ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (incidence 3%) are hypercalcemia, hypercalciuria, and skin discomfort. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Perrigo at 1-866-634-9120 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 clinical studies of drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.Calcitriol Ointment was studied in two vehicle-controlled trials and one open label trial, resulting in 743 subjects exposed to Calcitriol Ointment. Table describes adverse events in subjects treated with Calcitriol Ointment twice daily for 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.Table 1. Selected Adverse Events Occurring in at least 1% of Subjects in the Two Pooled Vehicle-Controlled TrialsCalcitriol Ointment (n=419)Vehicle Ointment(n=420)Discomfort Skin3%2%Pruritus1%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, however the elevation were less than 10% above the upper limit of normal [see WARNINGS AND PRECAUTIONS (5.1)]The open label study enrolled 324 subjects with psoriasis who were then treated for up to 52 weeks and included 239 subjects exposed for months and 116 subjects exposed for one year. Adverse events reported at rate of greater than or equal to 3% of subjects treated with Calcitriol Ointment were lab test abnormality (8%), urine abnormality (4%), psoriasis (4%), hypercalciuria (3%), and discomfort of skin (3%). Kidney stones were reported in subjects and confirmed in two.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during the world-wide post-approval use of Calcitriol Ointment: acute blistering dermatitis, erythema,and skin burning sensation. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. When calcitriol was applied topically to mice for up to 24 months, no significant changes in tumor incidence were observed. Concentrations of calcitriol in ointment base of (vehicle control), 0.3, 0.6 and 1.0 ppm were evaluated.A two-year carcinogenicity study was conducted in which calcitriol was orally administered to rats at dosages of approximately0.005, 0.03, and 0.1 mcg/kg/day (0.03, 0.18, and 0.6 mcg/m2/day, respectively). The incidence of benign pheochromocytomas was significantly increased in female rats. No other significant differences in tumor incidence data were observed.Calcitriol did not elicit genotoxic effects in the mouse lymphoma TK locus assay. Studies in which male and female rats received oral doses of calcitriol of up to 0.6 mcg/kg/day (3.6 mcg/m2/day) indicated no impairment of fertility or general reproductive performance.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. The contribution to efficacy of individual components of the vehicle has not been established. 12.1 Mechanism of Action. The mechanism of action of calcitriol in the treatment of psoriasis has not been established.. 12.3 Pharmacokinetics. The systemic exposure of calcitriol was assessed in subjects with chronic, plaque psoriasis. In the pivotal pharmacokinetic/pharmacodynamic study, calcitriol ointment mcg/g, was applied twice daily for 21 days (for total dose of 30 g/day) to 35% of the body surface area (psoriatic surrounding healthy skin) of subjects with at least 25% of body surface area involvement. At Day 21, the geometric mean plasma concentration values of Cmax increased by approximately 36% over baseline and the geometric mean value of AUC(0-12hr) increased by 44%. There was no correlation between the elevated calcitriol levels and the pharmacodynamic parameters or serum albumin adjusted calcium, serum phosphorus, urinary calcium and urinary phosphorus.Specific Populations Pediatric Patients The systemic exposure of calcitriol was assessed in pediatric subjects ages to 17 years with plaque psoriasis in two trials. In one trial, 25 subjects ages 12 to 17 applied calcitriol ointment mcg/g twice day for weeks to body surface area of 10% to 35%. The mean daily dose was 10.43 g/day. In the second trial, 17 subjects ages to 12 applied calcitriol ointment mcg/g twice day for 14 days to body surface area of 3% to 18%. The mean daily dose was 17.09 g/day. In both trials, the systemic concentrations of calcitriol post treatment were relatively flat and were generally comparable to the endogenous levels observed at baseline. The PK parameters could not be reliably estimated. There was no correlation between the elevated calcitriol levels and the pharmacodynamic parameters of serum albumin adjusted calcium, serum phosphorus, urinary calcium and urinary phosphorus.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. In two, multicenter, double-blind, vehicle-controlled studies, total of 839 subjects with psoriasis rated mild or moderate using an investigator global assessment scale were tested twice daily for weeks. Subjects were randomized in 1:1 ratio to receive either Calcitriol Ointment or vehicle ointment. The mean age of subjects was 48 years and 66% were male; most subjects were rated moderate at baseline.Success was defined as Clear or Minimal (up to light red or pink coloration, surface dryness with some white coloration, and slight elevation above normal skin) with at least 2-grade change from baseline. The success rates are displayed in the Table 2. Table 2. Percentage of Subjects with Clear or Minimal Disease AND Two Grade Improvement at End of Treatment (8 weeks)Study 1Study 2Calcitriol Ointment(N=209)Vehicle Ointment (N=209)Calcitriol Ointment (N=210)Vehicle Ointment (N=211)23.4%14.4%20.5%6.6%.

DOSAGE & ADMINISTRATION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. When calcitriol was applied topically to mice for up to 24 months, no significant changes in tumor incidence were observed. Concentrations of calcitriol in ointment base of (vehicle control), 0.3, 0.6 and 1.0 ppm were evaluated.A two-year carcinogenicity study was conducted in which calcitriol was orally administered to rats at dosages of approximately0.005, 0.03, and 0.1 mcg/kg/day (0.03, 0.18, and 0.6 mcg/m2/day, respectively). The incidence of benign pheochromocytomas was significantly increased in female rats. No other significant differences in tumor incidence data were observed.Calcitriol did not elicit genotoxic effects in the mouse lymphoma TK locus assay. Studies in which male and female rats received oral doses of calcitriol of up to 0.6 mcg/kg/day (3.6 mcg/m2/day) indicated no impairment of fertility or general reproductive performance.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Calcitriol Ointment have been established in pediatric patients age years and older for topical treatment of mild to moderate plaque psoriasis. Use of Calcitriol Ointment in this age group is supported by two adequate and well-controlled 8-week trials and an open label trial in adult subjects, and additional data from trials conducted in pediatric subjects to 17 years of age including:a vehicle controlled 8-week trial in 19 subjects to 12 years of age with mild to moderate plaque psoriasisan open-label 8-week safety and pharmacokinetics (PK) trial in 25 subjects 12 to 17 years of agean open-label 14-day safety and PK trial in 18 subjects to 17 years of age.an open-label 26-week safety and PK trial in 54 subjects to 17 years of age.Data from 63 subjects ages to 12 years, and 42 subjects ages 13 to 17 years showed no significant effects on indices of calcium metabolism. The systemic exposure of calcitriol in the pediatric subjects was generally comparable to the endogenous levels observed at baseline. No new safety signals were identified in subjects to 17 years [see Clinical Studies (14), Clinical Pharmacology (12.3) and Adverse Reactions (6.1)]. The safety and effectiveness of Calcitriol Ointment in pediatric subjects below the age of years has not been established.. vehicle controlled 8-week trial in 19 subjects to 12 years of age with mild to moderate plaque psoriasis. an open-label 8-week safety and pharmacokinetics (PK) trial in 25 subjects 12 to 17 years of age. an open-label 14-day safety and PK trial in 18 subjects to 17 years of age.. an open-label 26-week safety and PK trial in 54 subjects to 17 years of age.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The systemic exposure of calcitriol was assessed in subjects with chronic, plaque psoriasis. In the pivotal pharmacokinetic/pharmacodynamic study, calcitriol ointment mcg/g, was applied twice daily for 21 days (for total dose of 30 g/day) to 35% of the body surface area (psoriatic surrounding healthy skin) of subjects with at least 25% of body surface area involvement. At Day 21, the geometric mean plasma concentration values of Cmax increased by approximately 36% over baseline and the geometric mean value of AUC(0-12hr) increased by 44%. There was no correlation between the elevated calcitriol levels and the pharmacodynamic parameters or serum albumin adjusted calcium, serum phosphorus, urinary calcium and urinary phosphorus.Specific Populations Pediatric Patients The systemic exposure of calcitriol was assessed in pediatric subjects ages to 17 years with plaque psoriasis in two trials. In one trial, 25 subjects ages 12 to 17 applied calcitriol ointment mcg/g twice day for weeks to body surface area of 10% to 35%. The mean daily dose was 10.43 g/day. In the second trial, 17 subjects ages to 12 applied calcitriol ointment mcg/g twice day for 14 days to body surface area of 3% to 18%. The mean daily dose was 17.09 g/day. In both trials, the systemic concentrations of calcitriol post treatment were relatively flat and were generally comparable to the endogenous levels observed at baseline. The PK parameters could not be reliably estimated. There was no correlation between the elevated calcitriol levels and the pharmacodynamic parameters of serum albumin adjusted calcium, serum phosphorus, urinary calcium and urinary phosphorus.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from pregnancies that occurred during the clinical development of Calcitriol Ointment and published cases of oral and intravenous calcitriol use in pregnant women have not identified 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 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 Calcitriol Ointment.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 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/m2/day) and in which rabbits received topical application of calcitriol ointment (3ppm) 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 significantly elevated mean post-implantation loss and an increased incidence of minor skeletal abnormalities due to delayed ossification of the pubic bones. 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from pregnancies that occurred during the clinical development of Calcitriol Ointment and published cases of oral and intravenous calcitriol use in pregnant women have not identified 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 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 Calcitriol Ointment.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 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/m2/day) and in which rabbits received topical application of calcitriol ointment (3ppm) 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 significantly elevated mean post-implantation loss and an increased incidence of minor skeletal abnormalities due to delayed ossification of the pubic bones. 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. 8.2 Lactation. Risk Summary There are no data on the presence of calcitriol in human milk, the effects on the breastfed infant or on milk production after treatment with Calcitriol Ointment. It is not known whether topical administration of calcitriol 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 mothers clinical need for Calcitriol Ointment and any potential adverse effects on the breastfed infant from Calcitriol Ointment or from the underlying maternal conditions. Clinical Considerations Advise breastfeeding women not to apply Calcitriol Ointment directly to the nipple and areola to avoid direct infant exposure.. 8.4 Pediatric Use. The safety and effectiveness of Calcitriol Ointment have been established in pediatric patients age years and older for topical treatment of mild to moderate plaque psoriasis. Use of Calcitriol Ointment in this age group is supported by two adequate and well-controlled 8-week trials and an open label trial in adult subjects, and additional data from trials conducted in pediatric subjects to 17 years of age including:a vehicle controlled 8-week trial in 19 subjects to 12 years of age with mild to moderate plaque psoriasisan open-label 8-week safety and pharmacokinetics (PK) trial in 25 subjects 12 to 17 years of agean open-label 14-day safety and PK trial in 18 subjects to 17 years of age.an open-label 26-week safety and PK trial in 54 subjects to 17 years of age.Data from 63 subjects ages to 12 years, and 42 subjects ages 13 to 17 years showed no significant effects on indices of calcium metabolism. The systemic exposure of calcitriol in the pediatric subjects was generally comparable to the endogenous levels observed at baseline. No new safety signals were identified in subjects to 17 years [see Clinical Studies (14), Clinical Pharmacology (12.3) and Adverse Reactions (6.1)]. The safety and effectiveness of Calcitriol Ointment in pediatric subjects below the age of years has not been established.. vehicle controlled 8-week trial in 19 subjects to 12 years of age with mild to moderate plaque psoriasis. an open-label 8-week safety and pharmacokinetics (PK) trial in 25 subjects 12 to 17 years of age. an open-label 14-day safety and PK trial in 18 subjects to 17 years of age.. an open-label 26-week safety and PK trial in 54 subjects to 17 years of age.. 8.5 Geriatric Use. Clinical studies of Calcitriol Ointment did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported experience has not identified differences in responses between the elderly and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

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