use more than 100 grams per week. ( 2 ) Do not use with occlusive dressings unless directed by a healthcare provider. ( 2 ) Avoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site. ( 2 ) Not for oral, ophthalmic, or intravaginal use. ( 2 )

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypercalcemia and Hypercalciuria: Hypercalcemia and hypercalciuria have been reported. If either occurs, discontinue until parameters of calcium metabolism normalize. ( 5.1 ) Effects on Endocrine System: Can cause reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency during and after withdrawal of treatment. Risk factors include the use of high-potency topical corticosteroid, use over a large surface area or to areas under occlusion, prolonged use, altered skin barrier, liver failure, and use in pediatric patients. Modify use should HPA axis suppression develop. ( 5.2 , 8.4 ) Ophthalmic Adverse Reactions: May increase the risk of cataracts and glaucoma. If visual symptoms occur, consider referral to an ophthalmologist. ( 5.5 ) 5.1 Hypercalcemia and Hypercalciuria Hypercalcemia and hypercalciuria have been observed with use of Taclonex Topical Suspension. If hypercalcemia or hypercalciuria develop, discontinue treatment until parameters of calcium metabolism have normalized. The incidence of hypercalcemia and hypercalciuria following Taclonex Topical Suspension treatment of more than 8 weeks has not been evaluated [see Clinical Pharmacology (12.2) ]. 5.2 Effects on Endocrine System Hypothalamic-Pituitary-Adrenal Axis Suppression Taclonex Topical Suspension can cause reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for clinical glucocorticosteroid insufficiency. This may occur during treatment or upon withdrawal of treatment. Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure, and young age. Evaluation for HPA axis suppression may be done by using the adrenocorticotropic hormone (ACTH) stimulation test. If HPA axis suppression is documented, gradually withdraw Taclonex Topical Suspension, reduce the frequency of application, or substitute with a less potent corticosteroid. The following trials evaluated the effects of Taclonex Topical Suspension on HPA axis suppression: In a trial evaluating the effects of Taclonex Topical Suspension and Taclonex Ointment on the HPA axis, 32 adult subjects applied both Taclonex Topical Suspension on the scalp and Taclonex Ointment on the body. Adrenal suppression was identified in 5 of 32 subjects (16%) after 4 weeks of treatment and in 2 of 11 subjects (18%) who continued treatment for 8 weeks. In another trial, 36 adult subjects applied Taclonex Topical Suspension on the body and scalp and 7 subjects applied Taclonex Topical Suspension on the body. Adrenal suppression occurred in 3 out of 43 subjects (7%) after 4 weeks of treatment and in none of the 36 subjects who continued treatment for 8 weeks [ see Clinical Pharmacology (12.2) ]. In two trials, the effects of Taclonex Topical Suspension on the HPA axis were evaluated in 31 and 30 pediatric subjects aged 12 to 17 years old who applied Taclonex Topical suspension on the scalp and the scalp/body, respectively. Adrenal suppression occurred in 1 of 30 evaluable subjects (3%) after 4 weeks of treatment (scalp) and 5 of 31 evaluable subjects (16%) after up to 8 weeks of treatment (scalp and body) [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.2) ]. Cushing's Syndrome and Hyperglycemia Cushing's syndrome and hyperglycemia may occur due to the systemic effects of the topical corticosteroid. These complications are rare and generally occur after prolonged exposure to excessively large doses, especially of high-potency topical corticosteroids. Additional Considerations for Endocrine Adverse Reactions Pediatric patients may be more susceptible to systemic toxicity due to their larger skin surface to body mass ratios [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.2) ]. Use of more than one corticosteroid-containing product at the same time may increase the total systemic corticosteroid exposure. 5.3 Allergic Contact Dermatitis with Topical Corticosteroids Allergic contact dermatitis to a topical corticosteroid is usually diagnosed by observing a failure to heal rather than a clinical exacerbation. Such an observation should be corroborated with appropriate diagnostic patch testing. 5.4 Allergic Contact Dermatitis with Topical Calcipotriene Allergic contact dermatitis has been observed with use of topical calcipotriene. Such an observation should be corroborated with appropriate diagnostic patch testing. 5.5 Ophthalmic Adverse Reactions Use of topical corticosteroids, including Taclonex ® Topical Suspension, may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported with the postmarketing use of topical corticosteroid products [see Adverse Reactions (6.2) ]. Avoid contact of Taclonex Topical Suspension with eyes. Taclonex Topical Suspension may cause eye irritation. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

6 ADVERSE REACTIONS The most common adverse reactions (≥ 1%) are folliculitis and burning sensation of skin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact LEO Pharma Inc. at 1-877-494-4536 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 practice. Clinical Trials Conducted in Subjects 18 years and older with Psoriasis of the Scalp The rates of adverse reactions described below were from randomized, multicenter, vehicle- and/or active controlled clinical trials in adult subjects with psoriasis of the scalp [see Clinical Studies (14) ]. Subjects applied study product once daily for 8 weeks, and the median weekly dose was 12.6 grams. Adverse reactions that occurred in ≥ 1% of subjects treated with Taclonex Topical Suspension and at a rate higher than in subjects treated with vehicle are presented in Table 1. Table 1. Number and Percentage of Subjects with Adverse Reactions in Scalp Psoriasis Trials (Events Reported by ≥1% of Subjects and for Which a Relationship is Possible) Taclonex Topical Suspension Betamethasone Dipropionate in vehicle Calcipotriene in vehicle Vehicle N=1,953 N=1,214 N=979 N=173 Event # of subjects (%) Folliculitis 16 (1%) 12 (1%) 5 (1%) 0 (0%) Burning sensation of skin 13 (1%) 10 (1%) 29 (3%) 0 (0%) Other less common adverse reactions (<1% but >0.1%) were, in decreasing order of incidence: acne, exacerbation of psoriasis, eye irritation, and pustular rash. In a 52-week trial, adverse reactions that were reported by >1% of subjects treated with Taclonex Topical Suspension were pruritus (3.6%), psoriasis (2.4%), erythema (2.1%), skin irritation (1.4%), and folliculitis (1.2%). Clinical Trials Conducted in Subjects 18 years and older with Psoriasis of the Body In randomized, multicenter, vehicle- and/or active controlled clinical trials in adult subjects with plaque psoriasis on non-scalp areas, 824 subjects applied Taclonex Topical Suspension once daily for 8 weeks [see Clinical Studies (14) ]. The median weekly dose was 22.6 grams. There were no adverse reactions that occurred in ≥1% of subjects treated with Taclonex Topical Suspension and at a rate higher than in subjects treated with vehicle. Other less common adverse reactions (<1% but >0.1%) were, in decreasing order of incidence: rash and folliculitis. Clinical Trials Conducted in Subjects 12 to 17 years with Psoriasis of the Scalp In two uncontrolled clinical trials, 109 subjects aged 12 to 17 years with plaque psoriasis of the scalp applied Taclonex ® Topical Suspension once daily for up to 8 weeks. The median weekly dose was 40 grams. Adverse reactions included acne, acneiform dermatitis and application site pruritus (0.9% each) [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.2) ] . Clinical Trial Conducted in Subjects 12 to 17 years with Psoriasis of the Scalp and Body In an uncontrolled clinical trial, 107 subjects aged 12 to 17 years with plaque psoriasis of the scalp and body applied Taclonex Topical Suspension once daily for up to 8 weeks. The median weekly dose was 26.6 grams. Adverse reactions were folliculitis, acne, and erythema (0.9% each) [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.2) ] . 6.2 Postmarketing Experience Because adverse 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. Postmarketing reports for local adverse reactions to topical corticosteroids included atrophy, striae, telangiectasias, itching, dryness, hypopigmentation, perioral dermatitis, secondary infection, and miliaria. Ophthalmic adverse reactions of cataracts, glaucoma, increased intraocular pressure, and central serous chorioretinopathy have been reported during use of topical corticosteroids, including topical betamethasone products.

8.1 Pregnancy Risk Summary Available data with Taclonex Topical Suspension are not sufficient to evaluate a drug-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. Although there are no available data on use of the calcipotriene component in pregnant women, systemic exposure to calcipotriene after topical administration of Taclonex Topical Suspension is likely to be low [see Clinical Pharmacology (12.3) ]. Observational studies suggest an increased risk of having low birth weight infants with the maternal use of potent or super potent topical corticosteroids ( see Data ). Advise pregnant women that Taclonex Topical Suspension may increase the potential risk of having a low birth weight infant and to use Taclonex Topical Suspension on the smallest area of skin and for the shortest duration possible. In animal reproduction studies, oral administration of calcipotriene to pregnant rats during the period of organogenesis resulted in an increased incidence of minor skeletal abnormalities, including enlarged fontanelles and extra ribs ( see Data ). Oral administration of calcipotriene to pregnant rabbits during the period of organogenesis had no apparent effects on embryo-fetal development. Subcutaneous administration of betamethasone dipropionate to pregnant rats and rabbits during the period of organogenesis resulted in fetal toxicity, including fetal deaths, reduced fetal weight, and fetal malformations (cleft palate and crooked or short tail) ( see Data ). The available data do not allow the calculation of relevant comparisons between the systemic exposures of calcipotriene and betamethasone dipropionate observed in animal studies to the systemic exposures that would be expected in humans after topical use of Taclonex Topical Suspension. The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. All pregnancies have a background risk of birth defect, 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 is 2% to 4% and 15% to 20%, respectively. 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 super potent topical corticosteroids exceeded 300 grams during the entire pregnancy, maternal use was associated with an increased risk of low birth weight in infants. Animal Data Embryo-fetal development studies with calcipotriene were performed by the oral route in rats and rabbits. Pregnant rats received dosages of 0, 6, 18, or 54 mcg/kg/day (0, 36, 108, and 324 mcg/m 2 /day, respectively) on days 6-15 of gestation (the period of organogenesis). There were no apparent effects on maternal survival, behavior, or body weight gain, no effects on litter parameters, and no effects on the incidence of major malformations in fetuses. Fetuses from dams dosed at 54 mcg/kg/day exhibited a significantly increased incidence of minor skeletal abnormalities, including enlarged fontanelles and extra ribs. Pregnant rabbits were dosed daily with calcipotriene at exposures of 0, 4, 12, or 36 mcg/kg/day (0, 48, 144, and 432 mcg/m 2 /day, respectively) on days 6-18 of gestation (the period of organogenesis). Mean maternal body weight gain was reduced in animals dosed at 12 or 36 mcg/kg/day. The incidence of fetal deaths was increased in the group dosed at 36 mcg/kg/day; reduced fetal weight was also observed in this group. The incidence of major malformations among fetuses was not affected. An increase in the incidence of minor skeletal abnormalities, including incomplete ossification of sternebrae, pubic bones, and forelimb phalanges, was observed in the group dosed at 36 mcg/kg/day. Embryo-fetal development studies with betamethasone dipropionate were performed via subcutaneous injection in mice and rabbits. Pregnant mice were administered doses of 0, 156, 625, or 2500 mcg/kg/day (0, 468, 1875, and 7500 mcg/m 2 /day, respectively) on days 7 through 13 of gestation (the period of organogenesis). Betamethasone dipropionate induced fetal toxicity, including fetal deaths, reduced fetal weight, malformations (increased incidence of the cleft palate and crooked or short tail), and minor skeletal abnormalities (delayed ossification of vertebra and sternebrae). Fetal toxicity was observed at the lowest exposure that was evaluated (156 mcg/kg/day). Pregnant rabbits were injected subcutaneously at dosages of 0, 0.625, 2.5, and 10 mcg/kg/day (0, 7.5, 30, and 120 mcg/m 2 /day, respectively) on days 6 through 18 of gestation (the period of organogenesis). Betamethasone dipropionate induced fetal toxicity, including fetal deaths, reduced fetal weight, external malformations (including malformed ears, cleft palate, umbilical hernia, kinked tail, club foot, and club hand), and skeletal malformations (including absence of phalanges of the first digit and cranial dysplasia) at dosages of 2.5 mcg/kg/day and above. Calcipotriene was evaluated for effects on peri- and post-natal development when orally administered to pregnant rats at dosages of 0, 6, 18 or 54 mcg/kg/day (0, 36, 108, and 324 mcg/m 2 /day, respectively) from gestation day 15 through day 20 postpartum. No remarkable effects were observed on any parameter, including survival, behavior, body weight, litter parameters, or the ability to nurse or rear pups. Betamethasone dipropionate was evaluated for effects on peri- and post-natal development when orally administered to pregnant rats at dosages of 0, 100, 300, and 1000 mcg/kg/day (0, 600, 1800, and 6000 mcg/m 2 /day, respectively) from gestation day 6 through day 20 postpartum. Mean maternal body weight was significantly reduced on gestation day 20 in animals dosed at 300 and 1000 mcg/kg/day. The mean duration of gestation was slightly, but statistically significantly, increased at 100, 300, and 1000 mcg/kg/day. The mean percentage of pups that survived to day 4 was reduced in relation to dosage. On lactation day 5, the percentage of pups with a reflex to right themselves when placed on their back was significantly reduced at 1000 mcg/kg/day. No effects on the ability of pups to learn were observed, and the ability of the offspring of treated rats to reproduce was not affected.