NURSING MOTHERS SECTION.

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, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.

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; patent airway should be maintained.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse drug reactions are discussed in greater detail in other sections of the label:Systemic Adverse Reactions of Alpha-2 Adrenergic Agonists [see Warnings and Precautions (5.4)]Local Vasomotor Adverse Reactions [see Warnings and Precautions (5.5)]Hypersensitivity [see Warnings and Precautions (5.6)]. Systemic Adverse Reactions of Alpha-2 Adrenergic Agonists [see Warnings and Precautions (5.4)]. Local Vasomotor Adverse Reactions [see Warnings and Precautions (5.5)]. Hypersensitivity [see Warnings and Precautions (5.6)]. 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 . 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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. 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 - Adverse Reactions Reported in Clinical Trials by at Least 1% of Subjects Treated for 29 DaysPreferred TermMIRVASO Topical Gel(N=330)n (%)Vehicle Gel(N=331)n (%)Subjects with at least one adverse reaction, Number (%) of Subjects109 (33)91 (28)Erythema12 (4%)3 (1%)Flushing9 (3%)0Skin burning sensation5 (2%)2 (1%)Dermatitis contact3 (1%)1 (<1%)Dermatitis3 (1%)1 (<1%)Skin warm3 (1%)0Paraesthesia2 (1%)1 (<1%)Acne2 (1%)1 (<1%)Pain of skin2 (1%)0Vision blurred2 (1%)0Nasal congestion2 (1%)0Open-label, Long-term StudyAn 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. 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 dermatitisAllergic 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).. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of MIRVASO topical gel. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to estimate their frequency or establish causal relationship to drug exposure.Cardiovascular disorders: bradycardia, hypotension (including orthostatic hypotension)Immune system disorders: angioedema, hypersensitivity, lip swelling, swollen tongue, throat tightness, urticariaNervous systemic disorders: dizzinessSkin and subcutaneous disorders: pallor.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 21-month oral (diet) mouse carcinogenicity study and 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 mg/kg/day.In 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 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.MutagenesisBrimonidine tartrate was not mutagenic or clastogenic in series of in vitro and in vivo studies, including the Ames test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and three studies in CD1 mice (a host-mediated assay, cytogenetic study, and dominant lethal assay).Impairment of FertilityReproduction and fertility studies in rats with brimonidine tartrate demonstrated no adverse effects on male or female fertility at oral doses up to mg/kg/day.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Brimonidine is relatively selective alpha-2 adrenergic agonist. Topical application of MIRVASO topical gel may reduce erythema through direct vasoconstriction.. 12.3 Pharmacokinetics. AbsorptionThe absorption of brimonidine from MIRVASO topical gel was evaluated in clinical trial in 24 adult subjects with facial erythema associated with rosacea. All enrolled subjects received once daily topical application of MIRVASO topical gel 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.MetabolismBrimonidine is extensively metabolized by the liver.ExcretionUrinary excretion is the major route of elimination of brimonidine and its metabolites.

CLINICAL STUDIES SECTION.

14 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 weeks with either MIRVASO topical gel or vehicle. Overall, 99% of subjects were Caucasian and 76% were female. Baseline disease severity was graded using 5-point Clinical Erythema Assessment (CEA) scale and 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 2-grade improvement on both CEA and PSA measured at hours 3, 6, 9, and 12 on Day 29. Table 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 and for Studies and 2, respectively.Table 2: Summary of 2-grade Composite Success on Day 29SuccessStudy 1Study 2MIRVASO Topical Gel(N=129)Vehicle Gel(N=131)MIRVAO Topical Gel(N=148)Vehicle Gel(N=145)Hour 331%11%25%9%Hour 630%10%25%9%Hour 926%10%18%11%Hour 1223%9%22%10%2-grade Composite Success: 2-grade improvement on CEA and 2-grade improvement on PSA. figure2-2grade. figure1-2grade.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. MIRVASO topical gel is contratindicated in patients who have experienced 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).

DESCRIPTION SECTION.

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 molecular weight of 442.24 and appears as white to slightly yellowish powder.Each gram of MIRVASO (brimonidine) topical gel, 0.33% contains mg of the active ingredient brimonidine tartrate (equivalent to 3.3 mg of brimonidine free base), in 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Apply 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 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 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). Apply 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).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. MIRVASO (brimonidine) topical gel, 0.33% is white to light yellow opaque aqueous gel. Each gram of gel contains mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base.. Gel, 0.33%; Each gram of gel contains mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS . 7.1 Anti-hypertensives/Cardiac Glycosides Alpha-2 agonists, as 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.

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. MIRVASO (brimonidine) topical gel, 0.33% is white to light yellow opaque gel, supplied in laminated tube or pump with child resistant cap in the following sizes:30 gram tube NDC 0299-5980-3030 gram pump NDC 0299-5980-3545 gram tube NDC 0299-5980-45Store at 20C to 25C (68F to 77F), excursions permitted between 15C and 30C (59F and 86F) [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

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.. 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Patient Information and Instructions for Use)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, flushing or excessive whitening.Patients should report any adverse reactions to their physician.Keep out of reach of children.Marketed by:GALDERMA LABORATORIES, L.P., Fort Worth, Texas 76177 USAMade in Canada.All trademarks are the property of their respective owners.P52849-2 or P51217-3. 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, flushing or excessive whitening.. Patients should report any adverse reactions to their physician.. Keep out of reach of children.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn 21-month oral (diet) mouse carcinogenicity study and 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 mg/kg/day.In 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 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.MutagenesisBrimonidine tartrate was not mutagenic or clastogenic in series of in vitro and in vivo studies, including the Ames test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and three studies in CD1 mice (a host-mediated assay, cytogenetic study, and dominant lethal assay).Impairment of FertilityReproduction and fertility studies in rats with brimonidine tartrate demonstrated no adverse effects on male or female fertility at oral doses up to mg/kg/day.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 30g Pump Carton. Rx OnlyNDC 0299-5980-35Mirvaso(R) (brimonidine) topical gel, 0.33%PUMPEach gram of Mirvaso topical gel contains mg of brimonidine tartrate, equivalent to 3.3 mg of brimonidine free base For Topical Use OnlyKeep Out of Reach of ChildrenGALDERMANET WT. 30 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 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 25C (68 to 77F), excursions permitted between 15 and 30C (59 and 86F). [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.Fort Worth, TX 76177 USAMade in CanadaP52848-2.

PATIENT MEDICATION INFORMATION SECTION.

PATIENT INFORMATION. MIRVASO (Mer-VAY-soe)(brimonidine)topical gelImportant information: MIRVASO(R) topical gel is for use on the face only. Do not use MIRVASO topical gel in your eyes, mouth, or vagina. Keep MIRVASO topical gel out of the reach of children. If anyone, especially child, accidentally swallows MIRVASO topical gel, they may have serious side effects and need to be treated in hospital. Get medical help right away if you, child, or anyone else swallows MIRVASO topical gel and has any of these symptoms: lack of energy, trouble breathing or stops breathing, slow heart beat, confusion, sweating, restlessness, muscle spasms, or twitching. What is MIRVASO topical gelMIRVASO topical gel is prescription medicine that is used on your skin (topical) to treat facial redness due to rosacea that does not go away (persistent) in adults who are 18 years of age or older. It is not known if MIRVASO topical gel is safe and effective in children. Who should not use MIRVASO topical gelDo not use MIRVASO topical gel if you have had serious allergic reaction to any of the ingredients in MIRVASO topical gel. See the end of this Patient Information leaflet for list of ingredients in MIRVASO topical gel. See What are the possible side effects of MIRVASO topical gel What should tell my doctor before using MIRVASO topical gelBefore using MIRVASO topical gel, tell your doctor about all of your medical conditions including if you:o have depressiono have heart or blood vessel problemso have dizziness or blood pressure problemso have problems with blood circulation or have had strokeo have dry mouth or Sjogrens Syndromeo have skin tightening or sclerodermao have Raynauds phenomenono have irritated skin or open soreso plan to have any laser procedureso are pregnant or plan to become pregnant. It is not known if MIRVASO topical gel will harm your unborn baby.o are breastfeeding. It is not known if MIRVASO topical gel passes into your breast milk. You and your doctor should decide if you will use MIRVASO topical gel or breastfeed. You should not do both.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, skin products, vitamins, and herbal supplements. Using MIRVASO topical gel with certain other medicines may affect each other and can cause serious side effects.How should use MIRVASO topical gelSee the detailed Instructions for Use that comes with your MIRVASO topical gel tube or pump for information about how to apply MIRVASO topical gel correctly.o Use MIRVASO topical gel exactly as your doctor tells you. Do not use more MIRVASO topical gel than prescribed. Call your doctor if you are not sure.o You should not apply MIRVASO topical gel to irritated skin or open wounds.o MIRVASO topical gel is for use on your skin only. Do not use MIRVASO topical gel in your eyes, mouth, or vagina. Avoid contact with your lips and eyes. What are the possible side effects of MIRVASO topical gelMIRVASO topical gel may cause serious side effects, including:o See Important information at the beginning of this Patient Information leaflet.o Problems with blood circulation. People who use MIRVASO topical gel can have problems with blood circulation, including slow heart rate, low blood pressure, and dizziness. These problems may sometimes be serious and lead to hospitalization. See What should tell my doctor before using MIRVASO topical gel Serious allergic (hypersensitivity) reactions have happened in people who use MIRVASO topical gel. Stop using MIRVASO topical gel and go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serious allergic reaction including: swelling of your face, lips, tongue, or throato hiveso trouble breathingThe most common side effects of MIRVASO topical gel include:o redness flushing burning sensation of the skin skin reactions (contact dermatitis). Skin redness is common after applying MIRVASO topical gel, and may be worse than before you applied it. You may also develop redness on areas of your face that were not affected by rosacea, as well as on your neck and chest. Skin flushing is common and may happen off and on after applying MIRVASO topical gel. In some cases, the flushing may be new, may happen more often, or you may have increased redness with flushing. Pale colored skin or very white skin (excessive whitening) can happen at or outside the treated area. Tell your doctor if you get skin redness, flushing, and pale colored skin that is uncomfortable for you. These are not all the possible side effects of MIRVASO topical gel.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of MIRVASO topical gelMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your pharmacist or doctor for information about MIRVASO topical gel that is written for health professionals. Do not use MIRVASO topical gel for condition for which it was not prescribed. Do not give MIRVASO topical gel to other people, even if they have the same symptoms that you have. It may harm them. What are the ingredients in MIRVASO topical gelActive ingredient: brimonidineInactive ingredients: carbomer homopolymer type B, glycerin, methylparaben, phenoxyethanol, propylene glycol, purified water, sodium hydroxide, titanium dioxide. Marketed by: GALDERMA LABORATORIES, L.P., Fort Worth, TX 76177 USA Made in Canada. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: Nov 2017Instructions for Use MIRVASO (Mer-VAY-soe) (brimonidine)topical geltubeImportant: MIRVASO(R) topical gel is for use on the face only. Do not use MIRVASO topical gel in your eyes, mouth, or vagina. Keep MIRVASO topical gel out of the reach of children. If anyone, especially child, accidentally swallows MIRVASO topical gel, they may have serious side effects and need to be treated in hospital. Get medical help right away if you, child, or anyone else swallows MIRVASO topical gel and has any of these symptoms:o lack of energy, trouble breathing or stops breathing, slow heart beat, confusion, sweating, restlessness, muscle spasms, or twitching.Read and follow the steps below so that you use your tube of MIRVASO topical gel correctly: 1. Open the tube of MIRVASO topical gel by gently pressing down on the child resistant cap and twist in the direction of the arrow as shown below (counterclockwise). See Figures and B. To avoid spilling, do not squeeze the tube while opening or closing. Figure Figure 2. To apply MIRVASO topical gel to your face, squeeze pea-sized amount of MIRVASO topical gel from the tube onto your fingertip. See Figure C. Figure 3. Apply pea-sized amount of MIRVASO topical gel onto each of the five areas of your face (forehead, chin, nose, each cheek) time each day. You will use total of pea-sized amounts of MIRVASO topical gel. Spread the gel smoothly and evenly in thin layer over your face. Avoid contact with your eyes and lips. Do not apply MIRVASO topical gel to irritated skin or open wounds. 4. To close your MIRVASO topical gel tube, place the cap back on the tube. Gently press down on the child resistant cap and twist to the right (clockwise). See Figure D. Figure 5. Wash your hands right away after applying MIRVASO topical gel.How should store MIRVASO topical gelo Store MIRVASO topical gel at room temperature between 68F to 77F (20C to 25C). Keep MIRVASO topical gel and all medicines out of the reach of children.This Instructions for Use has been approved by the U.S. Food and Drug Administration. Marketed by: GALDERMA LABORATORIES, L.P. Fort Worth, TX 76177 USAMade in Canada.Revised: October 2015 Instructions for Use MIRVASO (Mer-VAY-soe) (brimonidine)topical gelPumpImportant: MIRVASO(R) topical gel is for use on the face only. Do not use MIRVASO topical gel in your eyes, mouth, or vagina. Keep MIRVASO topical gel out of the reach of children.If anyone, especially child, accidentally swallows MIRVASO topical gel, they may have serious side effects and need to be treated in hospital. Get medical help right away if you, child, or anyone else swallows MIRVASO topical gel and has any of these symptoms:o lack of energy, trouble breathing or stops breathing, slow heart beat, confusion, sweating, restlessness, muscle spasms, or twitching.Read and follow the steps below so that you use your MIRVASO topical gel correctly: 1. Push the cap down and turn it counter-clockwise until the cap can be removed. See Figures and B. The clear sticker will break when opening for the first time. Note: when the cap is removed, the pump is not child-resistant. Figure Figure Figure Before the first use, prime the pump by pressing down several times until the medicine is dispensed onto your fingertip. 2. To apply MIRVASO topical gel to your face, dispense pea-sized amount of MIRVASO topical gel from the pump onto your fingertip. See Figure C. 3. Apply pea-sized amount of MIRVASO topical gel onto each of the five areas of your face (forehead, chin, nose, each cheek) time each day. You will use total of pea-sized amounts of MIRVASO topical gel. Spread the gel smoothly and evenly in thin layer over your face. Avoid contact with your eyes and lips. Do not apply MIRVASO topical gel to irritated skin or open wounds. 4. To close your MIRVASO topical gel pump, place the cap back on the pump. Push down and turn the cap to the right (clockwise) until it stops. This pump is child-resistant again. See Figure D. Figure 5. Wash your hands right away after applying MIRVASO topical gel. How should store MIRVASO topical gelo Store MIRVASO topical gel at room temperature between 68F to 77F (20C to 25C). Keep MIRVASO topical gel and all medicines out of the reach of children.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Marketed by: GALDERMA LABORATORIES, L.P., Fort Worth, TX 76177 USA, Made in Canada Issued: November 2017.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Keep MIRVASO topical gel out of reach of children. Serious adverse reactions were experienced by two children of subject in clinical trial who accidentally ingested MIRVASO topical gel See Warnings and Precautions (5.3) ].Safety and effectiveness in pediatric patients have not been established.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionThe absorption of brimonidine from MIRVASO topical gel was evaluated in clinical trial in 24 adult subjects with facial erythema associated with rosacea. All enrolled subjects received once daily topical application of MIRVASO topical gel 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.MetabolismBrimonidine is extensively metabolized by the liver.ExcretionUrinary excretion is the major route of elimination of brimonidine and its metabolites.

PREGNANCY SECTION.

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 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 through 15 and mg/kg/day in pregnant rabbits during gestation days through 18.

RECENT MAJOR CHANGES SECTION.

Contraindications (4) 07/2016Warnings and Precautions (5.4, 5.5, 5.6) 07/2016. Contraindications (4) 07/2016. Warnings and Precautions (5.4, 5.5, 5.6) 07/2016.

SPL UNCLASSIFIED SECTION.

5.1 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.

USE IN SPECIFIC POPULATIONS SECTION.

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 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 through 15 and mg/kg/day in pregnant rabbits during gestation days 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, 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 subject in 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.

WARNINGS AND PRECAUTIONS SECTION.

5 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)Systemic Adverse Reactions of Alpha-2 Adrenergic Agonists (5.4)Local Vasomotor Adverse Reactions (5.5)Hypersensitivity (5.6). 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). 5.1 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.. 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 subject in 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.. 5.4 Systemic Adverse Reactions of Alpha-2 Adrenergic Agonists. 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.. 5.5 Local Vasomotor Adverse Reactions. ErythemaSome subjects in the clinical trials discontinued use of MIRVASO topical gel because of erythema. Some subjects in the clinical trials reported 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.FlushingSome 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 oferythema with the flushing. Additionally, some patients reported new onset of flushing.Pallor and Excessive WhiteningFrom postmarketing reports, some patients have experienced pallor or excessive whitening at or outside the application site following treatment with MIRVASO topical gel.. 5.6 Hypersensitivity. 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.