Topical Fluticasone Propionate

Abstract

Synopsis

Fluticasone propionate is a fluoromethyl androstane 17β-carbiothioate that is classified for dermatological use as a moderate potency corticosteroid. It is available in 0.05% cream and 0.005% ointment formulations for the treatment of patients with inflammatory dermatoses responsive to corticosteroids.

Although it demonstrates greater activity than other corticosteroids of similar potency in vasoconstrictor assays in humans, fluticasone propionate demonstrates low potential to cause significant systemic effects such as suppression of the hypothalamopituitary-adrenal (HPA) axis. This is because it has a high affinity for the glucocorticoid receptor and high lipophilicity, and the small amount of drug that is absorbed is rapidly metabolised to the inactive carboxylic acid derivative in the liver (i.e. it has low systemic bioavailability).

In clinical trials, the efficacy of fluticasone propionate cream at 4 weeks did not differ significantly from that of hydrocortisone butyrate 0.1% cream in patients with moderate to severe atopic dermatitis and betamethasone valerate 0.1% cream in patients with moderate to severe psoriasis. Likewise, after 4 weeks, the ointment form of fluticasone propionate had similar efficacy to betamethasone dipropionate 0.05% in patients with psoriasis or atopic dermatitis, although the latter agent may have a faster onset of activity in patients with atopic dermatitis. Fluticasone propionate ointment was generally more effective than hydrocortisone butyrate ointment in patients with psoriasis.

A sustained response was usually observed after about 1 weekś application of fluticasone propionate, and although once and twice daily administration had similar efficacy, a twice daily regimen may have a slightly faster onset of effect.

In trials which included both adults and children, the only adverse events reported were local cutaneous reactions (most frequently, pruritus).

Thus, fluticasone propionate, with its low potential for systemic toxicity and possible advantage of once daily administration, is a useful addition to the topical corticosteroids available for the treatment of psoriasis and atopic dermatitis.

Pharmacological Profile

Vasoconstriction assays in humans showed that fluticasone propionate is more active than beclomethasone dipropionate, betamethasone valerate, triamcinolone acetonide and fluocinolone acetonide. However, it caused little if any significant hypothalamopituitary-adrenal (HPA) axis suppression in studies conducted in patients and healthy volunteers.

Fluticasone propionate binds to the glucocorticoid receptor faster than several other corticosteroids and the fluticasone propionate-receptor complex dissociates more slowly. As a result, this complex (which is responsible for the therapeutic activity of corticosteroids) has a longer half-life than other corticosteroid-receptor complexes. Indeed, fluticasone propionate had a greater in vitro relative receptor affinity than 32 other corticosteroids. Importantly, fluticasone propionate is highly selective for the glucocorticoid receptor and has little or no activity at other steroid receptors.

Fluticasone propionate 0.05% cream produced only 3% skin thinning compared with placebo in a study which used pulsed A-scan ultrasound to assess changes. This effect was independent of the duration of treatment (2, 4, 6 or 8 weeks) in 40 healthy volunteers and was reversed within 2 to 4 weeks of treatment discontinuation.

The commercially available formulation of fluticasone propionate cream was preferred over commercially available preparations of betamethasone valerate, hydrocortisone valerate, fluocinonide, triamcinolone acetonide and mometasone creams in terms of appearance, cosmetic acceptability and physicochemical properties in a blinded laboratory analysis.

The pharmacokinetic profile of fluticasone propionate cream or ointment in healthy volunteers or patients has not been published.

In rats, radiolabelled fluticasone propionate cream or ointment had a long retention time at the application site. After administration of a single 1 g/kg dose (removed from the skin after 24 hours), percutaneous absorption was low with only about 5% of the dose being absorbed through the skin over a 7-day period. Results of in vitro analyses using homogenates of human skin suggest that fluticasone propionate is not metabolised in the skin.

After intravenous administration to 12 healthy volunteers, fluticasone propionate 0.25 to 1mg was extensively distributed within the body and then rapidly cleared by nonsaturable metabolism. Fluticasone propionate is poorly absorbed after oral administration and is then extensively metabolised. Thus, only small amounts of the drug enter the systemic circulation via this route.

The metabolite of fluticasone propionate is a 17β-carboxylic acid derivative which has no corticosteroid activity.

Therapeutic Use

In clinical trials, fluticasone propionate was generally administered for 4 weeks as a 0.05% cream or a 0.005% ointment. All trials were multicentre, randomised and double-blind.

Fluticasone propionate, as an ointment applied twice daily or a cream applied once or twice daily, has significantly superior efficacy to vehicle in patients with moderate to severe atopic dermatitis or psoriasis. Patients with atopic dermatitis receiving once daily fluticasone propionate used approximately half the amount of active treatment that twice daily recipients used and generally achieved a similar response. However, the twice daily regimen tended to have a faster onset of effect.

Sustained improvement is generally noted within 8 days of initiating treatment with fluticasone propionate; pruritus tends to resolve more rapidly than other symptoms.

The efficacy of fluticasone propionate cream is not significantly different from that of hydrocortisone butyrate 0.1% cream in patients with atopic dermatitis: in a trial which included 119 patients, atopic dermatitis was cleared in 36% of fluticasone propionate recipients and 40% of hydrocortisone butyrate recipients at completion of treatment. An additional 39% of fluticasone propionate, and 37% of hydrocortisone butyrate, recipients achieved good or excellent improvement. Similarly, fluticasone propionate 0.05% cream was not significantly different from betamethasone valerate 0.1% cream in 2 trials which enrolled patients with psoriasis.

Although there was no significant difference in efficacy between fluticasone propionate 0.005% and betamethasone dipropionate 0.05% ointments at 4 weeks in patients with moderate to severe atopic dermatitis or psoriasis, betamethasone dipropionate may have a faster onset of action in patients with atopic dermatitis. This formulation of fluticasone propionate was generally more effective than hydrocortisone butyrate 0.1% ointment in patients with psoriasis.

Two studies, each conducted in about 100 children with atopic dermatitis, showed fluticasone propionate 0.05% to have greater efficacy than hydrocortisone 1% cream and hydrocortisone butyrate 0.1% cream, respectively. The creams were applied twice daily for 2 weeks, then as required for 12 weeks.

Tolerability

Although efficacy was usually measured over 4 weeks, patients often received treatment with fluticasone propionate for 2 further 3-week periods; each treatment period was separated by an interval of 1 week, resulting in 12 weeks of study. Tolerability was assessed over the 12-week period in these trials.

Adverse events reported in patients using fluticasone propionate in clinical trials were usually local cutaneous reactions (most commonly pruritus, burning, dryness, stinging, folliculitis, irritation or exacerbation of the dermatological condition) which resolved spontaneously and affected up to 19% of patients. Overall, the most common adverse event reported during use of fluticasone propionate cream or ointment was pruritus.

The tolerability profile of fluticasone propionate cream or ointment was not significantly different from that reported for comparator topical corticosteroids or vehicle in clinical trials.

Fluticasone propionate is associated with a low incidence of systemic adverse events. Indeed, no systemic adverse effects related to application of fluticasone propionate cream or ointment were reported in clinical trials of the drug.

Hypersensitivity reactions are not common with fluticasone propionate cream or ointment; however, several trials excluded patients with a known hypersensitivity or previous reaction to corticosteroids.

Dosage and Administration

Fluticasone propionate 0.05% cream or 0.005% ointment is indicated for the symptomatic relief of inflammation and pruritus in patients with corticosteroid-responsive dermatoses. It should be applied as a thin film which is gently rubbed into affected skin areas once or twice daily. Like other corticosteroids, fluticasone propionate should not be used by patients hypersensitive to corticosteroids, those with rosacea, acne, perioral dermatitis, primary cutaneous viral, bacterial or fungal infections, perianal or genital pruritus, or children aged <1 year.