CLASSES

Other Corticosteroid Combinations
Topical Antipsoriasis Agents

DEA CLASS

Rx

DESCRIPTION

Topical combination product containing a synthetic corticosteroid and vitamin D3 analog
Available as an ointment, foam, cream, and suspension
Ointment and foam approved for use up to 4 weeks; cream and suspension can be applied for up to 8 weeks

COMMON BRAND NAMES

Enstilar, Taclonex, Taclonex Scalp, Wynzora

HOW SUPPLIED

Calcipotriene, Betamethasone/Calcipotriene, Betamethasone Dipropionate Topical Cream: 0.005-0.064%
Calcipotriene, Betamethasone/Calcipotriene, Betamethasone Dipropionate/Taclonex Topical Ointment: 0.005-0.064%
Calcipotriene, Betamethasone/Calcipotriene, Betamethasone Dipropionate/Taclonex/Taclonex Scalp Topical Susp: 0.005-0.064%
Enstilar Topical Foam: 0.005-0.064%

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

100 g cream/ointment/suspension per week topically, or 60 g foam every 4 days topically; treatment of more than 30% body surface area is not recommended.

100 g cream/ointment/suspension per week topically, or 60 g foam every 4 days topically; treatment of more than 30% body surface area is not recommended.

60 g ointment/suspension per week topically, or 60 g foam every 4 days topically; treatment of more than 30% body surface area is not recommended; safety and efficacy of the cream have not been established.

12 years and older: 60 g ointment/suspension per week topically, or 60 g foam every 4 days topically; treatment of more than 30% body surface area is not recommended; safety and efficacy of the cream have not been established.
1 to 11 years: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

For external use only; do not apply to face, axillae, or groin. Avoid contact with eyes.
Instruct patients to wash their hands before and after use.
Avoid concurrent treatment with other topical medications at the site of application; calcipotriene can become chemically unstable and inactive when combined with other topical preparations.
Do not use with occlusive dressings. Instruct patients not to bandage, cover, or wrap the treated area.
If applied to exposed portions of the body, avoid excessive exposure to natural or artificial sunlight.

STORAGE

Enstilar:
- Do not freeze
- Do Not Store at Temperatures Above 120 degrees F (49 degrees C)
- Flammable, keep away from heat and flame
- Product should be used within 6 months after opening
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Taclonex:
- Do not refrigerate
- Product should be used within 6 months after opening
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
- Store in carton
Taclonex Scalp:
- Do not refrigerate
- Product should be used within 6 months after opening
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
- Store in carton
Wynzora:
- Do not freeze
- Product should be used within 6 months after opening
- Protect from extreme heat
- Protect from light
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

CONTRAINDICATIONS / PRECAUTIONS

Calcipotriene; betamethasone is contraindicated in patients with a history of hypersensitivity reactions to the drug or to any components used in the preparation of the commercial combination product. Allergic contact dermatitis has been observed with the use of both topical calcipotriene and topical corticosteroids, and the diagnosis is usually observed by a failure to heal rather than a clinical exacerbation. Although true corticosteroid hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to betamethasone should not receive calcipotriene; betamethasone. It is possible, though also rare, that such patients will display cross-hypersensitivity to other corticosteroids. It is advisable that patients who have a hypersensitivity reaction to any corticosteroid undergo skin testing, which, although not a conclusive predictor, may help to determine if hypersensitivity to another corticosteroid exists. Such patients should be carefully monitored during and following the administration of any corticosteroid.

The safety and efficacy of calcipotriene; betamethasone has not been evaluated in patients with known or suspected disorders of calcium metabolism. Use is not recommended in patients with hypervitaminosis D. Manufacturers recommend suspending therapy in patients with hypercalcemia or hypercalciuria until parameters normalize. Use of topical calcipotriene; betamethasone has been linked to reports of alterations in calcium metabolism after 4 weeks of treatment; the effect on calcium metabolism beyond 8 weeks of treatment has not been studied. Caution is required when prescribing topical calcipotriene; betamethasone for patients at risk of hypercalciuria or with a history of renal calculi. Hypercalcemia and/or hypercalciuria may increase renal calculi formation in patients with a history of nephrolithiasis. Topical application of more than 100 g/week (or 60 g every 4 days for foam formulation) should be avoided as hypercalcemia is more likely when this dose is exceeded. Monitoring serum and urine calcium do not appear necessary during treatment at recommended dosages.

Prolonged topical administration of preparations containing corticosteroids, at recommended doses, may result in systemic absorption of the corticosteroid and may produce hypothalamic-pituitary-adrenal (HPA) axis suppression and manifestations of Cushing's syndrome; avoid prolonged use in patients with Cushing's syndrome. Factors that predispose patients to HPA axis suppression (during or upon withdrawal of treatment) include the use of high-potency steroids, treatment of large surface areas, prolonged use, altered skin barrier, hepatic disease, and young age. Patients receiving large doses or prolonged exposure to calcipotriene; betamethasone should be evaluated periodically for evidence of HPA axis suppression. If HPA axis suppression is observed, gradually withdraw the use of the drug, reduce the frequency of application, or switch to a less potent corticosteroid.[31986] [43708]

Caution should be observed when prescribing calcipotriene; betamethasone to patients with diabetes mellitus. Systemic absorption of topical corticosteroids may decrease glucose tolerance, produce hyperglycemia, and glucosuria , exacerbating diabetes mellitus. Additionally, use of topical corticosteroids may further delay healing of skin ulcers in patients with diabetes.

Topical corticosteroids may delay the healing of non-infected wounds such as venous stasis ulcers. Use calcipotriene; betamethasone with caution in patients with markedly impaired circulation or peripheral vascular disease; skin ulceration has been reported in these patients following topical corticosteroid use.

Conditions that increase systemic absorption of calcipotriene; betamethasone include the use over large surface areas, prolonged use, in areas where the epidermal barrier is disrupted (i.e., skin abrasion), and the use of an occlusive dressing. The use of an occlusive dressing is not recommended, as this may enhance the absorption of both betamethasone and calcipotriene.

Application of topical corticosteroids to areas of infection, including tuberculosis of the skin, dermatologic fungal infection, and cutaneous or systemic viral infection (e.g., herpes infection, measles, varicella), should be initiated or continued only if the appropriate antiinfective treatment is instituted. If the infection does not respond to the antimicrobial therapy, the concurrent use of calcipotriene; betamethasone should be discontinued until the infection is controlled.

In clinical experience with geriatric patients, no overall differences in safety or effectiveness of calcipotriene; betamethasone were observed. Nevertheless, elderly patients may be more likely to have decreased skin integrity secondary to aging. Extreme caution should be exercised when using high potency topical corticosteroids in the elderly, especially those who are small and frail who will have an increased ratio of skin surface to body mass; use of lower potency topical corticosteroids may be necessary in these patients. Additionally, in the elderly, analysis of severity of dermatologic reactions occurring during clinical trials with calcipotriene (single entity product) showed that subjects over 65 years had significantly more severe skin-related reactions than subjects under 65 years.

Calcipotriene; betamethasone should not be used in the presence of pre-existing skin atrophy at the treatment site. If treatment is necessary, then calcipotriene; betamethasone should be used for brief periods, or under close medical supervision in patients with evidence of pre-existing skin atrophy. Elderly patients may be more likely to have preexisting skin atrophy secondary to aging.

Prolonged use of super-potent topical corticosteroids or administration of the drug to a large surface area of the body may lead to systemic adverse effects such as osteoporosis and avascular necrosis of the bones. Use calcipotriene; betamethasone cautiously in elderly patients, debilitated patients, or postmenopausal patients because they are especially susceptible to these adverse effects.

Calcipotriene may increase the effects of UV radiation on skin tumor formation. Excessive natural or artificial sunlight (UV) exposure should be avoided when calcipotriene; betamethasone is being applied to an exposed area of the skin. Furthermore, clinicians may wish to limit or avoid use of phototherapy or other photosensitizing agents in patients using calcipotriene; betamethasone.

Calcipotriene; betamethasone should not be applied to the face, axillae, or groin; ocular exposure should be avoided. Likewise, accidental exposure to unaffected areas of skin may lead to skin irritation and should be avoided.

Safety and efficacy of calcipotriene; betamethasone topical ointment, foam, and suspension have not been established in neonates, infants, and children younger than 12 years of age. Safety and efficacy of the topical cream have not been established in pediatric patients under the age of 18 years. Children and infants are at a greater risk of developing systemic adverse effects to topical medications because of a higher ratio of skin surface area to body mass.

Data are insufficient to determine if the use of calcipotriene; betamethasone during human pregnancy poses a risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. However, observational studies suggest an association between maternal exposure to potent or very potent topical corticosteroids (dose exceeding 300 grams) and low infant birth weight. In animal studies, an increased incidence of minor skeletal abnormalities was observed in the offspring of rats administered oral calcipotriene during organogenesis. Also, subcutaneous administration of betamethasone dipropionate to pregnant rats and rabbits during organogenesis resulted in fetal deaths, reduced fetal weight, and fetal malformations (cleft palate, abnormal tails). Calcipotriene; betamethasone should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. If treatment during pregnancy is required, apply the drug to the smallest area of skin and for the short duration possible.[31986] [43708]

It is not known if topically administered calcipotriene; betamethasone is excreted into breast milk. According to the manufacturer, because many drugs are excreted in human milk, caution should be exercised when it is administered to a breast-feeding mother. If treatment of a lactating mother is required, apply the drug to the smallest area of skin and for the short duration possible. Also, instruct the mother to avoid application to the breast while breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.[31986]

The propellants used in the calcipotriene; betamethasone foam formulation are flammable. Instruct patients to avoid exposure to fire, flames, and tobacco smoking both during and immediately following application.

Treatment with systemic or topical corticosteroids, including calcipotriene; betamethasone, may increase the risk for posterior subcapsular cataracts and glaucoma exacerbation; therefore, caution is advised when considering the use of these products in patients with glaucoma, cataracts, or other visual problems. Preexisting glaucoma may be aggravated if calcipotriene; betamethasone is applied in the periorbital area. Visual impairment, ocular hypertension, and worsened cataracts have been reported with ocular exposure to other high potency topical corticosteroids. To prevent accidental ocular exposure, wash hands after each application. Patients receiving corticosteroids chronically should be periodically assessed for cataract formation, increased intraocular pressure, glaucoma, or any other visual disturbance. Consider referring patients who develop ocular symptoms to an ophthalmologist for evaluation.[31986]

ADVERSE REACTIONS

skin atrophy / Delayed / 0.1-1.9
hypervitaminosis D / Delayed / Incidence not known
ocular hypertension / Delayed / Incidence not known
visual impairment / Early / Incidence not known

erythema / Early / 0.4-2.1
contact dermatitis / Delayed / Incidence not known
hyperglycemia / Delayed / Incidence not known
hypercalcemia / Delayed / Incidence not known
hypercalciuria / Delayed / Incidence not known
glycosuria / Early / Incidence not known
Cushing's syndrome / Delayed / Incidence not known
physiological dependence / Delayed / Incidence not known
hypothalamic-pituitary-adrenal (HPA) suppression / Delayed / Incidence not known
adrenocortical insufficiency / Delayed / Incidence not known
impaired wound healing / Delayed / Incidence not known
skin ulcer / Delayed / Incidence not known
cataracts / Delayed / Incidence not known

pruritus / Rapid / 2.8-7.2
infection / Delayed / 0.8-7.0
pharyngitis / Delayed / 2.3-2.3
headache / Early / 2.0-2.0
skin hypopigmentation / Delayed / 0.1-1.4
folliculitis / Delayed / 0.1-1.4
skin irritation / Early / 0.4-1.4
paresthesias / Delayed / 0.2-1.4
rash / Early / 0.1-1.2
ecchymosis / Delayed / 1.0-1.0
skin hyperpigmentation / Delayed / 0.1-0.1
telangiectasia / Delayed / 0.1-0.1
striae / Delayed / Incidence not known
xerosis / Delayed / Incidence not known
miliaria / Delayed / Incidence not known

DRUG INTERACTIONS

Calcium Acetate: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Calcium Carbonate: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Calcium Carbonate; Magnesium Hydroxide: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Calcium Carbonate; Risedronate: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Calcium Carbonate; Simethicone: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Calcium Chloride: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Calcium Gluconate: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Calcium: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Calcium; Vitamin D: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Chromium: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Folic Acid, Vitamin B9: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Polycarbophil: (Moderate) Use calcipotriene cautiously with other agents that can produce hypercalcemia, including calcium polycarbophil. Each 625 mg of calcium polycarbophil contains a substantial amount of calcium (approximately 125 mg). There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use.
Porfimer: (Major) Avoid the concomitant use of porfimer with calcipotriene. Calcipotriene may enhance the ability of ultraviolet radiation to induce skin tumors. Coadministration of photosensitizing agents such as porfimer may increase this risk.
Pyridoxine, Vitamin B6: (Minor) There is evidence that calcipotriene can be absorbed in amounts that are sufficient to produce systemic effects, including elevated serum calcium; hypercalcemia has been observed in normal prescription use. Use calcipotriene cautiously with other agents that can produce hypercalcemia (e.g., calcium salts or supplements including calcium carbonate).
Verteporfin: (Major) Use caution if coadministration of verteporfin with calcipotriene is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like calcipotriene may increase the risk of a photosensitivity reaction.

PREGNANCY AND LACTATION

Data are insufficient to determine if the use of calcipotriene; betamethasone during human pregnancy poses a risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. However, observational studies suggest an association between maternal exposure to potent or very potent topical corticosteroids (dose exceeding 300 grams) and low infant birth weight. In animal studies, an increased incidence of minor skeletal abnormalities was observed in the offspring of rats administered oral calcipotriene during organogenesis. Also, subcutaneous administration of betamethasone dipropionate to pregnant rats and rabbits during organogenesis resulted in fetal deaths, reduced fetal weight, and fetal malformations (cleft palate, abnormal tails). Calcipotriene; betamethasone should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus. If treatment during pregnancy is required, apply the drug to the smallest area of skin and for the short duration possible.[31986] [43708]

It is not known if topically administered calcipotriene; betamethasone is excreted into breast milk. According to the manufacturer, because many drugs are excreted in human milk, caution should be exercised when it is administered to a breast-feeding mother. If treatment of a lactating mother is required, apply the drug to the smallest area of skin and for the short duration possible. Also, instruct the mother to avoid application to the breast while breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.[31986]

MECHANISM OF ACTION

Calcipotriene and betamethasone work in different ways to alleviate the signs and symptoms of psoriasis vulgaris (i.e., erythema, scaliness, and plaque elevation), although the mechanism for each is not completely understood. Calcipotriene and betamethasone each have major effects on markers of epidermal proliferation and keratinization. In the epidermis, keratin-10 is a marker of cell differentiation; calcipotriene has some effects on keratin-10 and betamethasone targets keratin-10 to normalize differentiation. Proliferating keratinocytes have Ki-67 positive nuclei, on which calcipotriene has significant effects. Betamethasone also reduces T-cell receptors, which decreases the production of cytokines. Overall, these actions exhibit a broad range of effects on inflammatory cells that cannot be achieved with the use of individual products.[31990] After the topical application of betamethasone; calcipotriene, clinical improvement of psoriatic lesions occurs within 1 to 2 weeks, with maximal benefits observed in 4 to 8 weeks.
 
Calcipotriene: The mechanism of action of calcipotriene, a synthetic analog of vitamin D3, is similar to that of naturally occurring calcitriol (i.e., active vitamin D3). Calcipotriene binds to vitamin D receptors on keratinocytes of both normal and psoriatic epidermal and tissue cells. Activation of this ligand-receptor complex results in inhibition of cell proliferation and induction of cell differentiation in psoriatic skin. These actions essentially reverse the abnormal cell changes occurring in psoriasis. Calcipotriene is also similar to calcitriol in its ability to suppress thymocyte proliferation, T-helper function, and lymphocyte proliferation. The exact role of these immunologic mechanisms in the reduction of psoriatic lesions is unknown. Nevertheless, the drug demonstrates a dose-dependent effect on erythema, thickness, and scaling of psoriatic lesions.[23819]
The binding affinity of calcipotriene to intestinal calcitriol receptors is similar to that of calcitriol (whose main function is to increase calcium absorption from the gut and promote normal bone formation and mineralization). However, animal studies demonstrated that calcipotriene is 100 to 200 times less potent than calcitriol on calcium metabolism when given systemically.[23816] It has been suggested that rapid liver metabolism or extensive metabolism of calcipotriene in epidermal keratinocytes is responsible for this difference.[23817] During short-term therapy of stable plaque psoriasis, calcium and bone metabolism in humans appear to be unaffected when calcipotriene is used at the recommended dosage (less than 100 grams per week). Calcipotriene administered for 4 weeks at the maximum weekly dosage (100 grams per week) resulted in significant increases in urine calcium.[23818] Additionally, systemic exposure of topical calcipotriene has been shown to induce alterations in intestinal calcium absorption leading to fluctuations in serum calcium, phosphate, and calcitriol levels.[31992]
 
Betamethasone: Corticosteroids exhibit anti-inflammatory, antipruritic, and vasoconstrictive properties. At the cellular level, corticosteroids induce peptides called lipocortins. Lipocortins antagonize phospholipase A2, an enzyme that causes the breakdown of leukocyte lysosomal membranes to release arachidonic acid. This action decreases the subsequent formation and release of endogenous inflammatory mediators including prostaglandins, kinins, histamines, liposomal enzymes, and the complement system. Early anti-inflammatory effects of topical corticosteroids include the inhibition of macrophage and leukocyte movement and activity in the inflamed area by reversing vascular dilation and permeability. Later inflammatory processes such as capillary production, collagen deposition, and keloid (scar) formation are also inhibited by corticosteroids. Clinically, these actions correspond to decreased edema, erythema, pruritus, plaque formation, and scaling in affected skin (i.e., psoriasis plaques).

PHARMACOKINETICS

Calcipotriene; betamethasone is applied topically to the skin. It is unknown if calcipotriene; betamethasone and its metabolites cross the placenta or are distributed into breast milk.
Calcipotriene: The distribution of absorbed calcipotriene and its metabolites have not been described, it is presumed to be similar to other vitamin D derivatives. Absorbed calcipotriene is rapidly and extensively converted in the liver to a 24-ketone and a 22,23-hydrogenated derivative. In vitro data have shown that the parent compound is also metabolized by human keratinocytes. All metabolites identified thus far have negligible activity compared with the parent compound.
Betamethasone: Betamethasone binds weakly to plasma proteins, and only the unbound portion of a circulating dose is active. Once absorbed, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. In addition, some corticosteroids and their metabolites are also excreted in the bile. The biological half-life of betamethasone is 35 to 54 hours.