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Mirvaso(Brimonidine Topical Gel)-酒石酸溴莫尼定外用凝胶

2013-11-19 01:14:14 作者：新特药房来源：互联网浏览次数：833 文字大小：【大】【中】【小】

简介： Mirvaso (Brimonidine Topical Gel)酒石酸溴莫尼定外用凝胶酒糟鼻的药物MIRVASO(brimonidine tartrate) gel[Galderma Laboratories, L.P.]Galderma公司的药物Mirvaso已成功获得美国食品及药物管理局认定 ...

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

Mirvaso (Brimonidine Topical Gel)酒石酸溴莫尼定外用凝胶酒糟鼻的药物
MIRVASO(brimonidine tartrate) gel
[Galderma Laboratories, L.P.]
Galderma公司的药物Mirvaso已成功获得美国食品及药物管理局认定，用于酒糟鼻的治疗。其主要成分为0.33%酒石酸溴莫尼定，一种α-2肾上腺素受体激动剂（alpha-2 adrenergic agonist）。mirvaso是外用凝胶，可以通过压缩面部扩张血管减少酒渣鼻发红。mirvaso使用豌豆大小的量，每日一次，每次脸上的五个区域可以使用：额头，下巴，鼻子和两颊。
据称，每日使用一次，mirvaso可迅速减少酒渣鼻的发红，并持续12小时。
该药物的验证采取了常规的对比验证，基于超过550例患者的样本，在一个月的时间内对两个3期小组（一为实验组，一为对照组）临床研究中所收集的数据。
研究的结果表明：
使用mirvaso凝胶的患者表现出比使用vehicle gel（嘛玩意？不知道什么药物）的患者面部发红有更大的改善。此外，还进行了长期的药物使用研究，有276名受试者使用mirvaso长达12个月。
副作用：
在临床试验中，最常见的不良反应包括红斑（≥1%），皮肤烧灼感和接触性皮炎。抑郁症患者注意，该药物可造成脑或冠状动脉供血不足，雷诺氏现象，体位性低血压，血栓闭塞性脉管炎，硬皮病，或öSJ干燥综合征。α-2肾上腺素能药物可降低血压。严重或不稳定或不受控制的心血管疾病患者慎用。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use MIRVASO® safely and effectively. See full prescribing information for MIRVASO.
MIRVASO (brimonidine) topical gel, for topical use
Initial U.S. Approval: 1996
INDICATIONS AND USAGE
MIRVASO (brimonidine) topical gel, 0.33% is an alpha adrenergic agonist indicated for the topical treatment of persistent (nontransient) facial erythema of rosacea in adults 18 years of age or older. (1)
DOSAGE AND ADMINISTRATION
Not for oral, ophthalmic, or intravaginal use. (2)
Apply a pea-size amount once daily to each of the five areas of the face (forehead, chin, nose, each cheek) avoiding the eyes and lips. (2)
Hands should be washed immediately after applying MIRVASO topical gel. (2)
DOSAGE FORMS AND STRENGTHS
Gel, 0.33%; Each gram of gel contains 5 mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base. (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
Potentiation of Vascular Insufficiency (5.1)
Severe Cardiovascular Disease (5.2)
Serious Adverse Reactions Following Ingestion of MIRVASO topical gel (5.3)
Erythema and Flushing (5.4)
ADVERSE REACTIONS
In controlled clinical trials with MIRVASO topical gel the most common adverse reactions (incidence > 1%) included erythema, flushing, skin burning sensation, and contact dermatitis. (6)
To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. (6)

See 17 for PATIENT COUNSELING INFORMATION.
Revised: 08/2013
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

MIRVASO (brimonidine) topical gel, 0.33% is an alpha adrenergic agonist indicated for the topical treatment of persistent (nontransient) erythema of rosacea in adults 18 years of age or older.

2 DOSAGE AND ADMINISTRATION

Apply a pea-size amount once daily to each of the five areas of the face: central forehead, chin, nose, each cheek. MIRVASO topical gel should be applied smoothly and evenly as a thin layer across the entire face avoiding the eyes and lips.

Wash hands after applying MIRVASO topical gel.

MIRVASO topical gel is not for oral, ophthalmic, or intravaginal use.

3 DOSAGE FORMS AND STRENGTHS

MIRVASO (brimonidine) topical gel, 0.33% is a white to light yellow opaque aqueous gel. Each gram of gel contains 5 mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Potentiation of Vascular Insufficiency

MIRVASO topical gel should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, thrombangiitis obliterans, scleroderma, or Sjögren’s syndrome.

5.2 Severe Cardiovascular Disease

Alpha-2 adrenergic agonists can lower blood pressure. MIRVASO topical gel should be used with caution in patients with severe or unstable or uncontrolled cardiovascular disease.

5.3 Serious Adverse Reactions Following Ingestion of MIRVASO topical gel

Two young children of a subject in a clinical trial experienced serious adverse reactions following accidental ingestion of MIRVASO topical gel. Adverse reactions experienced by one or both children included lethargy, respiratory distress with apneic episodes (requiring intubation), sinus bradycardia, confusion, psychomotor hyperactivity, and diaphoresis. Both children were hospitalized overnight and discharged the following day without sequelae.

Keep MIRVASO topical gel out of reach of children.

5.4 Erythema and Flushing

Some subjects in the clinical trials discontinued use of MIRVASO topical gel because of erythema or flushing.

The effect of MIRVASO topical gel may begin to diminish hours after application. For some subjects in the clinical trials, erythema was reported to return worse compared to the severity at baseline [see Adverse Reactions (6)].

Intermittent flushing occurred in some subjects treated with MIRVASO topical gel. The onset of flushing relative to application of MIRVASO topical gel varied, ranging from approximately 30 minutes to several hours [see Adverse Reactions (6)].

Erythema and flushing appeared to resolve after discontinuation of MIRVASO topical gel.

6 ADVERSE REACTIONS

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.

During clinical trials, 1210 subjects were exposed to MIRVASO topical gel. A total of 833 subjects were treated for persistent (nontransient) erythema associated with rosacea, and 330 of those were treated once daily for 29 days in vehicle-controlled trials.

Adverse reactions that occurred in at least 1% of subjects treated with MIRVASO topical gel once daily for 29 days and for which the rate for MIRVASO topical gel exceeded the rate for vehicle are presented in Table 1.

Table 1 - Adverse Reactions Reported in Clinical Trials by At Least 1% of Subjects Treated for 29 Days
Preferred Term	MIRVASO Topical Gel (N=330) n (%)	Vehicle Gel (N=331) n (%)
Subjects with at least one adverse reaction, Number (%) of Subjects	109 (33)	91 (28)
Erythema	12 (4%)	3 (1%)
Flushing	9 (3%)	0
Skin burning sensation	5 (2%)	2 (1%)
Dermatitis contact	3 (1%)	1 (<1%)
Dermatitis	3 (1%)	1 (<1%)
Skin warm	3 (1%)	0
Paraesthesia	2 (1%)	1 (<1%)
Acne	2 (1%)	1 (<1%)
Pain of skin	2 (1%)	0
Vision blurred	2 (1%)	0
Nasal congestion	2 (1%)	0

Open-label, Long-term Study

An open-label study of MIRVASO topical gel when applied once daily for up to one year was conducted in subjects with persistent (nontransient) facial erythema of rosacea. Subjects were allowed to use other rosacea therapies. A total of 276 subjects applied MIRVASO topical gel for at least one year. The most common adverse events (> 4% of subjects) for the entire study were flushing (10%), erythema (8%), rosacea (5%), nasopharyngitis (5%), skin burning sensation (4%), increased intraocular pressure (4%), and headache (4%).

Allergic contact dermatitis

Allergic contact dermatitis to MIRVASO topical gel was reported in approximately 1% of subjects across the clinical development program. Two subjects underwent patch testing with individual product ingredients. One subject was found to be sensitive to brimonidine tartrate, and one subject was sensitive to phenoxyethanol (a preservative).

7 DRUG INTERACTIONS

7.1 Anti-hypertensives/Cardiac Glycosides

Alpha-2 agonists, as a class, may reduce blood pressure. Caution in using drugs such as beta-blockers, anti-hypertensives and/or cardiac glycosides is advised.

7.2 CNS Depressants

Although specific drug-drug interactions studies have not been conducted with MIRVASO topical gel, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.

7.3 Monoamine Oxidase Inhibitors

Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine and potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B.

There are no adequate and well-controlled studies of MIRVASO topical gel in pregnant women. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. MIRVASO topical gel should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Brimonidine tartrate was not teratogenic when given at oral doses up to 2.5 mg/kg/day in pregnant rats during gestation days 6 through 15 and 5 mg/kg/day in pregnant rabbits during gestation days 6 through 18.

8.3 Nursing Mothers

It is not known whether brimonidine tartrate is excreted in human milk, although in animal studies, brimonidine tartrate has been shown to be excreted in breast milk. Because of the potential for serious adverse reactions from MIRVASO topical gel in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

Keep MIRVASO topical gel out of reach of children. Serious adverse reactions were experienced by two children of a subject in a clinical trial who accidentally ingested MIRVASO topical gel [See Warnings and Precautions (5.3)].

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

One hundred and five subjects aged 65 and older were included in clinical trials with MIRVASO topical gel. No overall differences in safety or effectiveness were observed between subjects > 65 years of age and younger adult subjects. Clinical studies of MIRVASO topical gel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

10 OVERDOSAGE

No information is available on overdose in adults with MIRVASO topical gel.

Oral overdoses of other alpha-2 adrenergic agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure.

Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained.

11 DESCRIPTION

MIRVASO (brimonidine) topical gel, 0.33% contains brimonidine tartrate, an alpha adrenergic agonist.

The molecular formula of brimonidine tartrate is C11H10BrN5 · C4H6O6. It has the following structural formula:

Chemically, brimonidine tartrate is 5-Bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate. Brimonidine tartrate has a molecular weight of 442.24 and appears as white to slightly yellowish powder.

Each gram of MIRVASO (brimonidine) topical gel, 0.33% contains 5 mg of the active 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.

14 CLINICAL STUDIES

MIRVASO topical gel was eva luated for the treatment of moderate to severe, persistent (nontransient) facial erythema of rosacea in two randomized, double-blind, vehicle-controlled clinical trials, which were identical in design. The trials were conducted in 553 subjects aged 18 years and older who were treated once daily for 4 weeks with either MIRVASO topical gel or vehicle. Overall, 99% of subjects were Caucasian and 76% were female. Baseline disease severity was graded using a 5-point Clinical Erythema Assessment (CEA) scale and a 5-point Patient Self Assessment (PSA) scale, on which subjects scored either “moderate” or “severe” on both scales.

The primary efficacy endpoint in both pivotal trials was 2-grade Composite Success, defined as the proportion of subjects with a 2-grade improvement on both CEA and PSA measured at hours 3, 6, 9, and 12 on Day 29. Table 2 presents the efficacy results. In addition to Day 29, efficacy was eva luated on Day 15 and Day 1, and the results are presented in Figures 1 and 2 for Studies 1 and 2, respectively.

Table 2: Summary of 2-grade Composite Success on Day 29
2-grade Composite Success: 2-grade improvement on CEA and 2-grade improvement on PSA.
Success	Study 1		Study 2
	MIRVASO Topical Gel (N=129)	Vehicle Gel (N=131)	MIRVASO Topical Gel (N=148)	Vehicle Gel (N=145)
Hour 3	31%	11%	25%	9%
Hour 6	30%	10%	25%	9%
Hour 9	26%	10%	18%	11%
Hour 12	23%	9%	22%	10%

Figure 1: 2-grade Composite Success by Hour and Day for Study 1

Figure 2: 2-grade Composite Success by Hour and Day for Study 2

16 HOW SUPPLIED/STORAGE AND HANDLING

MIRVASO (brimonidine) topical gel, 0.33% is a white to light yellow opaque gel, supplied in a laminated tube with a child resistant cap in the following sizes:

30 gram NDC 0299-5980-30

45 gram NDC 0299-5980-45

Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature].