brimonidine

1 INDICATIONS AND USAGE 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. 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 )

2 DOSAGE AND ADMINISTRATION Apply a pea-sized amount once daily to each of the five areas of the face: central forehead, chin, nose, each cheek. Brimonidine 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 brimonidine topical gel. Brimonidine 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 brimonidine topical gel. ( 2 ) • For topical use only ( 2 ) • Not for oral, ophthalmic, or intravaginal use. ( 2 )

3 DOSAGE FORMS AND STRENGTHS 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 )

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

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 ) ] In controlled clinical trials with brimonidine 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 Padagis ® at 1-866-634-9120 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 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 brimonidine 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 brimonidine topical gel once daily for 29 days and for which the rate for brimonidine 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 Brimonidine 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 brimonidine 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 brimonidine 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 brimonidine 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 brimonidine topical gel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular disorders: bradycardia, hypotension (including orthostatic hypotension) Immune system disorders: angioedema, hypersensitivity, lip swelling, swollen tongue, throat tightness, urticaria Nervous system disorders: dizziness Skin and subcutaneous disorders: pallor

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 brimonidine 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 brimonidine topical gel in pregnant women. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. Brimonidine 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 brimonidine 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 brimonidine 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 brimonidine 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 brimonidine topical gel. No overall differences in safety or effectiveness were observed between subjects ≥ 65 years of age and younger adult subjects. Clinical studies of brimonidine topical gel did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

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

11 DESCRIPTION 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 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 benzalkonium chloride, carbomer homopolymer type B, glycerin, propylene glycol, purified water, sodium hydroxide, and talc. Brimonidine Structure.jpg

10 OVERDOSAGE No information is available on overdose in adults with brimonidine 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 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 45802- 078 -94 45 gram tube NDC 45802- 078 -84 30 gram pump NDC 45802- 078 -30 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].