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 4 weeks of treatment. The effects of calcipotriene and betamethasone dipropionate ointment on calcium metabolism following treatment durations of longer than 4 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 a 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 a 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 5 of 32 subjects (15.6%) after 4 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 4 weeks have not been adequately studied.

If HPA axis suppression is documented, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid.

Cushing's 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 a failure to heal rather than a 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.

6.1 Clinical Trials Experience

Clinical Trials Conducted in Subjects 18 years and older with Plaque Psoriasis

The data described below reflect exposure to calcipotriene and betamethasone dipropionate ointment in 2448 subjects with plaque psoriasis, including 1992 exposed for 4 weeks, and 289 exposed for 8 weeks.

Calcipotriene and betamethasone dipropionate ointment was studied primarily in placebo- and active-controlled trials (N = 1176, and N = 1272, respectively). The population was 15-97 years old, 61% males and 39% females, mostly white (97%) and had a 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 1

Adverse Events Reported by ≥ 1% of Subjects by Preferred Term

A lesional/perilesional adverse event was generally defined as an adverse event located ≤ 2 cm from the lesional border.

Table 2

Lesional/Perilesional Adverse Events Reported by ≥1% of Subjects

For subjects who reported lesional/perilesional adverse events, the median time to onset was 7 days for calcipotriene and betamethasone dipropionate ointment, 7 days for calcipotriene, 5 days for betamethasone dipropionate, and 3 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 a 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 g 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 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 may also include: striae, dryness, acneiform eruptions, perioral dermatitis, secondary infection and miliaria.

8.1 Pregnancy

Risk Summary

Calcipotriene 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 a 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 a 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.

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/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 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/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 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/m2/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/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 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. 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 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 Considerations

To 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 a 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 4 weeks up to a maximum of 55.8 g 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 a possible treatment-related increase in urinary calcium [see Clinical Pharmacology (12.2)].

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 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 Cushing’s 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.

12.1 Mechanism of Action

Calcipotriene and Betamethasone Dipropionate Ointment combines the pharmacological effects of calcipotriene as a synthetic vitamin D3 analogue 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.

12.2 Pharmacodynamics

Vasoconstriction:

In a vasoconstrictor trial in healthy subjects, the skin blanching response of calcipotriene and betamethasone dipropionate ointment was consistent with that of a 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, C and D) following the application of calcipotriene and betamethasone dipropionate ointment.

In Trial A, calcipotriene and betamethasone dipropionate ointment was applied once daily for 4 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 a 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 a 30-minutes post-stimulation cortisol level < 18 mcg/dL was observed in 5 of 32 subjects (15.6%) after 4 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 4 weeks. Mean weekly dose was 29.6 g with a range of 8.1-55.8 g/week. Adrenal suppression as indicated by a 30-minute post-stimulation cortisol level ≤18 mcg/dL was observed in none of 32 evaluable subjects after 4 weeks of treatment [see Use in Specific Populations (8.4)].

Effects on Calcium Metabolism

In Trial C 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 1 of 35 subjects (2.9%) after 4 weeks of treatment.

In Trial D described above, calcium metabolism was evaluated in a 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 4 weeks. No cases of hypercalcemia and no clinically relevant changes in urinary calcium were reported. However, one subject had a normal urinary calcium: creatinine ratio at baseline (3.75 mmol/g), which increased above the normal range at week 4 (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

Absorption

In Trial C 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 4 weeks (maximum recommended duration of treatment) and also after 8 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 4 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 4 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.

Metabolism

Calcipotriene:

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.

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, 5 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). A treatment-related increase in benign C-cell adenomas was observed in the thyroid of females that received 15 mcg/kg/day. A 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.

16.1 How Supplied

Calcipotriene and Betamethasone Dipropionate Ointment, 0.005%/0.064% is off-white to yellow in color, available in collapsible tubes of:

60 gram (NDC 45802-816-96)

100 gram (NDC 45802-816-01)

16.2 Storage

Store Calcipotriene and Betamethasone Dipropionate Ointment, 0.005%/0.064% between 20°C-25°C (68°F-77°F); excursions permitted between 15°C-30°C (59°F-86°F). [see USP Controlled Room Temperature].

16.3 Handling

Keep out of reach of children.