Calcipotriene and Betamethasone Dipropionate

WYNZORA Cream is indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older. WYNZORA Cream is a combination of calcipotriene, a vitamin D analog, and betamethasone dipropionate, a corticosteroid, indicated for the topical treatment of plaque psoriasis in patients 18 years of age and older. ( 1 )

Cream: 0.005%/0.064%. Each gram of WYNZORA Cream contains 50 mcg of calcipotriene and 0.644 mg of betamethasone dipropionate in a white cream. Cream: 0.005%/0.064% ( 3 )

None. None ( 4 )

Hypercalcemia and Hypercalciuria : Hypercalcemia and hypercalciuria have been observed with use of topical calcipotriene. If either occurs, discontinue until parameters of calcium metabolism normalize. ( 5.1 ) Effects on Endocrine System: Can cause reversible hypothalamicpituitary-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 young age. Modify use should HPA axis suppression develop. ( 5.2 ) 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 topical calcipotriene. If hypercalcemia or hypercalciuria develop, discontinue treatment until parameters of calcium metabolism have normalized.

5.2 Effects on Endocrine System Hypothalamic-Pituitary-Adrenal Axis Suppression WYNZORA Cream 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 WYNZORA Cream, reduce the frequency of application, or substitute with a less potent corticosteroid. The following trial evaluated the effects of WYNZORA Cream on HPA axis suppression: HPA axis suppression was evaluated in adult subjects (N=27) with extensive psoriasis (including scalp). Adrenal suppression was seen in 6 out of 26 subjects (23%) after 4 weeks of treatment, and in 3 out of 25 subjects (12%) after 8 weeks of treatment [see 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 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) ] . Use of more than one corticosteroid-containing product at the same time may increase 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 WYNZORA Cream, may increase the risks of glaucoma and posterior subcapsular cataract. Cataracts and glaucoma have been reported with the postmarketing use of topical corticosteroid products [see Adverse Reactions (6.2) ]. Avoid contact of WYNZORA Cream with eyes. WYNZORA Cream may cause eye irritation. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

The most common adverse reactions reported by more than 1% of subjects treated with WYNZORA Cream were upper respiratory infection, headache, and application site irritation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact MC2 Therapeutics Ltd at 1-800-644-8240 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. The rates of adverse reactions given below were reported in a randomized, multicenter, prospective, vehicle and active controlled clinical trial in adult subjects with plaque psoriasis. Subjects applied WYNZORA Cream, calcipotriene/betamethasone dipropionate topical suspension, 0.005%/0.064% or vehicle once daily for 8 weeks. The mean weekly dose of WYNZORA Cream was 33.8 g. A total of 342 subjects were treated with WYNZORA Cream, 337 with calcipotriene/betamethasone dipropionate topical suspension, 0.005%/0.064% and 115 with vehicle. The majority of subjects were White (87%) and male (62%). Approximately 72% were non-Hispanic/Latino. The mean age was 52 years and ages ranged from 18 to 89 years. The most common adverse reactions reported by ≥1% of subjects treated with WYNZORA Cream and more frequently than vehicle are presented in Table 1 below. Table 1: Adverse Reactions Through Week 8 Preferred Term WYNZORA Cream (N=342) Vehicle Cream (N=115) Upper Respiratory Infection (URI) Includes nasopharyngitis, upper respiratory tract infection (URTI), and viral URTI 7% 5% Headache 2% 0% Application site irritation 1% 0%

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of topical corticosteroids. 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. 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, and increased intraocular pressure, have been reported during use of topical corticosteroids, including topical betamethasone products.

8.1 Pregnancy Risk Summary Available data with WYNZORA Cream 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 WYNZORA Cream is likely to be low [see Clinical Pharmacology (12.3) ]. Observational studies suggest an increased risk of having low birthweight infants with the maternal use of potent or very potent topical corticosteroids (see Data ) . Advise pregnant women that WYNZORA Cream may increase the potential risk of having a low birth weight infant and to use WYNZORA Cream 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 WYNZORA Cream. The background risk of major birth defects and miscarriage in 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 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 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.

8.2 Lactation Risk Summary There is no information regarding the presence of topically administered calcipotriene and betamethasone dipropionate in human milk, the effects on the breastfed infant, or the effects on milk production. Concentrations of calcipotriene in plasma are low after topical administration, and therefore, concentrations in human milk are likely to be low [see Clinical Pharmacology (12.3) ] . It is not known whether topically administered calcipotriene or corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for WYNZORA Cream and any potential adverse effects on the breastfed child from WYNZORA Cream or from the underlying maternal condition. Clinical Considerations To minimize potential exposure to the breastfed infant via breast milk, use WYNZORA Cream on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply WYNZORA Cream directly to the nipple and areola to avoid direct infant exposure.

8.4 Pediatric Use Safety and effectiveness of the use of WYNZORA Cream in adolescents and pediatric patients under the age of 18 years have not been established. Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of systemic toxicity when treated with topical corticosteroids. […]

WYNZORA Cream combines the pharmacological effects of calcipotriene as a synthetic vitamin D3 analog and betamethasone dipropionate as a synthetic corticosteroid. However, while their pharmacologic and clinical effects are known, the exact mechanisms of their actions in plaque psoriasis are unknown.