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  • CLASSES

    Other Corticosteroid Combinations
    Topical Antipsoriasis Products

    DEA CLASS

    Rx

    DESCRIPTION

    Novel topical combination product containing a synthetic corticosteroid and vitamin D3 analog
    Once daily topical treatment of psoriasis vulgaris (plaque psoriasis) in adults and children 12 years and older
    For short term use (4 weeks for topical ointment and foam; 8 weeks for topical suspension)

    COMMON BRAND NAMES

    Enstilar, Taclonex

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment of psoriasis vulgaris (i.e., plaque psoriasis).
    NOTE: The safety and efficacy of betamethasone; calcipotriene has not been determined in patients with erythrodermic, exfoliative, or pustular psoriasis.
    For the treatment of plaque psoriasis of the body.
    Topical dose (ointment)
    Adults

    Apply thin layer of ointment to affected areas topically once daily for up to 4 weeks. Treatment may be discontinued earlier if control is achieved.

    Children and Adolescents 12 to 17 years

    Apply thin layer of ointment to affected areas topically once daily for up to 4 weeks. Treatment may be discontinued earlier if control is achieved. 

    Topical dose (foam)
    Adults

    Apply thin layer to affected areas topically once daily for up to 4 weeks. Treatment may be discontinued earlier if control is achieved.

    Topical dose (suspension)
    Adults

    Apply thin layer to affected areas topically once daily for up to 8 weeks. Treatment may be discontinued earlier, if cleared.

    For the treatment of plaque psoriasis of the scalp.
    Topical dose (suspension)
    Adults

    Apply directly to the affected areas of the scalp once daily for up to 8 weeks. Treatment may be discontinued earlier, if cleared.

    Children and Adolescents 12 to 17 years

    Apply directly to the affected areas of the scalp once daily for up to 8 weeks. Treatment may be discontinued earlier, if cleared.

    MAXIMUM DOSAGE

    Adults

    100 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.

    Geriatric

    100 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.

    Adolescents

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

    Children

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

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

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

    ADMINISTRATION

    Topical 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.

    Cream/Ointment/Lotion Formulations

    Topical ointment: Apply a thin film to the affected area and rub into the skin gently and completely.

    Other Topical Formulations

    Topical suspension
    For body application
    Shake well before use. 
    Apply directly to the affected areas of the body. Rub in gently with fingertips.
    Do not take a bath or shower immediately after use.
     
    For scalp application
    Shake well before use. 
    It is not necessary to wash hair prior to application. 
    Apply directly to the affected areas of the scalp. Rub in gently with fingertips. 
    Do not wash hair immediately after use.
     
    Topical foam
    Shake well before use.
    Apply a thin film to the affected area and rub into the skin gently and completely.
    Do not apply more than 60 g every 4 days.
    The propellant is flammable. Avoid fire, flame, and smoking during and immediately following application.

    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:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Taclonex Scalp:
    - Do not refrigerate
    - Product should be used within 3 months after opening
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    Corticosteroid hypersensitivity

    Betamethasone; calcipotriene 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. Although true corticosteroid hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to betamethasone should not receive betamethasone; calcipotriene. 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.

    Hypercalcemia, hypercalciuria, hypervitaminosis D, nephrolithiasis

    The safety and efficacy of betamethasone; calcipotriene 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 betamethasone; calcipotriene 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 betamethasone; calcipotriene 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 does not appear necessary during treatment at recommended dosages.

    Cushing's syndrome

    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/or manifestations of Cushing's syndrome in some patients. HPA axis suppression has been observed with the administration of betamethasone; calcipotriene. Prolonged corticosteroid therapy can aggravate Cushing's syndrome and should be avoided in patients with Cushing's syndrome. Patients receiving large doses or prolonged exposure to betamethasone; calcipotriene should be evaluated periodically for evidence of HPA axis suppression.

    Diabetes mellitus

    Caution should be observed when prescribing betamethasone; calcipotriene 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.

    Peripheral vascular disease

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

    Occlusive dressing, skin abrasion

    Conditions that increase systemic absorption of betamethasone; calcipotriene 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.

    Fungal infection, herpes infection, infection, viral infection

    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 betamethasone; calcipotriene should be discontinued until the infection is controlled.

    Geriatric

    In clinical experience with geriatric patients, no overall differences in safety or effectiveness of betamethasone; calcipotriene 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.

    Skin atrophy

    Betamethasone; calcipotriene should not be used in the presence of pre-existing skin atrophy at the treatment site. If treatment is necessary, then betamethasone; calcipotriene 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.

    Osteoporosis

    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 betamethasone; calcipotriene cautiously in elderly patients, debilitated patients, or postmenopausal patients because they are especially susceptible to these adverse effects.

    Sunlight (UV) exposure

    Calcipotriene may increase the effects of UV radiation on skin tumor formation. Excessive natural or artificial sunlight (UV) exposure should be avoided when betamethasone; calcipotriene 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 betamethasone; calcipotriene.

    Accidental exposure, ocular exposure

    Betamethasone; calcipotriene 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.

    Children, infants, neonates

    Safety and efficacy of betamethasone; calcipotriene ointment and suspension have not been established in neonates, infants, and children younger than 12 years of age. Safety and efficacy of betamethasone; calcipotriene foam have not been established in any pediatric population. 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.

    Pregnancy

    Betamethasone; calcipotriene is classified as FDA pregnancy risk category C. Adequate studies in pregnant women of the combination product have not been conducted; no animal reproductive studies are available. Animal studies investigating the effect of calcipotriene on fetal development have shown the product to be fetotoxic when administered orally. When administered systemically, betamethasone dipropionate has been shown to be teratogenic. Betamethasone; calcipotriene should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.

    Breast-feeding

    It is not known if topically administered betamethasone; calcipotriene 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. Instruct mothers 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 ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Tobacco smoking

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

    ADVERSE REACTIONS

    Severe

    skin atrophy / Delayed / 0.1-1.9
    hypervitaminosis D / Delayed / Incidence not known

    Moderate

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

    Mild

    pruritus / Rapid / 2.8-7.2
    pharyngitis / Delayed / 2.3-2.3
    skin hypopigmentation / Delayed / 0.1-1.4
    paresthesias / Delayed / 0.2-1.4
    folliculitis / Delayed / 0.1-1.4
    skin irritation / Early / 0.4-1.4
    rash (unspecified) / Early / 0.1-1.2
    infection / Delayed / 0-1.0
    ecchymosis / Delayed / 1.0-1.0
    telangiectasia / Delayed / 0.1-0.1
    skin hyperpigmentation / Delayed / 0.1-0.1

    DRUG INTERACTIONS

    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; 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; 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 Salts: (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).
    Collagenase: (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).
    Cyanocobalamin, Vitamin B12: (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).
    Hetastarch; Dextrose; Electrolytes: (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).
    Iron Salts: (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).
    Pantothenic Acid, Vitamin B5: (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.
    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).
    Zinc Salts: (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).

    PREGNANCY AND LACTATION

    Pregnancy

    Betamethasone; calcipotriene is classified as FDA pregnancy risk category C. Adequate studies in pregnant women of the combination product have not been conducted; no animal reproductive studies are available. Animal studies investigating the effect of calcipotriene on fetal development have shown the product to be fetotoxic when administered orally. When administered systemically, betamethasone dipropionate has been shown to be teratogenic. Betamethasone; calcipotriene should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.

    It is not known if topically administered betamethasone; calcipotriene 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. Instruct mothers 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 ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Betamethasone and calcipotriene 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. Betamethasone and calcipotriene 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. 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.
     
    •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).
     
    •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.
     
    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—200 times less potent than calcitriol on calcium metabolism when given systemically. It has been suggested that rapid liver metabolism or extensive metabolism of calcipotriene in epidermal keratinocytes is responsible for this difference. 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 (<100 grams/week). Calcipotriene administered for 4 weeks at the maximum weekly dosage (100 grams/week) resulted in significant increases in urine calcium. Additionally, systemic exposure of topical calcipotriene has been shown to induce alterations in intestinal calcium absorption leading to fluctuations in serum calcium, phosphate, and/or calcitriol levels.

    PHARMACOKINETICS

    Betamethasone; calcipotriene is applied topically to the skin. It is unknown if betamethasone; calcipotriene and its metabolites cross the placenta or are distributed into breast milk.
    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—54 hours. 
    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.

    Topical Route

    The amount of betamethasone; calcipotriene absorbed following topical application is dependent on several factors including the integrity of the epidermal barrier (i.e., the presence of skin damage or inflammation), presence or absence of occlusive dressings, and the site of application (i.e., increased where the stratum corneum is thin such as the eyelids, genitalia, and face). 
    Betamethasone: Topical corticosteroids can be absorbed from normal intact skin, and there may be a small extent of systemic absorption. After topical application to intact skin, up to 14% can be absorbed systemically; the extent is increased in areas of compromised skin integrity or occlusion. Repeated application results in a cumulative depot effect in the skin, which may lead to a prolonged duration of action, increased side effects, and increased systemic absorption.
    Calcipotriene: Approximately 6% of a topical dose of calcipotriene is systemically absorbed when applied to psoriatic skin.