Mometasone (Mometasone Furoate Topical) - Description and Clinical Pharmacology

DESCRIPTION

Mometasone furoate ointment USP, 0.1% contains mometasone furoate USP for topical use. Mometasone furoate USP is a synthetic corticosteroid with anti-inflammatory activity.

Chemically, mometasone furoate USP is 9α,21-dichloro-11β,17-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione 17-(2-furoate), with the empirical formula C₂₇H₃₀Cl₂O₆, a molecular weight of 521.43 and the following structural formula:

Mometasone furoate USP is a white to off-white powder, soluble in acetone and methylene chloride.

Each gram of mometasone furoate ointment USP, 0.1% contains 1 mg mometasone furoate USP in an ointment base of hexylene glycol, phosphoric acid, propylene glycol stearate (55% monoester), white wax, white petrolatum, and purified water.

CLINICAL PHARMACOLOGY

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 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. Arachidonic acid is released from membrane phospholipids by phospholipase A₂.

Pharmacodynamics

Studies performed with mometasone furoate ointment 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 ointment on the HPA axis, 15 grams were applied twice daily for 7 days to 6 adult subjects with psoriasis or atopic dermatitis. The ointment 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 ].

Sixty-three pediatric subjects ages 6 to 23 months, with atopic dermatitis, were enrolled in an open label

HPA axis safety study. Mometasone furoate ointment was applied once daily for approximately 3 weeks over a mean body surface area of 39% (range 15%-99%). In approximately 27% 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 ointment. The criteria for suppression were: basal cortisol level of ≤5 mcg/dL, 30-minute post-stimulation level of ≤18mcg/dL or an increase of <7 mcg/dL. Follow-up testing 2 to 4 weeks after stopping treatment, available for 8 of the subjects, demonstrated suppressed HPA axis function in 3 subjects, using these same criteria [see Use in Specific Populations].

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 0.7% of the applied dose of mometasone furoate ointment 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.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of mometasone furoate ointment. 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 ointment on a mcg/m² basis). 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 ointment on a mcg/m² basis).

Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did not increase chromosomal aberrations in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivo mouse 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 vivo in 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 ointment on a mcg/m² basis)

CLINICAL STUDIES

The safety and efficacy of mometasone furoate ointment 0.1% for the treatment of corticosteroid-responsive dermatoses was demonstrated in two vehicle-controlled trials, one in psoriasis and one in atopic dermatitis. A total of 218 subjects received mometasone furoate ointment (109 subjects) or the vehicle ointment applied once daily for 21 days.