Fluticasone Propionate Cream USP, 0.05%

Absorption

The activity of fluticasone propionate cream is due to the parent drug, fluticasone propionate. 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 enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.

In a human study of 12 healthy males receiving 12.5 g of 0.05% fluticasone propionate cream twice daily for 3 weeks, plasma levels were generally below the level of quantification (0.05 ng/mL). In another study of six healthy males administered 25 g of 0.05% fluticasone propionate cream under occlusion for 5 days, plasma levels of fluticasone ranged from 0.07 to 0.39 ng/mL.

In an animal study using radiolabeled 0.05% fluticasone propionate cream and ointment preparations, rats received a topical dose of 1 g/kg for a 24 hour period. Total recovery of radioactivity was approximately 80% at the end of 7 days. The majority of the dose (73%) was recovered from the surface of the application site. Less than 1% of the dose was recovered in the skin at the application site. Approximately 5% of the dose was absorbed systemically through the skin. Absorption from the skin continued for the duration of the study (7 days), indicating a long retention time at the application site.

Distribution

Following intravenous administration of 1 mg fluticasone propionate in healthy volunteers, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The apparent volume of distribution averaged 4.2 L/kg (range 2.3-16.7 L/kg). The percentage of fluticasone propionate bound to human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin.

Metabolism

1. No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate. The total blood clearance of systemically absorbed fluticasone propionate averages 1,093 mL/min (range 618-1,702 mL/min) after a 1 mg intravenous dose, with renal clearance accounting for less than 0.02% of the total. Fluticasone propionate is metabolized in the liver by cytochrome P450 3A4-mediated hydrolysis of the 5-fluoromethyl carbothioate grouping. This transformation occurs in 1 metabolic step to produce the inactive 17-β-carboxylic acid metabolite, the only known metabolite detected in man.
   This metabolite has approximately 2,000 times less affinity than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.

Excretion

Following intravenous dose of 1 mg in healthy volunteers, fluticasone propionate showed polyexponential kinetics and had an average terminal half-life of 7.2 hours (range 3.2-11.2 hours).

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's syndrome, hyperglycemia and glucosuria can also be produced in some patients by systemic absorption of topical corticosteroids while on treatment.

Patients applying a potent 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.

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 steroid. 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.

Fluticasone propionate cream, 0.05% caused depression of A.M. plasma cortisol levels in 1 of 6 adult patients when used daily for 7 days in patients with psoriasis or eczema involving at least 30% of the body surface. After 2 days of treatment, this patient developed a 60% decrease from pretreatment values in the A.M. plasma cortisol level. There was some evidence of corresponding decrease in the 24-hour urinary free cortisol levels. The A.M. plasma cortisol level remained slightly depressed for 48 hours but recovered by day 6 of treatment.

Fluticasone propionate cream, 0.05%, caused HPA axis suppression in 2 of 43 pediatric patients, ages 2 and 5 years old, who were treated for 4 weeks covering at least 35% of the body surface area. Follow-up testing 12 days after treatment discontinuation, available for 1 of the 2 subjects, demonstrated a normally responsive HPA axis (see PRECAUTIONS: Pediatric Use).

Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios (see PRECAUTIONS: Pediatric Use).

Fluticasone propionate cream, 0.05%, may cause local cutaneous adverse reactions (see ADVERSE REACTIONS).

1. Fluticasone propionate cream, 0.05% contains the excipient imidurea which releases traces of formaldehyde as a breakdown product. Formaldehyde may cause allergic sensitization or irritation upon contact with the skin.

If irritation develops, fluticasone propionate cream, 0.05% 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 fluticasone propionate cream, 0.05% should be discontinued until the infection has been adequately controlled.

Fluticasone propionate cream, 0.05% should not be used in the presence of preexisting skin atrophy and should not be used where infection is present at the treatment site. Fluticasone propionate cream, 0.05% 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:

1. 1.This medication is to be used as directed by the physician. It is for external use only. Avoid contact with the eyes.
2. 2.This medication should not be used for any disorder other than that for which it was prescribed.
3. 3.The treated skin area should not be bandaged or otherwise covered or wrapped so as to be occlusive unless directed by the physician.
4. 4.Patients should report to their physicians any signs of local adverse reactions.
5. 5.Parents of pediatric patients should be advised not to use this medication in the treatment of diaper dermatitis. Fluticasone propionate cream, 0.05% should not be applied in the diaper areas as diapers or plastic pants may constitute occlusive dressing (see DOSAGE AND ADMINISTRATION).
6. 6.This medication should not be used on the face, underarms, or groin areas unless directed by a physician.
7. 7.As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, contact the physician.

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 a 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 15 and 30 times respectively the human systemic exposure following use of the recommended human topical dose of fluticasone propionate cream, 0.05%, assuming human percutaneous absorption of approximately 3% and the use in a 70-kg person of 15 g/day.

Nursing Mothers

Systemically administered corticosteroids 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 fluticasone propionate cream, 0.05% is administered to a nursing woman.

Pediatric Use

Fluticasone propionate cream, 0.05% may be used with caution in pediatric patients as young as 3 months of age. The safety and efficacy of drug use for longer than 4 weeks in this population have not been established. The safety and efficacy of fluticasone propionate cream, 0.05% in pediatric patients below 3 months of age have not been established.

Fluticasone propionate cream, 0.05%, caused HPA axis suppression in 2 of 43 pediatric patients, ages 2 and 5 years old, who were treated for 4 weeks covering at least 35% of the body surface area. Follow-up testing 12 days after treatment discontinuation, available for 1 of the 2 subjects, demonstrated a normally responsive HPA axis (see ADVERSE REACTIONS). Adverse effects including striae have been reported with use of topical corticosteroids in pediatric patients.

HPA axis suppression, Cushing's 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 to an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

Geriatric Use

A limited number of patients above 65 years of age (n=126) have been treated with fluticasone propionate cream in US and non-US clinical trials. While the number of patients is too small to permit separate analysis of efficacy and safety, the adverse reactions reported in this population were similar to those reported by younger patients. Based on available data, no adjustment of dosage of fluticasone propionate cream in geriatric patients warranted.

Atopic Dermatitis

Apply a thin film of fluticasone propionate cream, 0.05% to the affected skin areas once or twice daily. Rub in gently.

Other Corticosteroid-Responsive Dermatoses

Apply a thin film of fluticasone propionate cream, 0.05% to the affected skin areas twice daily. Rub in gently.

1. As with other corticosteroids, therapy should be discontinued when control is achieved. If no improvement is seen within 2 weeks, reassessment of diagnosis may be necessary.
2. Fluticasone propionate cream, 0.05% should not be used with occlusive dressings. Fluticasone propionate cream, 0.05% should not be applied in the diaper area: as diapers or plastic pants may constitute occlusive dressings.

Geriatric Use

In studies where geriatric patients (65 years of age or older, see PRECAUTIONS) have been treated with fluticasone propionate cream, 0.05%, safety did not differ from that in younger patients; therefore, no dosage adjustment is recommended.

Psoriasis Studies

In 2 vehicle-controlled studies, fluticasone propionate cream, 0.05% applied twice daily was significantly more effective than the vehicle in the treatment of moderate to severe psoriasis. The investigator's global evaluation after 28 days of treatment is shown in Table 3.

The clinical signs of psoriasis were scored on a scale of 0 = absent, 1 = mild, 2 = moderate, and 3 = severe. The mean improvements over baseline in the clinical signs at the end of treatment are shown in Table 4.

Atopic Dermatitis Studies: In 2 controlled 28-day studies. Fluticasone propionate cream, 0.05% once daily was equivalent to fluticasone propionate cream, 0.05% twice daily in the treatment of moderate to severe eczema. The investigator's global evaluation after 28 days of treatment is shown in Table 5.

The clinical signs and symptoms of atopic dermatitis were scored on a scale of 0 = absent, 1 = mild, 2 = moderate, 3 = severe. The mean improvements over baseline at the end of treatment are shown in Table 6.