5.1 Effects on Endocrine System

Systemic absorption of topical corticosteroids can produce reversible hypothalamic-pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or after withdrawal of 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. Factors that predispose a patient using a topical corticosteroid to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressings, altered skin barrier, liver failure and young age.

Because of the potential for systemic absorption, use of topical corticosteroids may require that patients be  periodically evaluated for HPA axis suppression. This may be done by using the adrenocorticotropic hormone (ACTH) stimulation test.

In a study evaluating the effects of mometasone furoate cream, USP, on the HPA axis, 15 grams were applied twice daily  for 7 days to six adult subjects with psoriasis or atopic dermatitis. The results show that the drug caused a slight lowering of adrenal corticosteroid secretion.

If HPA axis suppression is noted, an attempt should be made to gradually 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.

Pediatric patients may be more susceptible to systemic toxicity from equivalent doses due to their larger skin surface to body mass ratios [ seeUse in Specific Populations ( 8.4) ].

5.2 Ophthalmic Adverse Reactions

Use of topical corticosteroids may increase the risk of posterior subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported in postmarketing experience with the use of topical corticosteroids, including the topical mometasone products [see Adverse Reactions ( 6.2)] .

Avoid contact of mometasone furoate cream, USP, 0.1% with eyes. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

5.3 Allergic Contact Dermatitis

If irritation develops, mometasone furoate cream, USP, 0.1% should be discontinued and appropriate therapy instituted. Allergic contact dermatitis with corticosteroids is usually diagnosed by observing a 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.

5.4 Concomitant Skin Infections

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 mometasone furoate cream, USP, 0.1% should be discontinued until the infection has been adequately controlled.

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 clinical practice.

In controlled clinical trials involving 319 subjects, the incidence of adverse reactions associated with the use of mometasone furoate cream, USP, 0.1% was 1.6%. Reported reactions included burning, pruritus, and skin atrophy. Reports of rosacea associated with the use of mometasone furoate cream, USP, 0.1% have also been received. In controlled clinical trials (n=74) involving pediatric subjects 2 to 12 years of age, the incidence of adverse experiences associated with the use of mometasone furoate cream, USP, 0.1% was approximately 7%. Reported reactions included stinging, pruritus, and furunculosis.

The following adverse reactions were reported to be possibly or probably related to treatment with mometasone furoate cream, USP, 0.1% during clinical trials in 4% of 182 pediatric subjects 6 months to 2 years of age: decreased glucocorticoid levels, 2; paresthesia, 2; folliculitis, 1; moniliasis, 1; bacterial infection; 1 skin depigmentation, 1. The following signs of skin atrophy were also observed among 97 subjects treated with mometasone furoate cream, USP, 0.1% in a clinical trial: shininess, 4; telangiectasia, 1; loss of elasticity, 4; loss of normal skin markings, 4; thinness, 1; and bruising, 1.

6.2 Postmarketing Experience

Because adverse 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.

Postmarketing reports for local adverse reactions to topical corticosteroids include irritation, dryness, folliculitis, hypertrichosis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, striae, and miliaria. These adverse reactions may occur more frequently with the use of occlusive dressings.

Postmarketing reports for ophthalmic adverse reactions to topical corticosteroids include blurred vision, cataracts, glaucoma, increased intraocular pressure, and central serous chorioretinopathy.

To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy

Teratogenic Effects Pregnancy Category C:

There are no adequate and well-controlled studies in pregnant women. Therefore, mometasone furoate cream, USP, 0.1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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.

When administered to pregnant rats, rabbits, and mice, mometasone furoate increased fetal malformations. The doses that produced malformations also decreased fetal growth, as measured by lower fetal weights and/or delayed ossification. Mometasone furoate also caused dystocia and related complications when administered to rats during  the end of pregnancy.

In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above. Fetal survival was reduced at 180 mcg/kg. No toxicity was observed at 20 mcg/kg. (Doses of 20, 60, and 180 mcg/kg in the mouse are approximately 0.01, 0.02, and 0.05 times the estimated maximum clinical topical dose from mometasone furoate cream, USP, 0.1% on a mcg/m 2basis.)

In rats, mometasone furoate produced umbilical hernias at topical doses of 600 mcg/kg and above. A dose of 300  mcg/kg produced delays in ossification, but no malformations. (Doses of 300 and 600 mcg/kg in the rat are approximately 0.2 and 0.4 times the estimated maximum clinical topical dose from mometasone furoate cream, USP, 0.1% on a mcg/m 2basis.)

In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis,  umbilical hernia, hydrocephaly) at topical doses of 150 mcg/kg and above (approximately 0.2 times the estimated maximum clinical topical dose from mometasone furoate cream, USP, 0.1% on a mcg/m 2basis). In an oral study,  mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg. At 2800 mcg/kg most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg. (Doses at 140, 700, and 2800 mcg/kg in the rabbit are approximately 0.2, 0.9, and 3.6 times the estimated  maximum clinical topical dose from mometasone furoate cream, USP, 0.1% on a mcg/m 2basis.)

When rats received subcutaneous doses of mometasone furoate throughout pregnancy or during the later stages of  pregnancy, 15 mcg/kg caused prolonged and difficult labor and reduced the number of live births, birth weight, and early pup survival. Similar effects were not observed at 7.5 mcg/kg. (Doses of 7.5 and 15 mcg/kg in the rat are approximately 0.005 and 0.01 times the estimated maximum clinical topical dose from mometasone furoate cream, USP, 0.1% on a mcg/m 2basis.)

8.3 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 mometasone furoate cream, USP,0.1% is administered to a nursing woman.

8.4 Pediatric Use

Mometasone furoate cream, USP, 0.1% may be used with caution in pediatric patients 2 years of age or older, although the safety and efficacy of drug use for longer than 3 weeks have not been established. Since safety and efficacy of mometasone furoate cream, USP, 0.1% have not been established in pediatric patients below 2 years of age, its use in this age group is not recommended.

In a pediatric trial, 24 atopic dermatitis subjects, of whom 19 subjects were age 2 to 12 years, were treated with mometasone furoate cream, USP, 0.1% once daily. The majority of subjects cleared within 3 weeks. Mometasone furoate cream, USP, 0.1% caused HPA axis suppression in approximately 16% of pediatric subjects ages 6 to 23 months, who showed normal adrenal function by Cortrosyn test before starting treatment, and were treated for approximately 3 weeks over a mean body surface area of 41% (range 15%-94%). The criteria for suppression were: basal cortisol level of ≤5 mcg/dL, 30-minute post-stimulation level of ≤18 mcg/dL, or an increase of <7 mcg/dL.  Follow-up testing 2 to 4 weeks after trial completion, available for 5 of the subjects, demonstrated suppressed HPA  axis function in 1 subject, using these same criteria. Long-term use of topical corticosteroids has not been studied in this population [ see Clinical Pharmacology ( 12.2) ].

Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of HPA axis suppression and Cushing's syndrome when they are treated with topical corticosteroids. They are, therefore, also at greater risk of adrenal insufficiency during and/or after withdrawal of treatment. Pediatric patients may be more susceptible than adults to skin atrophy, including striae, when they are treated with topical corticosteroids. Pediatric patients applying topical corticosteroids to greater than 20% of body surface are at higher risk of HPA axis suppression.

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 children include low plasma cortisol levels and an absence of response to ACTH stimulation. Manifestations of intracranial hypertension include bulging fontanelles, headaches, and bilateral papilledema.

Mometasone furoate cream, USP, 0.1% should not be used in the treatment of diaper dermatitis.

8.5 Geriatric Use

Clinical studies of mometasone furoate cream, USP, 0.1% included 190 subjects who were 65 years of age and over and 39 subjects who were 75 years of age and over. 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

Like other topical corticosteroids, mometasone furoate 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 2inhibitory 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. Arachidonic acid is released from membrane phospholipids by phospholipase A 2.

12.2 Pharmacodynamics

Studies performed with mometasone furoate cream, USP, 0.1% indicate that it is in the medium range of potency as compared with other topical corticosteroids.

In a study evaluating the effects of mometasone furoate cream, USP, on the HPA axis, 15 grams were applied twice daily for 7 days to six adult subjects with psoriasis or atopic dermatitis. The cream was applied without occlusion to at least 30% of the body surface. The results showed that the drug caused a slight lowering of adrenal corticosteroid secretion [ see Warnings and Precautions ( 5.1) ]. 

Ninety-seven pediatric subjects ages 6 to 23 months with atopic dermatitis, were enrolled in an open-label, HPA axis safety study. Mometasone furoate cream, USP, 0.1% was applied once daily for approximately 3 weeks over a mean body surface area of 41% (range 15%-94%). In approximately 16% of subjects who showed normal adrenal function by Cortrosyn test before starting treatment, adrenal suppression was observed at the end of treatment with mometasone furoate cream, USP, 0.1%. The criteria for suppression were: basal cortisol level of ≤5 mcg/dL, 30-minute post-stimulation level of ≤18 mcg/dL, or an increase of <7 mcg/dL. Follow-up testing 2 to 4 weeks after stopping treatment, available for 5 of the subjects, demonstrated suppressed HPA axis function in one subject, using these same criteria [ seeUse in Specific Populations( 8.4) ].

12.3 Pharmacokinetics

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle and the integrity of the epidermal barrier. Studies in humans indicate that approximately 0.4% of the applied dose of mometasone furoate cream, USP, 0.1% enters the circulation after 8 hours of contact on normal skin without occlusion. Inflammation and/or other disease processes in the skin may increase percutaneous absorption.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of mometasone furoate cream, USP, 0.1%. Long-term carcinogenicity studies of mometasone furoate were conducted by the inhalation route in rats and mice. In a 2-year carcinogenicity study in Sprague Dawley rats, mometasone furoate demonstrated no statistically significant increase of tumors at inhalation doses up to 67 mcg/kg (approximately 0.04 times the estimated maximum clinical topical dose from mometasone furoate cream, USP, 0.1% on a mcg/m 2basis). In a 19-month carcinogenicity study in Swiss CD-1 mice, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 160 mcg/kg (approximately 0.05 times the estimated maximum clinical topical dose from mometasone furoate cream, USP, 0.1% on a mcg/m 2basis).

Mometasone furoate increased chromosomal aberrations in an in vitroChinese hamster ovary cell assay, but did not increase chromosomal aberrations in an in vitroChinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivomouse micronucleus  assay, a rat bone marrow chromosomal aberration assay, or a mouse male germ-cell chromosomal aberration assay.  Mometasone furoate also did not induce unscheduled DNA synthesis in vivoin rat hepatocytes.

In reproductive studies in rats, impairment of fertility was not produced in male or female rats by subcutaneous doses up to 15 mcg/kg (approximately 0.01 times the estimated maximum clinical topical dose from mometasone furoate cream 0.1% on a mcg/m 2basis).