Diflorasone is a high potency, topical, fluorinated corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of moderate to severe corticosteroid-responsive dermatoses. Diflorasone can also be used to treat psoriasis and is available in two different formulations. Very high potency diflorasone is available in an emollient cream and ointment and is comparable in efficacy to betamethasone dipropionate and topical clobetasol. High potency diflorasone is available in a regular cream or ointment formulation and is comparable to amcinonide, fluocinonide and betamethasone dipropionate. Long-term or extensive use can lead to systemic side effects, including hypothalamic-pituitary-adrenal (HPA) axis suppression.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Topical Administration
-For topical dermatologic use only. Not for ophthalmic, oral, or intravaginal use. Diflorasone is not generally recommended for use on the face, groin or in the axillae.
-Restrict application to the active lesions and try to avoid normal surrounding skin.
-The amount of cream or ointment needed to cover a certain area can be calculated. A 1 g application of cream covers 100 cm2 of skin. The entire skin surface of the average size adult will be covered by 30 g of topical steroid cream.
-The manufacturer states that diflorasone may be used under an occlusive dressing for psoriasis or recalcitrant conditions. However, due to the potential for adverse systemic effects with very high potency corticosteroids, occlusive dressings should be used cautiously, if at all.
-High potency corticosteroids such as diflorasone are not recommended for use in the diaper area of infants. If diflorasone is medically necessary, do not use tight fitting diapers or plastic pants on infants, as these garments may constitute occlusive dressings.
-Wash hands before and after application. Use gloves if required by universal precautions. Apply sparingly in a thin film and rub gently into affected area.
-Acute exudative inflammation, as occurs with poison ivy, may be best treated with the non-emollient cream formulation, which is drying. Dry, scaly dermatoses, as occur with eczema or psoriasis, may be best treated with emollient creams or ointments.
When used as directed for limited treatment periods, diflorasone topical preparations are usually well tolerated. The following adverse reactions (listed in decreasing order of occurrence) are reported with topical corticosteroids such as diflorasone and may occur more often when used with an occlusive dressing: skin irritation (including burning), pruritus, xerosis (dry skin), folliculitis, hypertrichosis, acneiform rash/eruptions, skin hypopigmentation, perioral dermatitis, maceration of the skin, secondary infection, skin atrophy, striae, and miliaria. Erythema, telangiectasia, purpura, and maculopapular rash may also occur. Although skin atrophy usually occurs after prolonged use of topical corticosteroids, this effect may occur even with short-term use on intertriginous or flexor areas or on the face. Some dermatologic effects may be permanent with prolonged treatment. If irritation develops, discontinue topical corticosteroids and institute appropriate therapy. The anti-inflammatory activity of topical corticosteroids may mask manifestations of infection. In the presence of dermatological infections, institute the use of an appropriate antifungal or antibacterial agent. If a favorable response does not promptly occur, discontinue the corticosteroid until the infection has been adequately controlled. Hypopigmented skin areas may repigment 1 to 2 months after steroid therapy is discontinued.
Signs and symptoms of corticosteroid withdrawal may occur with diflorasone dose reduction or discontinuation, and supplemental systemic corticosteroids may be needed. For example, disease flare may occur and HPA axis suppression may be present.
Systemic absorption of topical corticosteroids such as diflorasone can produce reversible hypothalamic-pituitary-adrenal (HPA) suppression with possible adrenocortical insufficiency after stopping treatment. In some patients, systemic absorption can produce manifestations of Cushing's syndrome, hypertension, hyperglycemia, and glycosuria. Percutaneous absorption of diflorasone is dependent on many factors including the vehicle, the integrity of the epidermal barrier, duration of use, and use of an occlusive dressing. Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios. HPA axis suppression and increased intracranial pressure have been reported in children receiving topical corticosteroids. Manifestations of adrenocortical insufficiency in children include linear growth inhibition, delayed weight gain, low plasma cortisol concentrations, and absence of response to ACTH stimulation. Clinical signs of intracranial hypertension include bulging fontanelles, headache, and bilateral papilledema (i.e., pseudotumor cerebri). Diflorasone is a very high potency corticosteroid, and the risk of HPA axis suppression is greater than with other topical corticosteroids. Patients applying diflorasone to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression (using the ACTH stimulation test and urinary free cortisol test). To minimize risk of HPA axis suppression, discontinue therapy when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, reduce the frequency of application, or substitute a less potent corticosteroid. Recovery of HPA axis function is usually rapid and complete when diflorasone treatment is discontinued. No evidence of significant systemic effects were reported in a 6-day trial in which subjects applied diflorasone cream or ointment once daily to over 75% of their body surface area. Investigators calculated the daily systemic dose of diflorasone to be roughly 0.35 mg.
Case reports describe visual impairment patients using topical corticosteroids for eczema of the face. The visual impairment was secondary to the onset of ocular hypertension. Such adverse effects, if they occur, could lead to blindness. Cataracts have also been reported, usually with large doses or therapy > 6 months. Any patient who develops changes in vision during topical corticosteroid therapy such as diflorasone should be evaluated for ocular hypertension. Low potency corticosteroids (e.g., hydrocortisone, dexamethasone) have been reported to be safer for short-term use around the eye area.
In general, excessive use of corticosteroids can lead to impaired wound healing. Since diflorasone is a topical corticosteroid, it should not be applied directly on or near healing wounds. A skin ulcer may develop in patients with markedly impaired circulation who use topical corticosteroids.
Tolerance may occur with the prolonged use of topical corticosteroids. Tolerance is usually described as a decreased acute vasoconstrictive response to the agent after a period of days to weeks. This may explain the dramatic responses noted initially by patients early in topical corticosteroid treatment and an apparent diminished response with time. Tolerance is reversible and may be attenuated by interrupted or cyclic schedules of application (e.g., diflorasone is given for 2-3 weeks, followed by a 1-week intermission).
Allergic contact dermatitis with corticosteroids such as diflorasone is usually diagnosed by observing a failure to heal. Appropriate diagnostic patch testing may help with the diagnosis.
Systemic absorption of topical corticosteroids has produced reversible hypothalamic-pituitary-adrenal (HPA) suppression, manifestations of Cushing's syndrome, hyperglycemia, and glucosuria in some patients. Conditions which increase systemic absorption include application of high-potency corticosteroids (such as diflorasone), use over large surface areas, prolonged use, use in areas where the epidermal barrier is disrupted (i.e., skin abrasion), and the use of an occlusive dressing. Patients receiving large doses of a potent topical corticosteroid applied to a large surface area or under an occlusive dressing should be evaluated periodically for evidence of HPA axis suppression using ACTH stimulation, AM plasma cortisol and urinary free-cortisol tests. If HPA axis suppression is noted, an attempt should be made to withdraw the drug, to reduce the frequency of application, or to substitute a less potent corticosteroid. Recovery of HPA axis function is generally prompt and complete upon discontinuation of the topical corticosteroid. Infrequently, signs and symptoms of corticosteroid withdrawal may occur, requiring supplemental systemic corticosteroids.
Topical corticosteroids, like diflorasone, should be used with caution in patients with diabetes mellitus. Exacerbation of diabetes may occur with systemic absorption of the topical corticosteroid. Use of topical corticosteroids may further delay healing of skin ulcers in diabetic patients.
Topical diflorasone preparations are generally not recommended for use in neonates, infants, and children under 12 years of age, except where the benefits of treatment would outweigh the potential risks of therapy. Pediatric patients may absorb proportionally larger amounts of topical corticosteroids due to a larger skin surface area to body weight ratio, and therefore are more susceptible to developing systemic toxicity, especially with very-high-potency products. Parents should be advised not to use tight-fitting diapers or plastic pants on a child being treated in the diaper area, as these garments constitute occlusive dressing and may increase the absorption of the topical corticosteroid. Hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's syndrome, and increased intracranial pressure have been reported in children receiving topical corticosteroids. Chronic corticosteroid therapy in children may also interfere with growth and development, resulting in growth inhibition. Administration of topical corticosteroids to children should be limited to the least amount compatible with an effective therapeutic regimen. Limited data on adverse reactions and efficacy exist for infants and children less than 12 years.
There are no adequate and well-controlled studies of topical application of diflorasone during pregnancy. Topical corticosteroids, including diflorasone, should not be used in large amounts, on large areas, or for prolonged periods of time in pregnant women. Guidelines recommend mild to moderate potency agents over potent corticosteroids, which should be used in short durations. Fetal growth restriction and a significantly increased risk of low birthweight has been reported with use of potent or very potent topical corticosteroids during the third trimester, particularly when using more than 300 grams. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. The more potent corticosteroids have been shown to be teratogenic after dermal application in laboratory animals.
It is not known whether topical administration of diflorasone could result in sufficient systemic absorption to produce detectable quantities in breast milk to cause issues during breast-feeding. However, most dermatologists stress that topical corticosteroids can be safely used during lactation. If applied topically, care should be used to ensure the infant will not come into direct contact with the area of application, such as the breast. Increased blood pressure has been reported in an infant whose mother applied a high potency topical corticosteroid ointment directly to the nipples. 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.
The normal inflammatory response to local infections can be masked by diflorasone. Application of topical corticosteroids to areas of infection, including tuberculosis of the skin, dermatologic fungal infection, and cutaneous or systemic viral infection (e.g., measles or varicella), should be initiated or continued only if the appropriate antiinfective treatment is instituted. Herpes infection may be transmitted to other sites, including the eye. If the infection does not respond to the antimicrobial therapy, the concurrent use of the topical corticosteroid should be discontinued until the infection is controlled. Topical corticosteroids may delay the healing of non-infected wounds, such as venous stasis ulcers. Use diflorasone preparations with caution in patients with markedly impaired circulation or peripheral vascular disease due to the potential for skin ulceration.
As with other potent fluorinated topical corticosteroids, diflorasone should not be used to treat acne vulgaris, acne rosacea, or perioral dermatitis. Diflorasone may aggravate these conditions. In general, diflorasone preparations should not be applied to the face, groin, or axillae. Care should be taken to avoid use around the eyes; ophthalmic administration should be avoided. Visual impairment, ocular hypertension and worsened cataracts have been reported with ocular exposure to other high potency topical corticosteroids. Preexisting glaucoma may be aggravated if diflorasone is used in the periorbital area.
Topical corticosteroids, like diflorasone, should be used for brief periods or under close medical supervision in patients with evidence of pre-existing skin atrophy, especially geriatric patients. Purpura and skin lacerations that may raise the skin and subcutaneous tissue from deep fascia may be more likely to occur with the use of topical corticosteroids in geriatric patients. Use of lower potency topical corticosteroids may be necessary in some patients.
Although true corticosteroid hypersensitivity is rare, patients who have demonstrated a prior hypersensitivity reaction to diflorasone should not receive any form of diflorasone. 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.
For the treatment of corticosteroid-responsive dermatoses, including atopic dermatitis, localized vitiligo, eczema, phimosis, lichen planus, and localized bullous pemphigoid:
Topical dosage (non-emollient cream or ointment, high potency):
Adults: Apply a thin layer topically to the affected skin area(s) 1 to 4 times daily.
Children and Adolescents: Apply a thin layer topically to the affected skin area(s) 1 to 4 times daily.
Topical dosage (emollient cream or ointment, very high potency):
Adults: Apply a thin layer topically to the affected skin area(s) 1 to 3 times daily.
For the treatment of vulvar lichen sclerosus*:
Topical dosage (emollient cream or ointment, very high potency, e.g. Florone E, Psorcon E):
Female Adults, Adolescents and Children: Apply a thin layer to the affected vulvar, labial, and perineal areas twice daily for 6 to 8 weeks. No significant adverse effects were noted during a 6-month to 3-year follow-up of 10 prepubertal girls.
For the treatment of cutaneous T-cell lymphoma (CTCL)* (aka mycosis fungoides*):
Topical dosage (non-emollient cream or ointment, high potency, e.g. Florone, Maxiflor):
Adults and Adolescents: Apply vigorously to the lesioned skin areas twice daily.
Topical dosage (emollient cream or ointment, very high potency, e.g. Florone E, Psorcon E):
Adults and Adolescents: Apply vigorously to the lesioned areas twice daily. One study demonstrated complete remission in 63% of stage T1 patients and 25% of stage T2 patients with patch-stage mycosis fungoides. Total response rates (complete plus partial remission) exceed 80% for stage T2 and 90% for stage T1. The very high potency (Class I compounds) were most effective. The investigators suggest to apply the cream vigorously instead of thinly or sparingly. Thirteen percent of patients experienced reversible suppression of the HPA axis with no clinical side effects. One patient discontinued therapy due to skin atrophy.
For the treatment of psoriasis:
Topical dosage (non-emollient cream or ointment):
Adults: Apply a thin layer topically to the affected skin area(s) 1 to 4 times daily. The duration of the therapy depends on factors such as the topical corticosteroid potency, disease severity and anatomic location, and age. After improvement, may consider transitioning to lower-potency corticosteroid, using intermittent therapy, and combining treatment with noncorticosteroidal agents. Taper by reducing use to every other day, then twice weekly, then discontinue if adequate control is maintained. Guidelines recommend class 1 to 5 topical corticosteroids for up to 4 weeks for plaque psoriasis not involving intertriginous areas and class 1 to 7 topical corticosteroids for a minimum of up to 4 weeks for scalp psoriasis. Use of topical corticosteroids for more than 12 weeks may be considered under careful supervision.
Children and Adolescents: Apply a thin layer topically to the affected skin area(s) 1 to 4 times daily. Guidelines recommend topical corticosteroids as monotherapy for short-term treatment of localized psoriasis.
Topical dosage (emollient cream or ointment):
Adults: Apply a thin layer topically to the affected skin area(s) 1 to 3 times daily. The duration of the therapy depends on factors such as the topical corticosteroid potency, disease severity and anatomic location, and age. After improvement, may consider transitioning to lower-potency corticosteroid, using intermittent therapy, and combining treatment with noncorticosteroidal agents. Taper by reducing use to every other day, then twice weekly, then discontinue if adequate control is maintained. Guidelines recommend class 1 to 5 topical corticosteroids for up to 4 weeks for plaque psoriasis not involving intertriginous areas and class 1 to 7 topical corticosteroids for a minimum of up to 4 weeks for scalp psoriasis. Use of topical corticosteroids for more than 12 weeks may be considered under careful supervision.
Maximum Dosage Limits:
-Adults
50 g/week topically.
-Elderly
50 g/week topically.
-Adolescents
50 g/week topically.
-Children
10 g/week topically.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Metyrapone: (Major) Medications which affect pituitary or adrenocortical function, including all corticosteroid therapy, should be discontinued prior to and during testing with metyrapone. Patients taking inadvertent doses of corticosteroids on the test day may exhibit abnormally high basal plasma cortisol levels and a decreased response to the test. Although systemic absorption of topical corticosteroids is minimal, temporary discontinuation of these products should be considered if possible to reduce the potential for interference with the test results.
Topical corticosteroids exhibit anti-inflammatory, antipruritic, and vasoconstrictive properties. At the cellular level, corticosteroids induce peptides called lipocortins. Lipocortins antagonize phospholipase A2, an enzyme which 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, histamine, 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, keloid (scar) formation also are inhibited by corticosteroids. Clinically, these actions correspond to decreased edema, erythema, pruritus, plaque formation and scaling of the affected skin.
Pharmacokinetics:
Diflorasone is administered topically to the skin as a cream or ointment. Anti-inflammatory effects are usually not seen for several hours after diflorasone application, since the mechanism of action requires alterations in synthesis of proteins. Because diflorasone is fluorinated and also contains a substituted 17-hydroxyl group, it is not metabolized in the skin. Once in the systemic circulation, diflorasone is metabolized in the liver, but systemic metabolism has not been fully quantified. Excretion of diflorasone and its metabolites occurs via the urine and bile.
-Route-Specific Pharmacokinetics
Topical Route
The extent of percutaneous absorption of the topical corticosteroids is dependent on many factors, including the pharmaceutical vehicle and the integrity of the epidermis. In one study, 24 hours after a diflorasone application, 37.5% of the dose had penetrated the skin and 1.1% was systemically absorbed and excreted. Repeated application results in a cumulative depot effect in the skin, which may lead to a prolonged duration of action and increased systemic absorption. Absorption after topical application of diflorasone is increased in areas that have skin damage, inflammation, occlusion, or in areas where the stratum corneum is thin such as the eyelids, genitalia, axillae, and face. The use of occlusive dressings with the application of diflorasone enhances penetration into the skin, and may increase the chance of systemic absorption. Ointments have a hydrating effect, are lipophilic, and enhance the penetration of diflorasone into the skin.