DailyMed Label: Mirvaso

DailyMed Label: Mirvaso

2022

DailyMed Prescription

Mirvaso

brimonidine tartrate

Galderma Laboratories, L.P.

NDC: 0299-5980

NDC: 0299-5980

NDC: 0299-5980

MIRVASO (brimonidine) topical gel, 0.33% contains brimonidine tartrate, an alpha adrenergic agonist. The molecular formula of brimonidine tartrate is C 11 H 10 BrN 5 • C 4 H 6 O 6 . 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. chem-structure

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. 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 )

Apply a pea-sized 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 for topical use only and not for oral, ophthalmic, or intravaginal use. Apply a pea-sized 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 ) For topical use only ( 2 ) Not for oral, ophthalmic, or intravaginal use. ( 2 )

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. Gel, 0.33%; Each gram of gel contains 5 mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base. ( 3 )

MIRVASO topical gel is contratindicated in patients who have experienced a hypersensitivity reaction to any component. Reactions have included angioedema, urticaria, and contact dermatitis [ see Warnings and Precautions (5.6) and Adverse Reactions (6.1 , 6.2 ) ]. Known hypersensitivity to any component of MIRVASO topical gel ( 4 )

Potentiation of Vascular Insufficiency ( 5.1 ) Severe Cardiovascular Disease ( 5.2 ) Serious Adverse Reactions Following Ingestion of MIRVASO topical gel ( 5.3 ) Systemic Adverse Reactions of Alpha-2 Adrenergic Agonists ( 5.4 ) Local Vasomotor Adverse Reactions ( 5.5 ) Hypersensitivity ( 5.6 ) 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. 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. 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 the reach of children. Postmarketing cases of bradycardia, hypotension (including orthostatic hypotension) and dizziness have been reported. Some cases required hospitalization. Some cases involved application of MIRVASO topical gel in unapproved dosing regimens and for unapproved indications, including the application of MIRVASO topical gel following laser procedures. Avoid applying MIRVASO topical gel to irritated skin or open wounds. Erythema Some subjects in the clinical trials discontinued use of MIRVASO topical gel because of erythema. Some subjects in the clinical trials reported a rebound phenomenon, where erythema was reported to return worse compared to the severity at baseline. Erythema appeared to resolve after discontinuation of MIRVASO topical gel .[see Adverse Reactions ( 6.1 )]. The treatment effect of MIRVASO topical gel may begin to diminish hours after application. From postmarketing reports, some patients have experienced erythema involving areas of the face that were previously not affected by erythema and in areas (e.g., neck and chest) outside of the treatment sites. Flushing Some subjects in the clinical trials discontinued use of MIRVASO topical gel because of flushing. Intermittent flushing occurred in some subjects treated with MIRVASO topical gel in the clinical trials. The onset of flushing relative to application of MIRVASO topical gel varied, ranging from approximately 30 minutes to several hours [ see Adverse Reactions ( 6.1 ) ]. Flushing appeared to resolve after discontinuation of MIRVASO topical gel. From postmarketing reports, some patients have experienced increased frequency of flushing and/or increased depth of erythema with the flushing. Additionally, some patients reported new onset of flushing. Pallor and Excessive Whitening From postmarketing reports, some patients have experienced pallor or excessive whitening at or outside the application site following treatment with MIRVASO topical gel. Allergic contact dermatitis was reported in the clinical trials for MIRVASO topical gel [ see Adverse Reactions ( 6.1 ) ]. Events reported post marketing with the use of MIRVASO topical gel include angioedema, throat tightening, tongue swelling, and urticaria, [ see Adverse Reactions ( 6.2 ) ]. Institute appropriate therapy and discontinue MIRVASO topical gel, if clinically significant hypersensitivity reaction occurs.

The following adverse drug reactions are discussed in greater detail in other sections of the label:

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. 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 (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.

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. 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. 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. 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.

MIRVASO (brimonidine) topical gel, 0.33% is a white to light yellow opaque gel, supplied in a laminated tube or pump with a child resistant cap in the following sizes: 30 gram tube NDC 0299-5980-30 30 gram pump NDC 0299-5980-35 45 gram tube 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].

Brimonidine is a relatively selective alpha-2 adrenergic agonist. Topical application of MIRVASO topical gel may reduce erythema through direct vasoconstriction. 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 (C max ) and area under the concentration-time curve (AUC) were highest on Day 15, with C max 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.

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.

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. Table 2: Summary of 2-grade Composite Success on Day 29 Success Study 1 Study 2 MIRVASO Topical Gel (N=129) Vehicle Gel (N=131) MIRVAO 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% 2-grade Composite Success: 2-grade improvement on CEA and 2-grade improvement on PSA. figure2-2grade figure1-2grade

Rx Only NDC 0299-5980-35 Mirvaso ® (brimonidine) topical gel, 0.33%* PUMP *Each gram of Mirvaso topical gel contains 5 mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base For Topical Use Only Keep Out of Reach of Children GALDERMA NET WT. 30 g Not for oral, ophthalmic or intravaginal use. To Open Pump: Push the cap down while turning it counter-clockwise to remove the cap. Usual Dosage: Apply a pea-size amount once daily to each of the five areas of the face (forehead, chin, nose, and each cheek) avoiding the eyes and lips. See package insert for complete prescribing information. Each gram contains the active ingredient brimonidine tartrate 5mg with the inactive ingredients carbomer homopolymer type B, glycerin, methylparaben, phenoxyethanol, propylene glycol, purified water, sodium hydroxide, and titanium dioxide. Storage: Store at 20° to 25°C (68° to 77°F), excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature]. See bottom of carton for lot number and expiration date. All trademarks are the property of their respective owners. Marketed by: GALDERMA LABORATORIES, L.P. Dallas, TX 75201 USA Made in Canada P52848-3