Drug Substance

Proper Name: fluticasone propionate (BAN, INN, USAN)

Chemical Name: S-fluoromethyl 6α,9α-difluoro-llβ-hydroxy-16α-methyl-3-oxo-17α-propionyloxyandrosta-l,4-diene-17β-carbothioate

Structural Formula:

Molecular Formula: C₂₅H₃₁F₃0₅S

Molecular Weight: 500.6

Description: Fluticasone propionate is a white to off-white powder.

Solubility: Fluticasone propionate is freely soluble in dimethyl sulfoxide and dimethylformamide, sparingly soluble in acetone, dichlo-romethane, ethyl acetate and chloroform, slightly soluble in methanol and 95% ethanol, and practically insoluble in water.

Melting Point: Fluticasone propionate decomposes without melting.Onset of decomposition occurs at about 225ûC.

Composition

Each gram of CUTIVATE (fluticasone propionate) Cream, 0.05% w/w contains fluticasone propionate 500 micrograms in a cream base. Non-medicinal ingredients: propylene glycol, mineral oil, cetostearyl alcohol, polyoxyl 20 cetostearyl ether, isopropyl myristate, dibasic sodium phosphate, citric acid, purified water and imidurea as a preservative.

CUTIVATE (fluticasone propionate) Cream, 0.05% is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. Studies performed with CUTIVATE Cream, 0.05% indicate that this is in the medium range of potency as compared with other topical corticosteroids.

Eczema: Apply a thin film of CUTIVATE (fluticasone propionate) Cream to the affected skin areas once or twice daily. Rub in gently.

Other Corticosteroid Responsive Dermatoses: Apply a thin film of CUTIVATE Cream 0.05% to the affected skin areas twice daily. Rub in gently.

Stability and Storage Recommendations

Store between 2° and 30°C.

Availability of Dosage

CUTIVATE (fluticasone propionate) Cream, 0.05% is supplied in 15 and 60 g tubes.

GlaxoSmithKline Consumer Healthcare Inc. 2030 Bristo Circlel, Oakville, Ontario. Date of Preparation: July 26, 2004. FAD Rev date: 4/16/2002

In controlled clinical trials, the total incidence of adverse reactions associated with the use of fluticasone propionate cream, 0.05% was approximately 4%. These adverse reactions were mild and self-limiting. For fluticasone propionate cream 0.05%, these reactions consisted primarily of pruritus, dryness, numbness of fingers, and burning. These events occurred in 2.9%, 1.2%, 1.0% and 0.6% of patients, respectively.

The following additional local adverse reactions have been reported infrequently with other topical corticosteroids, and they may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids. These reactions are listed in an approximately decreasing order of occurrence: irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, dilation of the superficial blood vessels and miliaria. Also, there are reports of the development of pustular psoriasis from chronic plaque psoriasis following reduction or discontinuation of potent topical steroid products.

In a clinical study that compared once daily to twice daily dosing of CUTIVATE (fluticasone propionate) cream, the local adverse events that were considered to be drug related were as follows.

Drug Related Adverse Events - Skin

No Information Provided.

Cutivate should not be used under occlusive dressing.

Avoid prolonged application to the face since the face, more than other areas of the body, may exhibit atrophic changes after prolonged treatment with potent topical corticosteroids. This must be borne in mind when treating such conditions as psoriasis, discoid lupus erythematosus and severe eczema.

If applied to the eyelids, care is needed to ensure that the preparation does not enter the eye to avoid the risk of local irritation or glaucoma.

General

Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticos-teroid insufficiency after withdrawal from treatment. Manifestations of CushingÕs syndrome, hyperglycemia, and glucosuria can also be produced in some patients by systemic absorption while on therapy.

Patients receiving a large dose of a potent topical steroid applied to a large surface area or under occlusive dressing should be evaluated periodically for evidence of HPA axis suppression. This may be done by using the ACTH stimulation, morning plasma cortisol, and urinary free cortisol tests.

Fluticasone propionate cream, 0.05% produced HPA axis suppression within seven days when used at a dose of 30 g per day in diseased patients. In a study of the effects of fluticasone propionate cream, 0.05% on the HPA axis, a total of 30 g per day was used in two applications daily for seven days to six patients with psoriasis or atopic dermatitis involving at least 30% of the body surface. One patient developed evidence of adrenal suppression after six days of treatment with a below normal plasma cortisol level that returned to low normal levels the following day. Another patient developed a 60% decrease (although never below normal) in the plasma cortisol level from pre-treatment values after 2 days of treatment. This suppression persisted at this level for 48 hours before recovering by day six of treatment. The results of this study indicate that fluticasone propionate cream, 0.05% may be able to suppress the HPA axis within a few days with a dose of 30g per day.

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 and complete upon discontinuation of topical glucocorticosteroids. Infrequently, signs and symptoms of glucocor-ticosteroid insufficiency may occur that require supplemental systemic corticos-teroids.For information on systemic supplementation, see prescribing information for those products.

Topical steroids may be hazardous in psoriasis for a number of reasons, including rebound relapses, development of tolerances, risk of generalized pustular psoriasis and development of local or systemic toxicity due to impaired barrier function of the skin. If used in psoriasis, careful patient supervision is important.

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 favourable response does not occur promptly, use of fluticasone propionate cream, 0.05% should be discontinued until the infection has been adequately controlled.

Use in Children

Safety and effectiveness in children and infants have not been established. Because of a higher ratio of skin surface to body mass, children are at greater risk than adults of HPA axis suppression when they are treated with topical corticos-teroids. Therefore, they are also at greater risk of glucocorticosteroid insufficiency after withdrawal of treatment and of CushingÕs syndrome while on treatment. Adverse effects including striae have been reported with inappropriate use of topical corticosteroids in infants and children.Calculation of the appropriate dosage for children should allow for their greater surface area to body weight.

HPA axis suppression, CushingÕs syndrome, and intracranial hypertension have been reported in children receiving topical corticosteroids. Manifestations of adrenal suppression in children include linear growth retardation, delayed weight gain, low plasma cortisol levels, and absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headache, and bilateral papilledema.

Use in Pregnancy

Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dose levels. The more potent corticos-teroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women. Fluticasone propionate ointment and cream should be used during pregnancy only if the potential benefit to the woman justifies the potential risk to the fetus.

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 corticos-teroids 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.

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.

Symptoms and Treatment of Overdosage

Overdosage may cause the features of hypercorticism to appear. As with any corticosteroid, treatment should be discontinued if the symptoms of hypercorticism appear.Topically applied fluticasone propionate cream, 0.05% can be absorbed in sufficient amounts to produce systemic effects. (See PRECAUTIONS)

Fluticasone propionate cream, 0.05% is not indicated in patients with a hypersensitivity to any of the components. The preparation also contraindicated in the treatment of rosacea, acne vulgaris, perioral dermatitis, primary cutaneous viral infections (i.e., herpes simplex, chickenpox), perianal and genital pruritus, primarily infected skin lesions caused by infection with fungi or bacteria and dermatoses in children, including dermatitis and diaper rash.

Fluticasone propionate is a synthetic, fluorinated corticosteroid. Like other topical corticosteroids, fluticasone propionate has anti-inflammatory, anti-pruritic, 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 A₂ 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, which is released from membrane phospholipids by phospholipase A₂.

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, while inflammation and/or other disease processes in the skin increase percutaneous absorption.

Fluticasone propionate is lipophilic and has a strong affinity for the glucocorticoid receptor. It has weak affinity to the progesterone receptor, and virtually no affinity for the mineralocorticoid, estrogen, or androgen receptors.The therapeutic potency of glucocorticoids is related to the half-life of the glucocorticoid-receptor complex. Fluticasone propionate binding to the glucocorticoid receptor is rapid.

The half life of the fluticasone propionate-glucocorticoid receptor complex is approximately 10 hours.

Fluticasone propionate absorbed systemically is rapidly metabolized in the liver by esterase -catalyzed hydrolysis to the 17-beta-carboxylic acid which has no significant glucocorticoid or anti-inflammatory activity.

Pharmacology

Animals

Fluticasone propionate was shown to be approximately twice as potent in topical activity as beclomethasone according to the McKenzie vasoconstrictor assay.

Although relative vasoconstrictor activity does not necessarily imply similar relative therapeutic efficacy, evidence for local anti-inflammatory action without systemic effects has been demonstrated by studies in laboratory animals and confirmed in human clinical pharmacology studies.

Animal studies of the relative anti-inflammatory and hypothalamic-pituitary-adrenal (HPA) axis inhibitory potencies of topically applied drug demonstrated that fluticasone propionate has an advantageous therapeutic index ( > 200 times that of beclomethasone dipropionate).

Studies in rodents were conducted to quantitate and compare anti-inflammatory activity after topical administration of fluticasone propionate and the ability to produce specific systemic steroid-related effects after topical, oral or parenteral administration.

Topical anti-inflammatory activity was measured in rats and mice using the inflammatory response to croton oil applied topically to the ear. Results showed that fluticasone propionate was essentially equipotent with fluocinolone acetonide in both rats and mice.

Systemic responses to repeated topical applications of fluticasone propionate were assessed by measurement of thymus involution and reduction in stress-induced plasma corticosterone (HPA axis suppression) in rats and mice, and adrenal atrophy in the rat. In these tests, fluticasone propionate was 50-100-fold less potent than fluocinolone acetonide in the rat (56-fold greater therapeutic index) and 100 times less potent than fluocinolone acetonide in mice (relative therapeutic index 91). Therefore, in both species, the separation between topical anti-inflammatory and systemic activity after topical application, was highly favourable to fluticasone propionate.

Comparison of systemic activity after topical and subcutaneous dosing of flutica-sone propionate showed that, in both rats and particularly in mice, fluticasone propionate is more potent when given subcutaneously.

In rats, fluticasone propionate given subcutaneously was compared with betamethasone alcohol and fluocinolone acetonide using thymus involution, adrenal atrophy, and inhibition of carrageenin granuloma formulation as assessments of systemic activity. Fluticasone propionate was equipotent with betametha-sone alcohol and between 13 and 38 times less potent than fluocinolone acetonide.

In mice, using thymus involution and HPA axis suppression, fluticasone propionate given subcutaneously, was approximately equipotent with betamethasone alcohol and approximately 4 times less potent than fluocinolone acetonide.

After oral dosing in the rat, fluticasone propionate caused some thymus involution, adrenal atrophy and HPA axis suppression but was 6 to 38 times less potent than betamethasone alcohol. In the mouse, oral fluticasone propionate is 60 to 200 times less potent than betamethasone alcohol.

Fluticasone propionate was screened for a wide range of steroid hormonal or anti-hormonal activity.To ensure significant systemic exposure fluticasone propionate was administered subcutaneously to rats and mice, and was found to be devoid of androgenic, anabolic, oestrogenic, and anti-gonadotrophic activity. Fluticasone propionate had some progestational activity in oestrogen-primed weanling rabbits, and also showed some anti-androgenic and anti-oestrogenic activity. Weak anti-anabolic activity, another characteristic of potent glucocorticoids, was observed in the castrated rat. Fluticasone propionate lacked mineralocorticoid activity but caused significant diuresis and urinary excretion of sodium and potassium.

Pharmacokinetics

Pharmacokinetic data from rat, dog and man indicate that clearance is high relative to hepatic blood flow. Consequently, first-pass metabolism is extensive and oral bioavailability is negligible.

Studies examining the distribution of radio labelled fluticasone propionate in the rat have shown that orally-administered drug is absorbed and then excreted in the bile on first-pass through the liver. Thus, only minute traces of radioactivity pass into the systemic circulation.

The vast majority of a radio labelled dose following intravenous (rat and dog), oral and subcutaneous (mouse, rat and dog) administration is excreted via the faeces, and evidence from bile duct-cannulated animals indicates that the major route of excretion is via the bile. Renal excretion is of minor importance, as urinary excretion accounts for less than 5% of a parenteral dose. No unchanged drug is excreted in the bile of rats or dogs, but a significant amount, (up to 40%) of unchanged compound was found in the faeces of dogs dosed orally with flutica-sone propionate.

Thus, the low oral bioavailability of fluticasone propionate expected due to extensive first-pass metabolism is compounded by incomplete absorption from the gastrointestinal tract particularly in the dog. The major route of metabolism in rat, dog and humans is the hydrolysis of the fluorinated carbothioate group to yield the inactive carboxylic acid.

When administered orally to pregnant rats (100 µg/kg) or rabbits (300 µg/kg), a very small fraction of the dose ( < 0.005%) passes across the placenta.

Studies performed in rats following topical administration of radio labelled flutica-sone propionate cream or ointment have shown that only about 5% of the dose is absorbed through the skin, the majority of which is excreted in the faeces. The majority of the dose (73%) is recovered from the surface of the application site. Fluticasone propionate is stable and is not metabolized by dermal enzymes when incubated with human skin homogenates in vitro or when applied dermally to rats.

Human

In human volunteers, fluticasone propionate was 9.5 times more potent than fluoci-nolone acetonide and intermediate in potency between betamethasone-17-valerate (less potent) and clobetasol- 17-propionate (more potent).

No evidence of HPA axis suppression was seen in 45 healthy volunteers who repeatedly applied large amounts (between 30 g and 50 g per day) of fluticasone propionate ointment or cream formulations with or without occlusion. This was despite the fact that 15 of the 45 volunteers had applied 0.05% fluticasone propionate ointment (a ten-fold higher concentration of ointment than that currently marketed). The minimal effects on the HPA axis probably result from the relatively poor penetration of fluticasone propionate through the various layers of the skin.

Specialized studies have shown fluticasone propionate to have no potential to cause irritancy, contact sensitization, photo toxicity or photo contact allergenicity, despite the aggressive nature of the dosing schedules employed. Fluticasone propionate ointment (0.05%) and cream (0.005% and 0.05%) preparations were applied in volumes of 0.1 mL for up to 26 days in these specialised studies.

Pharmacokinetics

The pharmacokinetic characteristics following administration of fluticasone propionate in man are similar to those of other glucocorticoids, except that oral bioavailability is extremely low. This low oral bioavailability, coupled with high plasma clearance and efficient biliary excretion of metabolites, enhances the topical versus systemic effects. Studies with radio labelled and unlabelled flutica-sone propionate administered orally to human volunteers indicate that the majority of the dose (87%-100%) is excreted in the faeces, with up to 75% as unchanged drug, depending on the dose administered. Between 1% and 5% of the dose is excreted as metabolites in urine.

Single intravenous doses of 2 mg in healthy volunteers revealed that the clearance of fluticasone propionate approximates liver blood flow, with renal clearance accounting for less than 1%.These results indicate that hepatic extraction is almost complete and that oral bioavailability is close to zero. The plasma elimination half-life is approximately 3 hours, and the volume of distribution is approximately 260 L.

The poor penetration of fluticasone propionate, suggested from the minimal effects on the HPA axis, was also evidenced by low plasma concentrations after dermal application. The application of 12.5 g of 0.05% fluticasone propionate cream twice daily for 21 days without occlusion to healthy male volunteers resulted in trough plasma concentrations generally below the limit of detection (0.05 ng/mL) throughout the study.

Maximum trough levels of 0.069 to 0.39 ng fluticasone propionate/mL were observed following the twice daily application of 50 g of 0.05% fluticasone propionate cream under occlusion for 5 days.

The twice daily application of 25 g of 0.005% fluticasone propionate ointment under occlusion for 5 days to healthy male volunteers resulted in maximum trough levels in the range of 0.22 to 0.77 ng/mL.

Toxicology

Acute Toxicity

Pharmacokinetic studies in the rat have shown that only 5% of the dermal dose is absorbed through the skin.

However, intravenous and subcutaneous dosing allows toxicity to be fully charac-terised after maximal systemic exposure.

The results of the acute toxicity studies with fluticasone propionate administered by inhalation, orally, subcutaneously and intravenously, demonstrated a large margin of safety over the anticipated exposure of humans following the dermal application of cream preparations containing 0.05% fluticasone propionate. Systemic exposure following the dermal application of 0.05% cream would be 45 µg/kg, assuming human percutaneous absorption of approximately 5% and the use in a 50 kg person of 90 g of cream in one day.The approximate LD₅₀ values are shown in the following table:

High oral doses of 1 g/kg were well tolerated in both the mouse and rat. The only (reversible) changes observed were a slowing in growth rate and microscopically-evident cortical depletion of the thymus of animals killed 3 days after dosing.

Subcutaneous doses of fluticasone propionate at 1 g/kg were administered to mice and rats. Animals progressively lost condition and body weight and the effects seen were thymic depletion and various lesions associated with a compromised immune system. In addition, gastric steroid ulcers were seen.These observed changes are the expected response to glucocorticoid therapy. The lack of reversible thymic effects in subcutaneously-dosed animals is almost certainly due to the deposition and leaching of insoluble steroid from the injection site.

When given intravenously to rats at a dose of 2 mg/kg, the only changes seen were slightly subdued behaviour immediately after treatment and reversible thymic involution.

Chronic Toxicity

Subacute toxicity studies were conducted in adult and juvenile rats for periods up to 35 days and in Beagle dogs for periods up to 44 days. Fluticasone propionate was administered as follows:

Clinical observations were similar for all routes of administration in both species. These consisted of reduced weight gain and general loss of condition. Inhalation studies in the dog resulted in clinical signs associated with the administration of a potent glucocorticoid and were consistent with the symptoms of Canine CushingsÕ Syndrome.

Changes typical of glucocorticoid overdosage were seen in both haematological and clinical chemistry parameters. Effects were seen on the red cell parameters and a characteristic leukopenia resulting from a lymphopenia accompanied by a neutrophilia. Endogenous cortisol and corticosterone were depressed in dogs and rats respectively.

Microscopic pathology was again consistent with the administration of a potent glucocorticoid showing thymic and adrenal atrophy, lymphoid depletion in rats and dogs and glycogenic vacuolation of the liver in dogs.

There were no specific effects on the maturation of juvenile rats after subcutaneous dosing.

The application of a cream formulation containing 0.05% fluticasone propionate and an ointment containing 0.05, 0.10 or 0.20% w/w fluticasone propionate to the abraded skin of rats for up to 35 days did not compromise the healing of damaged areas of skin. Some skin thinning was observed at the site of application. Expected glucocorticoid effects, namely reduced body weight gain and slight changes in hematology and clinical chemistry, were observed. However, absorption of flutica-sone propionate was of a low order as no significant differences were observed in the corticosterone levels between treated and control animals.

Fluticasone propionate ointment was well tolerated following daily applications to the skin of the rat at dose levels of 0.05, 0.10 and 0.20% w/w for 26 weeks. Thinning of the skin at the application sites, due to slight to moderate thinning of the dermal collagen, together with loss of fat was observed.

Daily dermal administration of 0.8% w/w of fluticasone propionate ointment under occlusion for up to 6.5 hours per day to Beagle dogs for 26 weeks was also well tolerated. A single papilloma was observed at the treatment site in each of 2 dogs at the high dose level. This may have been a consequence of local immunosup-pression. Three dogs at the high dose level showed moderate to large diffuse corneal opacities at the end of treatment. These animals had intercurrent ocular infections during the study. Increased susceptibility to ocular infection in these dogs may have occurred in part as a result of the recognised immunosuppressive effect of corticosteroids.

Mutagenicity

Fluticasone propionate did not induce gene-mutation in prokaryotic microbial cells and there was no evidence of toxicity or gene-mutational activity in eukaryotic Chinese hamster cells in vitro. The compound did not induce point-mutation in the Fluctuation assay, and did not demonstrate gene-convertogenic activity in yeast cells. No significant clastogenic effect was seen in cultured human peripheral lymphocytes in vitro and fluticasone propionate was not demonstrably clastogenic in the mouse micronucleus test when administered at high doses by oral or subcutaneous routes. Furthermore, the compound did not delay erythroblast division in bone marrow.

Reproduction and Teratology

Subcutaneous studies in the mouse and rat at 150 and 100 µg/kg/day respectively, revealed maternal and foetal toxicity characteristic of potent glucocorticoid compounds, including reduction in maternal weight gain, embryonic growth retardation, increased incidences of retarded cranial ossification, and of omphalo-coele and cleft palate in rats and mice, respectively. In the rabbit, subcutaneous doses of 30 µg/kg/day and above were incompatible with sustained pregnancy. This is not unexpected since rabbits are known to be particularly sensitive to glucocorticoid treatment.

Following oral administration of fluticasone propionate up to 300 µg/kg to the rabbit, there were no maternal effects nor increased incidence of external, visceral, or skeletal foetal defects. A very small fraction ( < 0.005%) of the dose crossed the placenta following oral administration to rats (100 µg/kg /day) and rabbits (300 µg/kg/day).

Carcinogenicity

No treatment related effects were observed on the type or incidence of neoplasia in an 80 week dermal oncogenicity study in mice treated with a 0.05% fluticasone propionate ointment, in an 18 month oral (gavage) study in mice administered fluticasone propionate at dose levels of up to 1 mg/kg/day. In a lifetime (2 years) snout-only inhalation study in rats, at dose levels of up to 57 µg/kg/day, there was an increase in the incidence of tumours in the mammary gland, liver and pancreas. These were not considered as evidence of tumorogenic effect of fluticasone propionate based on the absence of statistical support of an increase in incidence and the historical tumour data.

Local Tolerance

Little or no irritancy was observed following the application of ointment formulations containing up to 0.1% fluticasone propionate either as daily doses for 35 days to the skin of the rat or as single dose, non-occluded or occluded tests on intact or abraded guinea pig skin. Negligible irritancy was produced following the application of fluticasone propionate cream or ointment (containing up to 0.05% w/w flutica-sone propionate) formulations as single occluded doses on intact and abraded skin and as a series of 4 daily repeated non-occluded doses on the intact skin of the guinea pig.

A single application of 0.05% w/w fluticasone propionate ointment or cream to abraded skin sites on rats did not affect the normal wound healing process. Micronised fluticasone propionate was considered to be non-irritating in the rabbit eye when assessed using a modified Draize test and in the guinea pig split adjuvant test for evaluating contact sensitivity, results were completely negative.

REFERENCES OR SELECTED BIBLIOGRAPHY

1. Anon. Fluticasone propionate, In: Dollery C, ed.Therapeutic Drugs, Edinburgh: Churchill Livingstone, 1994; 102-105.

2. Goette DK and Odom RB. Adverse Effects of Corticosteroids. Cutis 1979; 23: 477-487.

3. Hill CJH and Rostenberg A. Adverse Effects from Topical Steroids. Cutis 1978; 21: 624-628.

4. Hogger P, Rawert J, Rohdewald P. Dissoluiton, tissue binding and kinetics of receptor binding of inhaled glucocorticoids. Eur Resp J 1993; 6(Suppl 17):584S.

5. Hogger P, Rohdewald P.Binding kinetics of fluticasone propionate to the human glucocorticoid receptor. Steroids 1994; 59:597-602.

6. McKenzie AW and Atkinson RM. Topical activities of betamethasone esters in man. Arch Dermatology 1964; 89: 741-6.

7. McKenzie AW and Stoughton RB. Method for comparing percutaneous absorption of steroids. Arch Dermatology 1962; 86: 608-10.

8. Miller JA and Munro DD.Topical Corticosteroids: Clinical Pharmacology and Therapeutic Use. Drugs 1980; 19: 119-134.

9. Morris HG. Mechanisms of action and therapeutic role of corticosteroids in asthma. J Allergy Clin Immunol 1985; 75(1): 1-13

10. Pauwels R. Mode of action of corticosteroids in asthma and rhinitis. Clin Allergy 1986; 16: 281-8.

11. Phillips GH. Structure-activity relationship of topically active steroids; the selection of fluticasone propionate. Respir Med 1990; 84(Suppl A): 19-23.

12. Polano MK. Topical Skin Therapeutics - Corticosteroids for Topical Use. Edinburgh: Churchill Livingstone 1984; 121-126.

13. Schopf E. Side Effects from Topical Corticosteroid Therapy. Annals of Clinical Research 1975; 7: 353-367.

14. Stoughton RB. Bio-assay system for formulations of topically-applied glucocor-ticosteroids. Arch Dermatology 1972; 106: 825-7.

15. Wurthwein G, Sehder S, Rohdewald P. Lipophilicity and receptor affinity of glucocorticoids. Pharm Zig Wiss 1992; 4:161-167.

16. Young MMR, Sohail N, Harding SM. A comparison of the systemic fluticasone propionate and betanethasone valerate after topical application of cream formulations. Br J Dermatology 1994; 131(Suppl 44):35-36.

CUTIVATE CREAM
(fluticasone propionate)

WHAT YOU SHOULD KNOW ABOUT CUTIVATE CREAM

Please read this leaflet carefully before you start to use your medicine.

This provides a summary of the information available on your medicine.For further information or advice, ask your doctor or pharmacist.

THE NAME OF YOUR MEDICINE

The name of your medicine is CUTIVATE cream. It contains fluticasone propionate. This medicine is one of a group of medicines called topical steroids. ÒTopicalÓ means they are put on the skin. (They should not be confused with ÒanabolicÓ steroids misused by some body builders and taken as tablets or injections).

HOW TO OBTAIN YOUR MEDICINE

This medicine can only be obtained with a prescription from a doctor.

THE PURPOSE OF YOUR MEDICINE

Your doctor has prescribed this cream to treat an inflamed skin condition such as eczema, psoriasis or dermatitis.

HOW YOUR MEDICINE WORKS

CUTIVATE cream is used to reduce the redness and itchiness of certain skin problems.

IMPORTANT POINTS TO NOTE BEFORE USING YOUR MEDICINE

Have you ever had to stop using a similar medicine because you were allergic to it or it caused problems?

If the answer to this question is YES, tell your doctor or pharmacist as soon as possible if you have not already done so.

DO not use this cream for any other skin problems as it could make them worse, especially: - acne, skin infections (cold sores, herpes, impetigo, athletes foot, chicken pox, ringworm, thrush), itchiness of the anus, itchiness of the genitals, conditions called rosacea and dermatitis around the mouth.

THE USE OF THIS MEDICINE DURING PREGNANCY AND BREAST-FEEDING

Tell your doctor if you are pregnant or breast feeding a baby.

Your doctor may decide not to prescribe this medicine during the first three months of pregnancy, or if you are breast feeding a baby. However, there may be circumstances when your doctor advises you differently.

HOW TO USE YOUR MEDICINE

Use the cream as your doctor prescribed. If you are not sure how much to use or how often, ask your doctor or pharmacist.

Unless used for treating the hands wash them again after using the cream. You should not use more than you are told.

CUTIVATE cream should not be used in children under 12 years of age.

You should not use the cream on large areas of the body for a long time.

Do not let the cream get into your eyes.

If your doctor has prescribed this cream for psoriasis, you should let your doctor review your progress at regular intervals, as such treatment needs careful supervision.

AFTER USING YOUR MEDICINE

If you experience wheeziness and tightness of chest, swelling of eyelids, face or lips or develop skin lumps or hives, or skin rash (e.g. red spots), tell your doctor immediately. Do not use any more cream unless your doctor tells you to do so. He may decide to stop your treatment.

You may experience local burning or itchiness or your condition may get worse. There is no need to stop the cream, but you should tell your doctor of any of these symptoms as soon as possible.

Use of this cream for a long period of time on large areas may cause thinning of the skin or streaks in the skin. Blood vessels at the surface of the skin may become more pronounced. Also, excessive hairiness of the skin or decreased colouring of the skin may be seen.

If you feel unwell or have any symptoms that you do not understand, you should contact your doctor as soon as possible.

WHAT TO DO IF AN OVERDOSE IS USED

It is important to stick to the dose on the label of your medicine.Using more than this is unlikely to be dangerous unless a lot is used all at once. In that case, ask your doctor what to do.

STORING YOUR MEDICINE

Keep your cream in a safe place where children cannot reach it.Your medicine may harm them.

CUTIVATE cream should not be frozen.

WHAT TO DO IF YOU STOP YOUR MEDICINE

If your doctor decides to stop the treatment, do not keep any leftover cream unless your doctor tells you to.

WHAT IS IN YOUR MEDICINE

CUTIVATE cream contains 0.05% fluticasone propionate.

A REMINDER

REMEMBER: This medicine is for you. Only a doctor can prescribe it for you. Never give it to someone else. It may harm them even if their symptoms are the same as yours.

FURTHER INFORMATION

If you have any questions or are not sure about your medication, then you should ask your doctor or pharmacist.

You may want to read this leaflet again. PLEASE DO NOT THROW IT AWAY until you have finished your medicine.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

FLUTICASONE PROPIONATE CREAM - TOPICAL

(flew-TICK-uh-sown)

COMMON BRAND NAME(S): Cutivate

USES: This medication is used to treat a variety of skin conditions (e.g., eczema, dermatitis, allergies, rash). Fluticasone reduces the swelling, itching and redness that can occur in these types of conditions. This medication is a medium-strength corticosteroid.

HOW TO USE: Use this medication on the skin only. However, do not use it on the face, groin, or underarms, or for diaper rash, unless directed to do so by your doctor.

Wash and dry your hands before using. Clean and dry the affected area. Apply a thin film of medication to the affected area and gently rub in, usually 1-2 times daily or as directed by your doctor. Do not bandage, cover or wrap the area unless directed to do so by your doctor. If used in the diaper area on an infant, do not use tight-fitting diapers or plastic pants.

After applying the medication, wash your hands, unless you are using this medication to treat the hands. When applying this medication near the eyes, avoid getting it in the eyes because this may worsen or cause glaucoma. Also, avoid getting this medication in the nose or mouth. If you get this medication in your eyes, nose, or mouth, rinse with plenty of water.

Use this medication only for the condition prescribed. Do not use it on a child for longer than 4 weeks in a row unless directed to do so by your doctor.

Inform your doctor if your condition persists or worsens after 2 weeks.

SIDE EFFECTS: Stinging, burning, itching, irritation, dryness, or redness of the skin may occur when first applied to the skin. This should disappear in a few days as your body adjusts to the medication. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: stretch marks, skin thinning/discoloration, acne, excessive hair growth, hair bumps (folliculitis).

Skin infections can become worse when using this medication. Notify your doctor promptly if redness, swelling or irritation does not improve.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using fluticasone, tell your doctor or pharmacist if you are allergic to it; or to other corticosteroids (e.g., hydrocortisone, prednisone); or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: poor blood circulation, diabetes, immune system problems, other skin conditions (e.g., rosacea, perioral dermatitis).

Do not use if there is an infection or sore in the area to be treated.

Though very unlikely, it is possible this medication will be absorbed into your bloodstream. This may have undesirable consequences that may require additional corticosteroid treatment. This is especially true for children and for those who have used this drug for an extended period of time, especially if they also have serious medical problems such as serious infections, injuries, or surgeries. This precaution applies for up to one year after stopping use of this drug. Tell your doctor immediately if any of the following side effects occur: vision problems, persistent headache, increased thirst or urination, unusual weakness, unusual weight loss, dizziness.

Consult your doctor or pharmacist for more details, and inform them that you use or have used this medication.

Children may be more sensitive to the effects of steroid excess. Though it is unlikely to occur with topical corticosteroids, this medication may affect growth in infants and children, if used for long periods. Monitor your child's height and rate of growth from time to time.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk when applied to the skin. Similar medications pass into breast milk when taken by mouth. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

Before using this medication, tell your doctor or pharmacist of all prescription or nonprescription/herbal products you may use, especially of: oral corticosteroids (e.g., prednisone), other topical corticosteroids (e.g., hydrocortisone), drugs that suppress the immune system (e.g., cyclosporine).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. This medication may be harmful if swallowed.

NOTES: Do not share this medication with others. This medication has been prescribed for your current condition only. Do not use it later for other skin problems unless told to do so by your doctor. A different medication may be necessary in those cases.

Laboratory and/or medical tests (e.g., adrenal gland function tests, morning cortisol blood test) may be performed periodically to monitor your progress or check for side effects, especially if you use this drug for an extended period of time, apply it over large areas of the body, or bandage/wrap the treated areas. Consult your doctor for more details.

Inform all your doctors you use or have used this medication.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 36-86 degrees F (2-30 degrees C) away from heat and light. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition may cause complications in a medical emergency. For enrollment information in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.