Vectical

1 INDICATIONS AND USAGE VECTICAL Ointment is a vitamin D analog indicated for the topical treatment of mild to moderate plaque psoriasis in adult and pediatric patients 2 years and older. ( 1.1 ) Limitations of Use The safety and effectiveness of VECTICAL Ointment in patients with known or suspected disorders of calcium metabolism have not been evaluated. ( 1.2 ) 1.1 Indication VECTICAL Ointment is indicated for the topical treatment of mild to moderate plaque psoriasis in adults and pediatric patients 2 years and older. 1.2 Limitations of Use The safety and effectiveness of VECTICAL Ointment in patients with known or suspected disorders of calcium metabolism have not been evaluated.

2 DOSAGE AND ADMINISTRATION Apply VECTICAL Ointment to affected areas twice daily, morning and evening Adults: • The maximum weekly dose should not exceed 200 grams. Pediatrics: • 2 to 6 years of age: the maximum weekly dose should not exceed 100 grams • 7 years of age and older: the maximum weekly dose should not exceed 200 grams VECTICAL Ointment should not be applied to the eyes, lips, or facial skin. VECTICAL Ointment is for topical use only. VECTICAL Ointment is not for oral, ophthalmic or intravaginal use. Apply VECTICAL Ointment to affected areas of the body twice daily. ( 2 ) Adults: • The maximum weekly dose should not exceed 200 grams. ( 2 ) Pediatrics: • 2 to 6 years of age: the maximum weekly dose should not exceed 100 grams. ( 2 ) • 7 years of age and older: the maximum weekly dose should not exceed 200 grams. ( 2 ) For topical use only. ( 2 ) Not for oral, ophthalmic, or intravaginal use. ( 2 )

4 CONTRAINDICATIONS None None ( 4 )

5 WARNINGS AND PRECAUTIONS Effects on Calcium metabolism: Risk of hypercalcemia. If aberrations in parameters of calcium metabolism are noted discontinue VECTICAL Ointment until these normalize. Increased absorption may occur with occlusive use. ( 5.1 ) VECTICAL Ointment should be used with caution in patients receiving medications known to increase the serum calcium level, such as thiazide diuretics, and in patients receiving calcium supplements or high doses of vitamin D. ( 5.1 ) 5.1 Effects on Calcium Metabolism In controlled clinical trials hypercalcemia was observed in subjects exposed to VECTICAL Ointment. If aberrations in parameters of calcium metabolism occur, treatment should be discontinued until these parameters have normalized. The effects of VECTICAL Ointment on calcium metabolism following treatment durations greater than 52 weeks have not been evaluated. Increased absorption may occur with occlusive use. VECTICAL Ointment should be used with caution in patients receiving medications known to increase the serum calcium level, such as thiazide diuretics, and in patients receiving calcium supplements or high doses of vitamin D.

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 3%) are hypercalcemia, hypercalciuria, and skin discomfort. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact: Galderma Laboratories, L.P. at 866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. VECTICAL Ointment was studied in two vehicle-controlled trials and one open label trial, resulting in 743 subjects exposed to VECTICAL Ointment. Table 1 describes adverse events in subjects treated with VECTICAL Ointment twice daily for 8 weeks. The population included subjects ages 13 to 87 years, males (284) and females (135), Caucasians (372) and non-Caucasians (47); with mild (105) to moderate (313) chronic plaque psoriasis. Four hundred and nineteen subjects were treated with VECTICAL Ointment twice daily for 8 weeks. The population included subjects ages 13 to 87, males (284) and females (135), Caucasians (372) and non-Caucasians (47); with mild (105) to moderate (313) chronic plaque psoriasis. Table 1. Selected Averse Events Occurring in at least 1% of Subjects in the Two Pooled Vehicle-Controlled Trials VECTICAL (n = 419) Vehicle Ointment (n = 420) Discomfort skin 3% 2% Pruritus 1% 1% Among subjects having laboratory monitoring, hypercalcemia was observed in 24% (18/74) of subjects exposed to active drug and in 16% (13/79) of subjects exposed to vehicle, the elevations were less than 10% above the upper limit of normal ) [see Warnings and Precautions ( 5.1 ) ]. The open label trial enrolled 324 subjects with psoriasis who were treated for up to 52 weeks and included 239 subjects exposed for 6 months and 116 subjects exposed for one year. Adverse events reported at a rate of greater than or equal to 3% of subjects treated with VECTICAL Ointment were lab test abnormality (8%), urine abnormality (4%), psoriasis (4%), hypercalciuria (3%), and discomfort of skin (3%). Kidney stones were reported in 3 subjects and confirmed in two. 6.2 Postmarketing Experience The following adverse reactions have been identified during world-wide post-approval use of VECTICAL Ointment: acute blistering dermatitis, erythema and skin burning sensation. 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.

8.1 Pregnancy Risk Summary Available data from pregnancies that occurred during the clinical development of VECTICAL Ointment and published case series of oral and intravenous calcitriol use in pregnant women have not identified a drug associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. In animal reproduction studies, topical administration of calcitriol to pregnant rabbits during the period of organogenesis resulted in an increased incidence of fetal deaths, as well as an increased incidence of minor skeletal abnormalities (see Data) . The available data do not allow the calculation of relevant comparisons between the systemic exposures of calcitriol observed in animal studies to the systemic exposures that would be expected in humans after topical use of VECTICAL Ointment. 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. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Embryo-fetal development studies with calcitriol were performed in which rats were treated orally at dosages up to 0.9 mcg/kg/day (5.4 mcg/m 2 /day) and in which rabbits received topical application of calcitriol ointment (3 ppm) to 6.4% of the body surface area. No effects on reproductive or fetal parameters were observed in rats. In rabbits, topically applied calcitriol induced a significantly elevated mean post-implantation loss and an increased incidence of minor skeletal abnormalities due to delayed ossification of the pubic bones. A slightly increased incidence of skeletal variation (extra 13th rib, reduced ossification of epiphyses) was also observed. These effects may have been secondary to maternal toxicity.