DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Apply an adequate layer of Calcipotriene and Betamethasone Dipropionate Ointment to the affected area(s) once daily for up to weeks. Calcipotriene and Betamethasone Dipropionate Ointment should be rubbed in gently and completely. Patients should wash their hands after applying Calcipotriene and Betamethasone Dipropionate Ointment. Therapy should be discontinued when control is achieved.Patients 18 years and older should not use more than 100 per week and patients 12 to 17 years should not use more than 60 per week. Treatment of more than 30% body surface area is not recommended.Calcipotriene and Betamethasone Dipropionate Ointment should not be used with occlusive dressings unless directed by physician. Avoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site. Calcipotriene and Betamethasone Dipropionate Ointment is not for oral, ophthalmic, or intravaginal use.. oApply Calcipotriene and Betamethasone Dipropionate Ointment to affected area(s) once daily for up to weeks. Discontinue therapy when control is achieved. (2)oAdult patients should not use more than 100 per week. (2)oPatients ages 12 to 17 years should not use more than 60 per week. (2)oTreatment of more than 30% body surface area is not recommended. (2)oDo not use with occlusive dressings unless directed by physician. (2)oAvoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site. (2)oNot for oral, ophthalmic, or intravaginal use. (2). oApply Calcipotriene and Betamethasone Dipropionate Ointment to affected area(s) once daily for up to weeks. Discontinue therapy when control is achieved. (2). oAdult patients should not use more than 100 per week. (2). oPatients ages 12 to 17 years should not use more than 60 per week. (2). oTreatment of more than 30% body surface area is not recommended. (2). oDo not use with occlusive dressings unless directed by physician. (2). oAvoid use on the face, groin, or axillae, or if skin atrophy is present at the treatment site. (2). oNot for oral, ophthalmic, or intravaginal use. (2).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. The most common adverse reactions (>=1%) are pruritus and scaly rash. (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. Clinical Trials Conducted in Subjects 18 years and older with Plaque PsoriasisThe data described below reflect exposure to calcipotriene and betamethasone dipropionate ointment in 2448 subjects with plaque psoriasis, including 1992 exposed for weeks, and 289 exposed for weeks.Calcipotriene and betamethasone dipropionate ointment was studied primarily in placebo- and active-controlled trials (N 1176, and = 1272, respectively). The population was 15-97 years old, 61% males and 39% females, mostly white (97%) and had baseline disease severity ranging from mild to very severe. Most subjects received once daily application, and the median weekly dose was 24.5 g.The percentage of subjects reporting at least one adverse event was 27.1% in the calcipotriene and betamethasone dipropionate ointment group, 33.0% in the calcipotriene group, 28.3% in the betamethasone group, and 33.4% in the vehicle group.Table 1Adverse Events Reported by >=1% of Subjects by Preferred TermCalcipotriene and betamethasone dipropionate ointmentN 2448CalcipotrieneN 3197Betamethasone dipropionateN 1164VehicleN 470Any Adverse Event663 (27.1)1055 (33.0)329 (28.3)157 (33.4)Preferred Term of subjects (%)Pruritus75 (3.1)183 (5.7)38 (3.3)43 (9.1)Headache69 (2.8)75 (2.3)44 (3.8)12 (2.6)Nasopharyngitis56 (2.3)77 (2.4)34 (2.9)9 (1.9)Psoriasis30 (1.2)47 (1.5)14 (1.2)5 (1.1)Rash scaly30 (1.2)40 (1.3)0 (0.0)1 (0.2)Influenza23 (0.9)34 (1.1)14 (1.2)6 (1.3)Upper respiratory tract infection20 (0.8)19 (0.6)12 (1.0)3 (0.6)Erythema15 (0.6)54 (1.7)3 (0.3)5 (1.1)Application site pruritus13 (0.5)24 (0.8)10 (0.9)6 (1.3)Skin irritation11 (0.4)60 (1.9)8 (0.7)5 (1.1)Pain7 (0.3)12 (0.4)3 (0.3)5 (1.1)Burning sensation6 (0.2)30 (0.9)3 (0.3)6 (1.3)A lesional/perilesional adverse event was generally defined as an adverse event located <= cm from the lesional border.Table 2Lesional/Perilesional Adverse Events Reported by >=1% of SubjectsCalcipotriene and betamethasone dipropionate ointmentN 2448CalcipotrieneN 3197Betamethasone dipropionateN 1164VehicleN 470Any Adverse Event213 (8.7)419 (13.1)85 (7.3)76 (16.2)Preferred Term of subjects (%)Pruritus69 (2.8)170 (5.3)31 (2.7)41 (8.7)Rash scaly29 (1.2)38 (1.2)0 (0.0)0 (0.0)Application site pruritus12 (0.5)24 (0.8)10 (0.9)6 (1.3)Erythema9 (0.4)36 (1.1)2 (0.2)4 (0.9)Skin irritation9 (0.4)51 (1.6)8 (0.7)5 (1.1)Burning sensation6 (0.2)25 (0.8)3 (0.3)5 (1.1)For subjects who reported lesional/perilesional adverse events, the median time to onset was days for calcipotriene and betamethasone dipropionate ointment, days for calcipotriene, days for betamethasone dipropionate, and days for vehicle.Other less common reactions (less than 1% but more than 0.1%) were, in decreasing order of incidence, folliculitis, rash papular, rash pustular, and skin hypopigmentation. Skin atrophy, telangiectasia and skin hyperpigmentation were reported infrequently (0.1%).In separate trial, subjects (N 207) with at least moderate disease severity were given calcipotriene and betamethasone dipropionate ointment intermittently on an as needed basis for up to 52 weeks. The median use was 15.4 per week. The effects of calcipotriene and betamethasone dipropionate ointment on calcium metabolism were not studied and the effects on the HPA axis were not adequately studied. The following adverse reactions were reported by 1% or more of the subjects: pruritus (7.2%), psoriasis (3.4%), skin atrophy (1.9%), folliculitis (1.4%), burning sensation (1.4%), skin depigmentation (1.4%), ecchymosis (1.0%), erythema (1.0%) and hand dermatitis (1.0%). One case of serious flare-up of psoriasis was reported.. 6.2 Postmarketing Experience. The following adverse reactions associated with the use of calcipotriene and betamethasone dipropionate ointment have been identified post-approval: pustular psoriasis and rebound effect.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.Postmarketing reports for local adverse reactions to topical corticosteroids may also include: striae, dryness, acneiform eruptions, perioral dermatitis, secondary infection and miliaria.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30 mcg/kg/day (9, 30 and 90 mcg/m2/day, respectively), no significant changes in tumor incidence were observed when compared to control.A 104-week oral carcinogenicity study was conducted with calcipotriene in male and female rats at doses of 1, and 15 mcg/kg/day (6, 30, and 90 mcg/m2/day, respectively). Beginning week 71, the dosage for high-dose animals of both genders was reduced to 10 mcg/kg/day (60 mcg/m2/day). treatment-related increase in benign C-cell adenomas was observed in the thyroid of females that received 15 mcg/kg/day. treatment-related increase in benign pheochromocytomas was observed in the adrenal glands of males that received 15 mcg/kg/day. No other statistically significant differences in tumor incidence were observed when compared to control. The relevance of these findings to patients is unknown.When betamethasone dipropionate was applied topically to CD-1 mice for up to 24 months at dosages approximating 1.3, 4.2 and 8.5 mcg/kg/day in females, and 1.3, 4.2, and 12.9 mcg/kg/day in males (up to 26 mcg/m2/day and 39 mcg/m2/day, in females and males, respectively), no significant changes in tumor incidence were observed when compared to control.When betamethasone dipropionate was administered via oral gavage to male and female Sprague Dawley rats for up to 24 months at dosages of 20, 60, and 200 mcg/kg/day (120, 360, and 1200 mcg/m2/day, respectively), no significant changes in tumor incidence were observed when compared to control.Calcipotriene did not elicit any genotoxic effects in the Ames mutagenicity assay, the mouse lymphoma TK locus assay, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Betamethasone dipropionate did not elicit any genotoxic effects in the Ames mutagenicity assay, the mouse lymphoma TK locus assay, or in the rat micronucleus test.Studies in rats with oral doses of up to 54 mcg/kg/day (324 mcg/m2/day) of calcipotriene indicated no impairment of fertility or general reproductive performance. Studies in male rats at oral doses of up to 200 mcg/kg/day (1200 mcg/m2/day), and in female rats at oral doses of up to 1000 mcg/kg/ day (6000 mcg/m2/day), of betamethasone dipropionate indicated no impairment of fertility.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Calcipotriene and Betamethasone Dipropionate Ointment combines the pharmacological effects of calcipotriene as synthetic vitamin D3 analogue and betamethasone dipropionate as synthetic corticosteroid. However, while their pharmacologic and clinical effects are known, the exact mechanisms of their actions in plaque psoriasis are unknown.. 12.2 Pharmacodynamics. Vasoconstriction:In vasoconstrictor trial in healthy subjects, the skin blanching response of calcipotriene and betamethasone dipropionate ointment was consistent with that of potent corticosteroid when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression:HPA axis suppression was evaluated in four trials (Trial A, B, and D) following the application of calcipotriene and betamethasone dipropionate ointment.In Trial A, calcipotriene and betamethasone dipropionate ointment was applied once daily for weeks to adult subjects (N 12) with plaque psoriasis to study its effects on the hypothalamic-pituitary-adrenal (HPA) axis. Of eleven subjects tested, none demonstrated adrenal suppression as indicated by 30-minute post-stimulation cortisol level <= 18 mcg/dL.In Trial B, calcipotriene and betamethasone dipropionate ointment was evaluated in adult subjects with plaque psoriasis (N 19). One subject demonstrated adrenal suppression.In Trial C, HPA axis suppression was evaluated in adult subjects (N=32) with extensive plaque psoriasis involving at least 30% of the scalp and, in total, 15-30% of the body surface area. Treatment consisted of once daily application of calcipotriene and betamethasone dipropionate topical suspension on the scalp in combination with calcipotriene and betamethasone dipropionate ointment on the body. Adrenal suppression as indicated by 30-minutes post-stimulation cortisol level 18 mcg/dL was observed in of 32 subjects (15.6%) after weeks of treatment as per the recommended duration of use [see Dosage and Administration (2)].In Trial D, HPA axis suppression was evaluated in subjects 12 to 17 years (N=32) with plaque psoriasis of the body involving 5-30% of the body surface area. Treatment consisted of once daily application of calcipotriene and betamethasone dipropionate ointment to the affected areas for up to weeks. Mean weekly dose was 29.6 with range of 8.1-55.8 g/week. Adrenal suppression as indicated by 30-minute post-stimulation cortisol level <=18 mcg/dL was observed in none of 32 evaluable subjects after weeks of treatment [see Use in Specific Populations (8.4)].Effects on Calcium MetabolismIn Trial described above, the effects of once daily application of calcipotriene and betamethasone dipropionate ointment on the body in combination with calcipotriene and betamethasone dipropionate topical suspension on the scalp on calcium metabolism were also examined. Elevated urinary calcium levels outside the normal range were observed in of 35 subjects (2.9%) after weeks of treatment.In Trial described above, calcium metabolism was evaluated in total of 33 subjects aged 12 to 17 years with plaque psoriasis involving 5-30% of the body surface area who underwent once daily application of calcipotriene and betamethasone dipropionate ointment for up to weeks. No cases of hypercalcemia and no clinically relevant changes in urinary calcium were reported. However, one subject had normal urinary calcium: creatinine ratio at baseline (3.75 mmol/g), which increased above the normal range at week (16 mmol/g). There were no relevant changes in albumin-corrected serum calcium or other markers of calcium metabolism for this subject. The clinical significance of this finding is unknown.. 12.3 Pharmacokinetics. AbsorptionIn Trial described above, the systemic effect of calcipotriene and betamethasone dipropionate ointment in extensive plaque psoriasis was investigated. In this trial, the serum levels of calcipotriene and betamethasone dipropionate and their major metabolites were measured after weeks (maximum recommended duration of treatment) and also after weeks of once daily application of calcipotriene and betamethasone dipropionate ointment on the body in combination with calcipotriene and betamethasone dipropionate topical suspension on the scalp. Both calcipotriene and betamethasone dipropionate were below the lower limit of quantification in all serum samples of the 34 subjects evaluated. However, one major metabolite of calcipotriene (MC1080) was quantifiable in 10 of 34 (29.4%) subjects at week and in five of 12 (41.7%) subjects at week 8. The major metabolite of betamethasone dipropionate, betamethasone 17-propionate (B17P) was also quantifiable in 19 of 34 (55.9%) subjects at week and seven of 12 (58.3%) subjects at week 8. The serum concentrations for MC1080 ranged from 20-75 pg/mL. The clinical significance of this finding is unknown.MetabolismCalcipotriene:Calcipotriene metabolism following systemic uptake is rapid and occurs in the liver. The primary metabolites of calcipotriene are less potent than the parent compound.Calcipotriene is metabolized to MC1046 (the alpha, beta-unsaturated ketone analogue of calcipotriene), which is metabolized further to MC1080 (a saturated ketone analogue). MC1080 is the major metabolite in plasma. MC1080 is slowly metabolized to calcitroic acid.Betamethasone dipropionate:Betamethasone dipropionate is metabolized to betamethasone 17-propionate and betamethasone, including the 6beta-hydroxy derivatives of those compounds by hydrolysis. Betamethasone 17-propionate (B17P) is the primary metabolite.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Clinical Trials Conducted in Subjects 18 years and older with Plaque PsoriasisIn an international, multi-center, double-blind, vehicle- and active-controlled, parallel-group trial, 1603 subjects with mild to very severe plaque psoriasis on trunk and limbs were treated once daily for weeks. Subjects were randomized to one of four treatment arms: calcipotriene and betamethasone dipropionate ointment, calcipotriene hydrate 50 mcg/g in the same vehicle, betamethasone dipropionate 0.64 mg/g in the same vehicle, and vehicle alone. The mean age of the subjects was 48.4 years and 60.5% were male. Most subjects had disease of moderate severity at baseline.Efficacy was assessed as the proportion of subjects with absent or very mild disease according to the Investigators Global Assessment of Disease Severity at end of treatment (4 weeks). Absent disease was defined as no evidence of redness, thickness, or scaling. Very mild disease was defined as controlled disease, but not entirely cleared: lesions with some discoloration with absolutely minimal thickness, i.e. the edges to the lesion(s) could just be felt. Table contains the response rates for this trial.Table 3Percentage of Subjects with Absent or Very Mild Disease According to the Investigators Global Assessment of Disease Severity at End of Treatment (4 weeks).Calcipotriene and betamethasone dipropionate ointmentN 490CalcipotrieneN 480Betamethasone dipropionateN 476VehicleN 157Absent or very mild disease48.0%16.5%26.3%7.6% Subjects with mild disease at baseline were required to have Absent disease to be considered success.In addition to the pivotal trial (N 490), four randomized, double-blind, vehicle- or active-controlled, parallel-group trials were conducted and provided supportive evidence of efficacy. These trials included total of 1058 subjects treated with calcipotriene and betamethasone dipropionate ointment once daily for up to weeks.Clinical Trial Conducted in Subjects 12 to 17 years with Plaque PsoriasisA prospective, uncontrolled trial (N=33) was conducted in pediatric subjects ages 12 to 17 years with plaque psoriasis involving 5-30% of the body surface area. Approximately 91% of subjects had moderate disease at baseline. Subjects were treated once daily for up to weeks with calcipotriene and betamethasone dipropionate ointment. All subjects were evaluated for safety including calcium metabolism (N=33) and 32 subjects were evaluated for HPA axis suppression [see Clinical Pharmacology (12.2)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information)Inform patients of the following:oInstruct adult patients (18 years and older) not to use more than 100 per week.oInstruct pediatric patients (12 to 17 years) not to use more than 60 per week.oDiscontinue therapy when control is achieved unless directed otherwise by the physician.oAvoid use of Calcipotriene and Betamethasone Dipropionate Ointment on the face, underarms, groin or eyes. If this medicine gets on face or in eyes, wash area right away.oDo not occlude the treatment area with bandage or other covering unless directed by the physician.oNote that local reactions and skin atrophy are more likely to occur with occlusive use, prolonged use or use of higher potency corticosteroids.oWash hands after application.oAdvise patients to report any visual symptoms to their healthcare providers.oAdvise woman to use Calcipotriene and Betamethasone Dipropionate Ointment on the smallest area of skin and for the shortest duration possible while pregnant or breastfeeding. Advise breastfeeding women not to apply Calcipotriene and Betamethasone Dipropionate Ointment directly to the nipple and areola to avoid direct infant exposure.oInstruct patients not to use other products containing calcipotriene or corticosteroid should not be used with Calcipotriene and Betamethasone Dipropionate Ointment without first talking to the physician.oInstruct patients who use Calcipotriene and Betamethasone Dipropionate Ointment to avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.).Made in IsraelManufactured By PerrigoYeruham, IsraelDistributed ByPerrigo(R)Allegan, MI 49010 www.perrigo.comRev 02-191V200 RC J1. oInstruct adult patients (18 years and older) not to use more than 100 per week.. oInstruct pediatric patients (12 to 17 years) not to use more than 60 per week.. oDiscontinue therapy when control is achieved unless directed otherwise by the physician.. oAvoid use of Calcipotriene and Betamethasone Dipropionate Ointment on the face, underarms, groin or eyes. If this medicine gets on face or in eyes, wash area right away.. oDo not occlude the treatment area with bandage or other covering unless directed by the physician.. oNote that local reactions and skin atrophy are more likely to occur with occlusive use, prolonged use or use of higher potency corticosteroids.. oWash hands after application.. oAdvise patients to report any visual symptoms to their healthcare providers.. oAdvise woman to use Calcipotriene and Betamethasone Dipropionate Ointment on the smallest area of skin and for the shortest duration possible while pregnant or breastfeeding. Advise breastfeeding women not to apply Calcipotriene and Betamethasone Dipropionate Ointment directly to the nipple and areola to avoid direct infant exposure.. oInstruct patients not to use other products containing calcipotriene or corticosteroid should not be used with Calcipotriene and Betamethasone Dipropionate Ointment without first talking to the physician.. oInstruct patients who use Calcipotriene and Betamethasone Dipropionate Ointment to avoid excessive exposure to either natural or artificial sunlight (including tanning booths, sun lamps, etc.).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. When calcipotriene was applied topically to mice for up to 24 months at dosages of 3, 10 and 30 mcg/kg/day (9, 30 and 90 mcg/m2/day, respectively), no significant changes in tumor incidence were observed when compared to control.A 104-week oral carcinogenicity study was conducted with calcipotriene in male and female rats at doses of 1, and 15 mcg/kg/day (6, 30, and 90 mcg/m2/day, respectively). Beginning week 71, the dosage for high-dose animals of both genders was reduced to 10 mcg/kg/day (60 mcg/m2/day). treatment-related increase in benign C-cell adenomas was observed in the thyroid of females that received 15 mcg/kg/day. treatment-related increase in benign pheochromocytomas was observed in the adrenal glands of males that received 15 mcg/kg/day. No other statistically significant differences in tumor incidence were observed when compared to control. The relevance of these findings to patients is unknown.When betamethasone dipropionate was applied topically to CD-1 mice for up to 24 months at dosages approximating 1.3, 4.2 and 8.5 mcg/kg/day in females, and 1.3, 4.2, and 12.9 mcg/kg/day in males (up to 26 mcg/m2/day and 39 mcg/m2/day, in females and males, respectively), no significant changes in tumor incidence were observed when compared to control.When betamethasone dipropionate was administered via oral gavage to male and female Sprague Dawley rats for up to 24 months at dosages of 20, 60, and 200 mcg/kg/day (120, 360, and 1200 mcg/m2/day, respectively), no significant changes in tumor incidence were observed when compared to control.Calcipotriene did not elicit any genotoxic effects in the Ames mutagenicity assay, the mouse lymphoma TK locus assay, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Betamethasone dipropionate did not elicit any genotoxic effects in the Ames mutagenicity assay, the mouse lymphoma TK locus assay, or in the rat micronucleus test.Studies in rats with oral doses of up to 54 mcg/kg/day (324 mcg/m2/day) of calcipotriene indicated no impairment of fertility or general reproductive performance. Studies in male rats at oral doses of up to 200 mcg/kg/day (1200 mcg/m2/day), and in female rats at oral doses of up to 1000 mcg/kg/ day (6000 mcg/m2/day), of betamethasone dipropionate indicated no impairment of fertility.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Vasoconstriction:In vasoconstrictor trial in healthy subjects, the skin blanching response of calcipotriene and betamethasone dipropionate ointment was consistent with that of potent corticosteroid when compared with other topical corticosteroids. However, similar blanching scores do not necessarily imply therapeutic equivalence.Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression:HPA axis suppression was evaluated in four trials (Trial A, B, and D) following the application of calcipotriene and betamethasone dipropionate ointment.In Trial A, calcipotriene and betamethasone dipropionate ointment was applied once daily for weeks to adult subjects (N 12) with plaque psoriasis to study its effects on the hypothalamic-pituitary-adrenal (HPA) axis. Of eleven subjects tested, none demonstrated adrenal suppression as indicated by 30-minute post-stimulation cortisol level <= 18 mcg/dL.In Trial B, calcipotriene and betamethasone dipropionate ointment was evaluated in adult subjects with plaque psoriasis (N 19). One subject demonstrated adrenal suppression.In Trial C, HPA axis suppression was evaluated in adult subjects (N=32) with extensive plaque psoriasis involving at least 30% of the scalp and, in total, 15-30% of the body surface area. Treatment consisted of once daily application of calcipotriene and betamethasone dipropionate topical suspension on the scalp in combination with calcipotriene and betamethasone dipropionate ointment on the body. Adrenal suppression as indicated by 30-minutes post-stimulation cortisol level 18 mcg/dL was observed in of 32 subjects (15.6%) after weeks of treatment as per the recommended duration of use [see Dosage and Administration (2)].In Trial D, HPA axis suppression was evaluated in subjects 12 to 17 years (N=32) with plaque psoriasis of the body involving 5-30% of the body surface area. Treatment consisted of once daily application of calcipotriene and betamethasone dipropionate ointment to the affected areas for up to weeks. Mean weekly dose was 29.6 with range of 8.1-55.8 g/week. Adrenal suppression as indicated by 30-minute post-stimulation cortisol level <=18 mcg/dL was observed in none of 32 evaluable subjects after weeks of treatment [see Use in Specific Populations (8.4)].Effects on Calcium MetabolismIn Trial described above, the effects of once daily application of calcipotriene and betamethasone dipropionate ointment on the body in combination with calcipotriene and betamethasone dipropionate topical suspension on the scalp on calcium metabolism were also examined. Elevated urinary calcium levels outside the normal range were observed in of 35 subjects (2.9%) after weeks of treatment.In Trial described above, calcium metabolism was evaluated in total of 33 subjects aged 12 to 17 years with plaque psoriasis involving 5-30% of the body surface area who underwent once daily application of calcipotriene and betamethasone dipropionate ointment for up to weeks. No cases of hypercalcemia and no clinically relevant changes in urinary calcium were reported. However, one subject had normal urinary calcium: creatinine ratio at baseline (3.75 mmol/g), which increased above the normal range at week (16 mmol/g). There were no relevant changes in albumin-corrected serum calcium or other markers of calcium metabolism for this subject. The clinical significance of this finding is unknown.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionIn Trial described above, the systemic effect of calcipotriene and betamethasone dipropionate ointment in extensive plaque psoriasis was investigated. In this trial, the serum levels of calcipotriene and betamethasone dipropionate and their major metabolites were measured after weeks (maximum recommended duration of treatment) and also after weeks of once daily application of calcipotriene and betamethasone dipropionate ointment on the body in combination with calcipotriene and betamethasone dipropionate topical suspension on the scalp. Both calcipotriene and betamethasone dipropionate were below the lower limit of quantification in all serum samples of the 34 subjects evaluated. However, one major metabolite of calcipotriene (MC1080) was quantifiable in 10 of 34 (29.4%) subjects at week and in five of 12 (41.7%) subjects at week 8. The major metabolite of betamethasone dipropionate, betamethasone 17-propionate (B17P) was also quantifiable in 19 of 34 (55.9%) subjects at week and seven of 12 (58.3%) subjects at week 8. The serum concentrations for MC1080 ranged from 20-75 pg/mL. The clinical significance of this finding is unknown.MetabolismCalcipotriene:Calcipotriene metabolism following systemic uptake is rapid and occurs in the liver. The primary metabolites of calcipotriene are less potent than the parent compound.Calcipotriene is metabolized to MC1046 (the alpha, beta-unsaturated ketone analogue of calcipotriene), which is metabolized further to MC1080 (a saturated ketone analogue). MC1080 is the major metabolite in plasma. MC1080 is slowly metabolized to calcitroic acid.Betamethasone dipropionate:Betamethasone dipropionate is metabolized to betamethasone 17-propionate and betamethasone, including the 6beta-hydroxy derivatives of those compounds by hydrolysis. Betamethasone 17-propionate (B17P) is the primary metabolite.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryCalcipotriene and Betamethasone Dipropionate Ointment contains calcipotriene and bethamethasone dipropionate. The limited data with Calcipotriene and Betamethasone Dipropionate Ointment and calcipotriene use in pregnant women are not sufficient to evaluate Calcipotriene and Betamethasone Dipropionate Ointment-associated or calcipotriene-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes.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 Calcipotriene and Betamethasone Dipropionate Ointment may increase the potential risk of having low birth weight infant and to use Calcipotriene and Betamethasone Dipropionate Ointment 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 diproprionate observed in animal studies to the systemic exposures that would be expected in humans after topical use of calcipotriene and betamethasone dipropionate ointment.The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. 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.DataHuman DataAvailable observational studies in pregnant women did not identify 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 during the entire pregnancy, maternal use was associated with an increased risk of low birth weight in infants.Animal DataEmbryo-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/m2/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 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/m2/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/m2/day, respectively) on days 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/m2/day, respectively) on days 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/m2/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/m2/day, respectively) from gestation day 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 was reduced in relation to dosage. On lactation day 5, the percentage of pups with 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryCalcipotriene and Betamethasone Dipropionate Ointment contains calcipotriene and bethamethasone dipropionate. The limited data with Calcipotriene and Betamethasone Dipropionate Ointment and calcipotriene use in pregnant women are not sufficient to evaluate Calcipotriene and Betamethasone Dipropionate Ointment-associated or calcipotriene-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes.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 Calcipotriene and Betamethasone Dipropionate Ointment may increase the potential risk of having low birth weight infant and to use Calcipotriene and Betamethasone Dipropionate Ointment 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 diproprionate observed in animal studies to the systemic exposures that would be expected in humans after topical use of calcipotriene and betamethasone dipropionate ointment.The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. 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.DataHuman DataAvailable observational studies in pregnant women did not identify 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 during the entire pregnancy, maternal use was associated with an increased risk of low birth weight in infants.Animal DataEmbryo-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/m2/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 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/m2/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/m2/day, respectively) on days 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/m2/day, respectively) on days 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/m2/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/m2/day, respectively) from gestation day 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 was reduced in relation to dosage. On lactation day 5, the percentage of pups with 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 SummaryThere 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. 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 mothers clinical need for Calcipotriene and Betamethasone Dipropionate Ointment and any potential adverse effects on the breastfed child from Calcipotriene and Betamethasone Dipropionate Ointment or from the underlying maternal condition.Clinical ConsiderationsTo minimize potential exposure to the breastfed infant via breast milk, use Calcipotriene and Betamethasone Dipropionate Ointment on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply Calcipotriene and Betamethasone Dipropionate Ointment directly to the nipple and areola to avoid direct infant exposure [see Use in Specific Populations (8.4)].. 8.4 Pediatric Use. Safety and effectiveness of the use of Calcipotriene and Betamethasone Dipropionate Ointment in pediatric patients under the age of 12 years have not been established.The safety and effectiveness of Calcipotriene and Betamethasone Dipropionate Ointment for the treatment of plaque psoriasis have been established in the age group 12 to 17 years. In prospective, uncontrolled trial, 33 pediatric subjects ages 12-17 years with plaque psoriasis on the body were treated with calcipotriene and betamethasone dipropionate ointment for weeks up to maximum of 55.8 per week. Subjects were assessed for HPA axis suppression and effects on calcium metabolism. No adverse effects on adrenal suppression were observed. No hypercalcemia was observed but one subject had possible treatment-related increase in urinary calcium [see Clinical Pharmacology (12.2)].Because of higher ratio of skin surface area to body mass, pediatric patients are at greater risk than adults of systemic toxicity when treated with topical drugs. They are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency upon the use of topical corticosteroids [see Warnings and Precautions (5.2)].Rare systemic toxicities such as Cushings syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients, especially those with prolonged exposure to large doses of high potency topical corticosteroids.Local adverse reactions including striae have also been reported with use of topical corticosteroids in pediatric patients.. 8.5 Geriatric Use. Of the total number of subjects in the clinical studies of calcipotriene and betamethasone dipropionate ointment, approximately 14% were 65 years and older and approximately 3% were 75 years and over.No overall differences in safety or effectiveness of calcipotriene and betamethasone dipropionate ointment were observed between these subjects and younger subjects. All other reported clinical experience has not identified any differences in response between elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oHypercalcemia and hypercalciuria have been observed. If either occurs, discontinue treatment until parameters of calcium metabolism normalize. (5.1)oCalcipotriene and Betamethasone Dipropionate Ointment can produce 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 large surface area or to areas under occlusion, prolonged use, concomitant use of more than one corticosteroid-containing product, altered skin barrier, liver failure, and use in pediatric patients. Modify use should HPA axis suppression develop. (5.2, 8.4)oCalcipotriene and Betamethasone Dipropionate Ointment may increase the risk of cataract and glaucoma. If visual symptoms occur, consider referral to an ophthalmologist. (5.3). oHypercalcemia and hypercalciuria have been observed. If either occurs, discontinue treatment until parameters of calcium metabolism normalize. (5.1). oCalcipotriene and Betamethasone Dipropionate Ointment can produce 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 large surface area or to areas under occlusion, prolonged use, concomitant use of more than one corticosteroid-containing product, altered skin barrier, liver failure, and use in pediatric patients. Modify use should HPA axis suppression develop. (5.2, 8.4). oCalcipotriene and Betamethasone Dipropionate Ointment may increase the risk of cataract and glaucoma. If visual symptoms occur, consider referral to an ophthalmologist. (5.3). 5.1 Hypercalcemia and Hypercalciuria. Hypercalcemia and hypercalciuria have been observed with use of calcipotriene and betamethasone dipropionate ointment. If hypercalcemia or hypercalciuria develops, treatment should be discontinued until parameters of calcium metabolism have normalized. In the trials that included assessment of the effects of calcipotriene and betamethasone dipropionate ointment on calcium metabolism, such testing was done after weeks of treatment. The effects of calcipotriene and betamethasone dipropionate ointment on calcium metabolism following treatment durations of longer than weeks have not been evaluated [see Clinical Pharmacology (12.2)].. 5.2 Effects on Endocrine System. Calcipotriene and betamethasone dipropionate ointment 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 patient to HPA axis suppression include the use of high-potency corticosteroids, large treatment surface areas, prolonged use, concomitant use of more than one corticosteroid-containing product, use of occlusive dressings, altered skin barrier, liver failure, and young age. Evaluation for HPA axis suppression may be done by using the cosyntropin stimulation test [see Clinical Pharmacology (12.2)]. In trial evaluating the effects of calcipotriene and betamethasone dipropionate topical suspension and calcipotriene and betamethasone dipropionate ointment on the HPA axis, 32 adult subjects were treated with calcipotriene and betamethasone dipropionate topical suspension on the scalp and calcipotriene and betamethasone dipropionate ointment on the body. Adrenal suppression was identified in of 32 subjects (15.6%) after weeks of treatment [see Clinical Pharmacology (12.2)]. The effects of calcipotriene and betamethasone dipropionate ointment on the HPA axis following treatment durations of longer than weeks have not been adequately studied.If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with less potent corticosteroid.Cushings syndrome and hyperglycemia may also occur due to the systemic effects of topical corticosteroids. These complications are rare and generally occur after prolonged exposure to excessively large doses, especially of high-potency topical corticosteroids.Pediatric patients may be more susceptible to systemic toxicity due to their higher skin surface to body mass ratios [see Use in Specific Populations (8.4), 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 Ophthalmic Adverse Reactions. Use of topical corticosteroids, including Calcipotriene and Betamethasone Dipropionate Ointment, may increase the risks of glaucoma and posterior subcapsular cataract. Glaucoma and cataracts have been reported in postmarketing experience with the use of topical corticosteroid products, including topical clobetasol products.Avoid contact of Calcipotriene and Betamethasone Dipropionate Ointment with eyes. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.. 5.4 Allergic Contact Dermatitis with Topical Corticosteroids. Allergic contact dermatitis to any component of topical corticosteroids is usually diagnosed by failure to heal rather than clinical exacerbation. Clinical diagnosis of allergic contact dermatitis can be confirmed by patch testing.. 5.5 Allergic Contact Dermatitis with Topical Calcipotriene. Allergic contact dermatitis has been observed with use of topical calcipotriene. Clinical diagnosis of allergic contact dermatitis can be confirmed by patch testing.. 5.6 Skin Irritation. If irritation develops, treatment with Calcipotriene and Betamethasone Dipropionate Ointment should be discontinued and appropriate therapy instituted.. 5.7 Risk of Ultraviolet Light Exposure. Patients who apply Calcipotriene and Betamethasone Dipropionate Ointment to exposed skin should avoid excessive exposure to either natural or artificial sunlight, including tanning booths, sun lamps, etc. Physicians may wish to limit or avoid use of phototherapy in patients who use Calcipotriene and Betamethasone Dipropionate Ointment.