酒石酸溴莫尼定Mirvaso (Brimonidine Topical Gel)外用凝胶酒糟鼻的药物 - America[美国药品]

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酒石酸溴莫尼定Mirvaso (Brimonidine Topical Gel)外用凝胶酒糟鼻的药物(五)

2013-10-22 23:45:33 来源: 作者: 【大中小】浏览:7594次评论:0条

ive ingredient brimonidine tartrate (equivalent to 3.3 mg of brimonidine free base), in a white to light yellow opaque gel composed of the inactive ingredients carbomer homopolymer type B, glycerin, methylparaben, phenoxyethanol, propylene glycol, purified water, sodium hydroxide, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Brimonidine is a relatively selective alpha-2 adrenergic agonist. Topical application of MIRVASO topical gel may reduce erythema through direct vasoconstriction.

12.3 Pharmacokinetics

Absorption

The absorption of brimonidine from MIRVASO topical gel was eva luated in a clinical trial in 24 adult subjects with facial erythema associated with rosacea. All enrolled subjects received once daily topical application of MIRVASO topical gel 1 gram to the entire face for 29 days. Pharmacokinetic assessments were performed on Day 1, Day 15, and Day 29. The mean plasma maximum concentration (Cmax) and area under the concentration-time curve (AUC) were highest on Day 15, with Cmax and AUC values (± standard deviation) of 46 ± 62 pg/mL and 417 ± 264 pg.hr/mL, respectively. The systemic drug exposure was slightly lower on Day 29 indicating no further drug accumulation.

Metabolism

Brimonidine is extensively metabolized by the liver.

Excretion

Urinary excretion is the major route of elimination of brimonidine and its metabolites.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 21-month oral (diet) mouse carcinogenicity study and a 24-month oral (diet) rat carcinogenicity study, no drug-related neoplasms were observed in mice at oral doses of brimonidine tartrate up to 2.5 mg/kg/day or in rats at oral doses of brimonidine tartrate up to 1 mg/kg/day.

In a dermal rat carcinogenicity study with MIRVASO topical gel, brimonidine tartrate was administered to Wistar rats at topical doses of 0.9 (0.03% gel), 1.8 (0.06% gel), and 5.4 mg/kg/day (0.18% gel) in males and 5.4 (0.18% gel), 30 (1% gel) during Days 1-343/10.8 (0.36% gel) thereafter, and 60 (2% gel) during Days 1-343/21.6 mg/kg/day (0.72% gel) thereafter in females once daily for 24 months. No drug-related neoplasms were observed in this study.

In a 12-month dermal photo-carcinogenicity study, topical doses of 0% (MIRVASO topical gel vehicle), 0.18%, 1% and 2% brimonidine tartrate gel were administered to hairless albino mice once daily, five days per week, with concurrent exposure to simulated sunlight. No drug-related adverse effects were observed in this study. The results of this study suggest that topical treatment with MIRVASO topical gel would not enhance photo-carcinogenesis.

Mutagenesis

Brimonidine tartrate was not mutagenic or clastogenic in a series of in vitro and in vivo studies, including the Ames test, a chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and three studies in CD1 mice (a host-mediated assay, a cytogenetic study, and a dominant lethal assay).

Impairment of Fertility

Reproduction and fertility studies in rats with brimonidine tartrate demonstrated no adverse effects on male or female fertility at oral doses up to 1 mg/kg/day.