Brimonidine (topical)

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# Overview
Brimonidine (topical) is an alpha adrenergic agonist that is FDA approved for the treatment of facial erythema of rosacea.   Common adverse reactions include erythema, flushing, skin burning sensation, and contact dermatitis.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)

# Indications
- 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.

# Dosage
- 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.

# 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Brimonidine (topical) in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Brimonidine (topical) in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Brimonidine (topical) in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Brimonidine (topical) in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Brimonidine (topical) in pediatric patients.

# Contraindications
- None

# Warnings
Potentiation of Vascular Insufficiency
- MIRVASO topical gel should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynauds phenomenon, orthostatic hypotension, thrombangiitis obliterans, scleroderma, or Sjogrens syndrome.
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.
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.
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 .
- 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.
- Erythema and flushing appeared to resolve after discontinuation of MIRVASO topical gel.

# Adverse Reactions

## 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.
- 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.
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).

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Brimonidine (topical) in the drug label.

# Drug Interactions
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.
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.
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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Brimonidine (topical) in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Brimonidine (topical) during labor and delivery.

### Nursing Mothers
There is no FDA guidance on the use of Brimonidine (topical) with respect to nursing mothers.

### Pediatric Use
There is no FDA guidance on the use of Brimonidine (topical) with respect to pediatric patients.

### Geriatic Use
There is no FDA guidance on the use of Brimonidine (topical) with respect to geriatric patients.

### Gender
There is no FDA guidance on the use of Brimonidine (topical) with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Brimonidine (topical) with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Brimonidine (topical) in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Brimonidine (topical) in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Brimonidine (topical) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Brimonidine (topical) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Topical

### Monitoring
There is limited information regarding Monitoring of Brimonidine (topical) in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Brimonidine (topical) in the drug label.

# 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

# Pharmacology

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

## Structure
- 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.

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Brimonidine (topical) in the drug label.

## Pharmacokinetics
Absorption
- The absorption of brimonidine from MIRVASO topical gel was evaluated 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.

## Nonclinical Toxicology
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.

# Clinical Studies
- MIRVASO topical gel was evaluated 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 evaluated on Day 15 and Day 1, and the results are presented in Figures 1 and 2 for Studies 1 and 2, respectively.

# How Supplied
- 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

## Storage
- Store at 20C to 25C (68F to 77F), excursions permitted between 15C and 30C (59F and 86F).

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Patients using MIRVASO topical gel should receive the following information and instructions:
- This medication is to be used as directed by the physician.
- It is for external use only.
- MIRVASO topical gel should not be applied to irritated skin or open wounds.
- Avoid contact with the eyes and lips.
- Patients should wash their hands immediately after applying the medication.
- Some patients using MIRVASO topical gel may experience erythema or flushing.
- Patients should report any adverse reactions to their physician.
- Keep out of reach of children.

# Precautions with Alcohol
- Alcohol-Brimonidine (topical) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- MIRVASO 

# Look-Alike Drug Names
There is limited information regarding Brimonidine (topical) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price