CUTIVATE® Ointment is a corticosteroid indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses in adult patients.

5.1 Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression and Other Adverse Endocrine Effects

 

Topical corticosteroids, including CUTIVATE® Ointment, can produce reversible HPA axis suppression with the potential for clinical glucocorticoid insufficiency. Factors that predispose to HPA axis suppression include large treatment surface areas, prolonged use, use under occlusion, altered skin barrier, liver failure, and young age. Cushing’s syndrome, hyperglycemia, and unmasking of latent diabetes mellitus can also result from systemic absorption of topical corticosteroids.

 

HPA axis suppression may occur during or after withdrawal of treatment. If HPA axis suppression is suspected, gradually withdraw the drug, reduce the frequency of application, or substitute with a less potent corticosteroid. Evaluation of HPA axis suppression may be done by using the cosyntropin stimulation test.

 

Pediatric patients may be at greater risk of HPA axis suppression due to their higher skin surface area to body mass ratios [see Use in Specific Populations (8.4)].

5.2 Local Adverse Reactions

 

The following local adverse reactions have been reported with topical corticosteroids. They may occur more frequently with the use of occlusive dressings and higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, hypertrichosis, and miliaria.

5.3 Allergic Contact Dermatitis

 

Allergic contact dermatitis with topical corticosteroids is usually diagnosed by observing failure to heal rather than noting a clinical exacerbation. Such an observation can be corroborated with appropriate diagnostic patch testing. Discontinue CUTIVATE® Ointment if appropriate.

5.4 Skin Infections

 

If concomitant skin infections are present or develop, use an appropriate antimicrobial. If a favorable response does not occur promptly, discontinue use of CUTIVATE® Ointment until the infection has been adequately controlled.

5.5 Ophthalmic Adverse Reactions

Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported postmarketing with the use of topical corticosteroids.

Avoid contact of CUTIVATE® Ointment with eyes. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

6.1 Clinical Trials Experience

 

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

 

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, urticaria, irritation, and lightheadedness. Each of these events occurred individually in less than 1% of subjects.

6.2 Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

 

The following local adverse reactions have been identified during post-approval use of CUTIVATE® Ointment: acneiform dermatitis, edema, rash, hypoaesthesia, pustular psoriasis, skin atrophy.

 

The following systemic adverse reactions have been identified during post-approval use of CUTIVATE® Cream and CUTIVATE® Ointment: immunosuppression/Pneumocystis jirovecii pneumonia/leukopenia/thrombocytopenia; hyperglycemia/glycosuria; Cushing syndrome; generalized body edema/blurred vision; and acute urticarial reaction (edema, urticaria, pruritus, and throat swelling).

The following local adverse reactions have been reported with the use of topical corticosteroids: telangiectasia, striae, dryness, folliculitis, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, and miliaria.

 

Ophthalmic adverse reactions including cataracts, glaucoma and increased intraocular pressure have been reported with the use of topical corticosteroids.

8.1 Pregnancy

8.2 Lactation

Risk Summary

There are no data on the presence of fluticasone propionate in human milk, its effects on the breastfed infant, or its effects on milk production. It is not known whether topical administration of CUTIVATE® Ointment could result in sufficient systemic absorption to produce detectable quantities in human milk (see Clinical Considerations).

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for

CUTIVATE® Ointment and any potential adverse effects on the breastfed child from CUTIVATE® Ointment or from the

underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breast milk, use CUTIVATE® Ointment on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply CUTIVATE® Ointment directly to the nipple and areola prior to breastfeeding to avoid direct infant exposure [see Use in Specific Populations (8.4)].

8.4 Pediatric Use

 

The safety and effectiveness of CUTIVATE® Ointment have not been established in pediatric patients. Use of CUTIVATE® Ointment in pediatric patients is not recommended.

 

Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of systemic effects when treated with topical drugs. They are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency upon the use of topical corticosteroids [see Warnings and Precautions (5.1)].

 

In a trial of 35 pediatric subjects treated with fluticasone propionate ointment, 0.005% for atopic dermatitis over at least 35% of body surface area, subnormal adrenal function was observed with cosyntropin stimulation testing at the end of 3 to 4 weeks of treatment in 4 subjects who had normal testing prior to treatment. It is not known if these subjects had recovery of adrenal function because follow-up testing was not performed. The decreased responsiveness of cosyntropin testing was not correlated to age of subject, amount of fluticasone propionate ointment used, or serum levels of fluticasone propionate.

 

In the above trial, telangiectasia on the face was noted in one subject on the eighth day of a 4-week treatment period. Facial use was discontinued and the telangiectasia resolved.

 

HPA axis suppression, Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients receiving topical corticosteroids.

8.5 Geriatric Use

 

A limited number of patients above 65 years of age (n = 203) have been treated with CUTIVATE® Ointment in US and non-US clinical trials. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.

12.1 Mechanism of Action

Corticosteroids play a role in cellular signaling, immune function, inflammation, and protein regulation; however, the precise mechanism of action of CUTIVATE® Ointment in corticosteroid-responsive dermatoses is unknown.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

 

Absorption
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 study of 6 healthy subjects applying 25 g of fluticasone propionate ointment 0.005% twice daily to the trunk and legs for up to 5 days under occlusion, plasma levels of fluticasone ranged from 0.08 to 0.22 ng/mL.

 

Distribution
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
No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate.

 

Fluticasone propionate is metabolized in the liver by cytochrome P450 3A4-mediated hydrolysis of the 5-fluoromethyl carbothiolate grouping. This transformation occurs in 1 metabolic step to produce the inactive 17β-carboxylic acid metabolite, the only known metabolite detected in man. This metabolite has approximately 2000 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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

 

In an oral (gavage) mouse carcinogenicity study, doses of 0.1, 0.3, and 1 mg/kg/day fluticasone propionate were administered to mice for 18 months. Fluticasone propionate demonstrated no tumorigenic potential at oral doses up to 1 mg/kg/day in this study.

 

In a dermal mouse carcinogenicity study, 0.05% fluticasone propionate ointment (40 μL) was topically administered for 1, 3, or 7 days/week for 80 weeks. Fluticasone propionate demonstrated no tumorigenic potential at dermal doses up to 6.7 μg/kg/day in this study.

 

Fluticasone propionate was not mutagenic or clastogenic in five in vitro genotoxicity tests (Ames assay, E. coli fluctuation test, S. cerevisiae gene conversion test, Chinese hamster ovary cell chromosome aberration assay and human lymphocyte chromosome aberration assay) and one in vivo genotoxicity test (mouse micronucleus assay).

 

In a fertility study, male and female rats received subcutaneous doses of fluticasone propionate at doses up to 50 μg/kg/day. No impairment of fertility or mating performance was observed.

Store between 2° and 30°C (36° and 86° F).