CUTIVATE Ointment, 0.005% contains fluticasone propionate [(6(alpha),11(beta),16(alpha),17(alpha))-6,9,-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy) androsta-1,4-diene-17-carbothioic acid, S-fluoromethyl ester], a synthetic fluorinated corticosteroid, for topical dermatologic use. The topical corticosteroids constitute a class of primarily synthetic steroids used as anti-inflammatory and antipruritic agents.
Chemically, fluticasone propionate is C 25 H 31 F 3 O 5 S.
Fluticasone propionate has a molecular weight of 500.6. It is a white to off-white powder and is insoluble in water.
Each gram of CUTIVATE Ointment contains fluticasone propionate 0.05 mg in a base of propylene glycol, sorbitan sesquioleate, microcrystalline wax, and liquid paraffin.
Like other topical corticosteroids, fluticasone propionate has anti-inflammatory, antipruritic, and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase A 2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Archidonic acid is released from membrane phospholipids by phospholipase A 2 .
: The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressing with hydrocortisone for up to 24 hours has not been demonstrated to increase penetration; however, occlusion of hydrocortisone for 96 hours markedly enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.
Studies performed with CUTIVATE Ointment indicate that it is in the medium range of potency as compared with other topical corticosteroids.
CUTIVATE Ointment is a medium potency corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.
CUTIVATE Ointment is contraindicated in those patients with a history of hypersensitivity to any of the components of the preparation.
General: Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal from treatment. Manifestations of Cushing' syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment.
Patients applying a topical steroid to a large surface area or to areas under occlusion should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, A.M. plasma cortisol, and urinary free cortisol tests.
Fluticasone propionate ointment, 0.05% (a concentration 10 times that of fluticasone propionate ointment, 0.005%) suppressed 24-hour urinary free cortisol levels in 2 of 6 patients when used at a dose of 30 g/day for a week in patients with psoriasis or atopic eczema. In a second study, fluticasone propionate ointment, 0.05% caused depression of A.M. plasma cortisol levels in 3 of 12 normal volunteers when applied at doses of 50 g/day for 21 days. Morning plasma levels returned to normal levels within the first week upon discontinuation of fluticasone propionate. In this study there was no corresponding decrease in 24-hour urinary free cortisol levels.
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 upon discontinuation of topical corticosteroids. Infrequently, signs and symptoms of glucocorticosteroid insufficiency may occur, requiring supplemental systemic corticosteroids. For information on systemic supplementation, see prescribing information for those products.
Children may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios (see PRECAUTIONS : Pediatric Use).
If irritation develops, CUTIVATE Ointment should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation as with most topical products not containing corticosteroids. Such an observation should be corroborated with appropriate diagnostic patch testing.
If concomitant skin infections are present or develop, an appropriate antifungal or antibacterial agent should be used. If a favorable response does not occur promptly, use of CUTIVATE Ointment should be discontinued until the infection has been adequately controlled.
CUTIVATE Ointment should not be used in the treatment of preexisting skin atrophy and should not be used where infection is present at the treatment site. CUTIVATE Ointment should not be used in the treatment of rosacea and perioral dermatitis.
Information for Patients: Patients using topical corticosteroids should receive the following information and instructions:
Laboratory Tests: The following tests may be helpful in evaluating patients for HPA axis suppression:
ACTH stimulation test
A.M. plasma cortisol test
Urinary free cortisol test
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Two 18-month studies were performed in mice to evaluate the carcinogenic potential of fluticasone propionate when given topically (as an 0.05% ointment) and orally. No evidence of carcinogenicity was found in either study.
Fluticasone propionate was not mutagenic in the standard Ames test, E. coli fluctuation test, S. cerevisiae gene conversion test, or Chinese Hamster ovarian cell assay. It was not clastogenic in mouse micronucleus or cultured human lymphocyte tests.
In a fertility and general reproductive performance study in rats, fluticasone propionate administered subcutaneously to females at up to 50 mcg/kg per day and to males at up to 100 mcg/kg per day (later reduced to 50 mcg/kg per day) had no effect upon mating performance or fertility. These doses are approximately 150 and 300 times, respectively, the human systemic exposure following use of the recommended human topical dose of fluticasone propionate ointment, 0.005%, assuming human percutaneous absorption of approximately 3% and the use in a 70-kg person of 15 g/day.
Pregnancy Teratogenic Effects: Pregnancy Category C. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. Teratology studies in the mouse demonstrated fluticasone propionate to be teratogenic (cleft palate) when administered subcutaneously in doses of 45 mcg/kg per day and 150 mcg/kg per day. This dose is approximately 140 and 450 times, respectively, the human topical dose of fluticasone propionate ointment, 0.005%. There are no adequate and well-controlled studies in pregnant women. CUTIVATE Ointment should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Systemically administered cortico-steroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Because many drugs are excreted in human milk, caution should be exercised when CUTIVATE Ointment is administered to a nursing woman.
HPA axis suppression, Cushing' syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids. Manifestations of adrenal suppression in pediatric patients include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.
In controlled clinical trials, the total incidence of adverse reactions associated with the use of CUTIVATE Ointment was approximately 4%. These adverse reactions were usually mild, self-limiting, and consisted primarily of pruritus, burning, hypertrichosis, increased erythema, hives, irritation, and lightheadedness. Each of these events occurred individually in less than 1% of patients.
The following additional local adverse reactions have been reported infrequently with topical corticosteroids, including fluticasone propionate, and they may occur more frequently with the use of occlusive dressings and higher potency corticosteroids. These reactions are listed in an approximately decreasing order of occurrence: dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria. Also, there are reports of the development of pustular psoriasis from chronic plaque psoriasis following reduction or discontinuation of potent topical corticosteroid products.
Topically applied CUTIVATE Ointment can be absorbed in sufficient amounts to produce systemic effects (see PRECAUTIONS ).
Apply a thin film of CUTIVATE Ointment to the affected skin areas twice daily. Rub in gently.
CUTIVATE Ointment, 0.005% is supplied in 15-g (NDC 0173-0431-00), 30-g (NDC 0173-0431-01), and 60-g (NDC 0173-0431-02) tubes.
Glaxo Wellcome Inc., Research Triangle Park, NC 27709