Brimonidine Tartrate

RECENT MAJOR CHANGES SECTION Warnings and Precautions ( 5.3 ) 9/2025

1 INDICATIONS & USAGE Brimonidine tartrate ophthalmic solution, 0.2% is indicated for lowering intraocular pressure in patients with open-angle glaucoma or ocular hypertension. The IOP lowering efficacy of Brimonidine tartrate ophthalmic solution, 0.2% diminishes over time in some patients. This loss of effect appears with a variable time of onset in each patient and should be closely monitored. Brimonidine Tartrate Ophthalmic Solution, 0.2% is an alpha adrenergic agonist indicated for lowering intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dosage is one drop of brimonidine tartrate ophthalmic solution 0.1% or 0.15% in the affected eye(s) three times daily, approximately 8 hours apart. Brimonidine tartrate ophthalmic solution 0.1% or 0.15% may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart. One drop in the affected eye(s) three times daily, approximately 8 hours apart. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Ophthalmic solution containing 0.1% (1 mg/mL) or 0.15% (1.5 mg/mL) brimonidine tartrate. Ophthalmic solution containing 0.1% (1 mg/mL) or 0.15% (1.5 mg/mL) brimonidine tartrate. ( 3 )

4 CONTRAINDICATIONS Brimonidine Tartrate Ophthalmic Solution, 0.2% is contraindicated in patients with hypersensitivity to brimonidine tartrate or any component of this medication. It is also contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy. Neonates and infants (under the age of 2 years). ( 4.1 ) 4.1 Neonates and Infants (under the age of 2 years) Brimonidine tartrate ophthalmic solution, 0.2% is contraindicated in neonates and infants (under the age of 2 years) [ see Use in Specific Populations ( 8.4)] . 4.2 Hypersensitivity Reactions Brimonidine tartrate ophthalmic solution, 0.2% is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this medication in the past [ see Adverse Reactions ( 6.1 ) and ( 6.2 )].

6 ADVERSE REACTIONS Most common adverse reactions occurring in approximately 5% to 20% of patients receiving brimonidine ophthalmic solution (0.1% to 0.2%) included allergic conjunctivitis, burning sensation, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, hypertension, ocular allergic reaction, oral dryness and visual disturbance. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Upsher-Smith Laboratories, LLC at 1-855-899-9180 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are described elsewhere in the labeling: • Potentiation of Vascular Insufficiency [see Warnings and Precautions (5.1) ] • Severe Cardiovascular Disease [see Warnings and Precautions ( 5.2 ) ] • Contamination of Topical Ophthalmic Products after Use [see Warnings and Precautions ( 5.3 ) ] • Neonates and Infants (Pediatric Patients Younger than 2 Years Old) [see Contraindications ( 4.1 ) ] 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. Adverse reactions occurring in approximately 10% to 20% of the subjects receiving brimonidine ophthalmic solution (0.1% to 0.2%) included: allergic conjunctivitis, conjunctival hyperemia, and eye pruritus. Adverse reactions occurring in approximately 5% to 9% included: burning sensation, conjunctival folliculosis, hypertension, ocular allergic reaction, oral dryness, and visual disturbance. Adverse reactions occurring in approximately 1% to 4% of the subjects receiving brimonidine ophthalmic solution (0.1% to 0.2%) included: abnormal taste, allergic reaction, asthenia, blepharitis, blepharoconjunctivitis, blurred vision, bronchitis, cataract, conjunctival edema, conjunctival hemorrhage, conjunctivitis, cough, dizziness, dyspepsia, dyspnea, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, fatigue, flu syndrome, follicular conjunctivitis, foreign body sensation, gastrointestinal disorder, headache, hypercholesterolemia, hypotension, infection (primarily colds and respiratory infections), insomnia, keratitis, lid disorder, pharyngitis, photophobia, rash, rhinitis, sinus infection, sinusitis, somnolence, stinging, superficial punctate keratopathy, tearing, visual field defect, vitreous detachment, vitreous disorder, vitreous floaters, and worsened visual acuity. The following reactions were reported in less than 1% of subjects: corneal erosion, hordeolum, nasal dryness, and taste perversion. 6.2 Postmarketing Experience The following reactions have been identified during postapproval use of brimonidine tartrate ophthalmic solutions. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Bradycardia, depression, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), syncope, and tachycardia. Apnea, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions.

The following serious adverse reactions are described elsewhere in the labeling: • Potentiation of Vascular Insufficiency [see Warnings and Precautions (5.1) ] • Severe Cardiovascular Disease [see Warnings and Precautions ( 5.2 ) ] • Contamination of Topical Ophthalmic Products after Use [see Warnings and Precautions ( 5.3 ) ] • Neonates and Infants (Pediatric Patients Younger than 2 Years Old) [see Contraindications ( 4.1 ) ]

7 DRUG INTERACTIONS Antihypertensives/cardiac glycosides may lower blood pressure. ( 7.1 ) Use with CNS depressants may result in an additive or potentiating effect. ( 7.2 ) Tricyclic antidepressants may potentially blunt the hypotensive effect of systemic clonidine. ( 7.3 ) Monoamine oxidase inhibitors may result in increased hypotension. ( 7.4 ) 7.1 Antihypertensives/Cardiac Glycosides Because brimonidine tartrate ophthalmic solution 0.1% and 0.15% may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with brimonidine tartrate ophthalmic solution 0.1% and 0.15% is advised. 7.2 CNS Depressants Although specific drug interaction studies have not been conducted with brimonidine tartrate ophthalmic solution 0.1% and 0.15%, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered. 7.3 Tricyclic Antidepressants Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with brimonidine tartrate ophthalmic solution 0.1% and 0.15% in humans can lead to resulting interference with the IOP lowering effect. Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines. 7.4 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 Use with caution in pediatric patients aged 2 years and older. ( 8.4 ) 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with brimonidine tartrate ophthalmic solution 0.1% and 0.15% in pregnant women. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent (see Data) . Because animal reproduction studies are not always predictive of human response, brimonidine tartrate ophthalmic solution 0.1% and 0.15% should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Data Human Data Limited available data from postmarketing safety reports and published literature with topical use of brimonidine ophthalmic solution in pregnant women are insufficient to inform a drug-associated risk of pregnancy-related adverse outcomes including miscarriage, stillbirth, congenital anomaly, and events experienced by offspring while breastfeeding. Animal Data Embryofetal studies were conducted in pregnant rabbits administered brimonidine tartrate by daily oral gavage on gestation days 6 to 18, to target the period of organogenesis. Brimonidine caused miscarriage at 5 mg/kg/day (approximately 70- or 50-times the recommended human ophthalmic dose [RHOD] based on AUC, respectively for brimonidine tartrate 0.1% and 0.15%). The no observed adverse effect level (NOAEL) for developmental toxicity in rabbits was 1 mg/kg/day (approximately 9- and 6-fold the RHOD based on AUC, respectively for brimonidine tartrate 0.1% and 0.15%). No treatment-related malformations were observed in rabbits. Signs of maternal sedation and fatigue were observed at all dose levels; the lowest observed adverse effect level (LOAEL) for maternal toxicity was 5 mg/kg/day, based on the dose response for these signs. Embryofetal studies were conducted in pregnant rats administered brimonidine tartrate by daily oral gavage on gestation days 6 to 15, to target the period of organogenesis. The NOAEL for developmental toxicity was 2.5 mg/kg/day (approximately 1100- and 750-fold the RHOD based on AUC, respectively for brimonidine tartrate 0.1% and 0.15%). No treatment-related malformations were observed in rats. The LOAEL for maternal toxicity was 2.5 mg/kg/day, based on signs of sedation and fatigue. The maternal NOAEL was 1.0 mg/kg/day (250- and 180-fold the RHOD based on AUC, respectively for brimonidine tartrate 0.1% and 0.15%). After pregnant rats received a single oral dose of 14 C-brimonidine tartrate, brimonidine and metabolites crossed the placenta and were detectable in fetal blood and organs. 8. 2 Lactation Risk Summary It is not known whether brimonidine tartrate is excreted in human milk. In animal studies, brimonidine tartrate has been shown to cross the blood-brain barrier and is excreted into breast milk after oral administration to lactating rats ( see Data) . Because of the potential for serious adverse reactions, including central nervous system depression and apnea, from brimonidine tartrate ophthalmic solution 0.1% and 0.15% in nursing infants, brimonidine tartrate ophthalmic solution 0.1% and 0.15% is not recommended for use during lactation. Data Animal Data After a single oral dose of 14 C-labeled brimonidine tartrate to lactating rats, brimonidine and metabolites were detected in milk. After male and female rats received a single oral dose of 14 C-brimonidine tartrate, brimonidine crossed the blood-brain barrier. Radiolabel was detected in the cerebellum, cerebrum, and spinal cord. 8.4 Pediatric Use Brimonidine tartrate ophthalmic solution 0.1% and 0.15% is contraindicated in pediatric patients younger than 2 years old [ see Contraindications ( 4.1 )] . During postmarketing surveillance, apnea, bradycardia, coma, hypotensi …

12.1 Mechanism of Action Brimonidine tartrate ophthalmic solution 0.1% and 0.15% is a relatively selective alpha-2 adrenergic receptor agonist with a peak ocular hypotensive effect occurring at two hours post-dosing. Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action by reducing aqueous humor production and increasing uveoscleral outflow.

11 DESCRIPTION Brimonidine tartrate ophthalmic solution 0.1% or 0.15%, sterile, is a relatively selective alpha-2 adrenergic receptor agonist for topical ophthalmic use. The structural formula of brimonidine tartrate is: 5-Bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate; MW= 442.24 In solution, brimonidine tartrate ophthalmic solution 0.1% and 0.15% has a clear, greenish-yellow color. It has an osmolality of 250-350 mOsmol/kg and a pH of 7.4-8.0 (0.1%) or 6.9-7.4 (0.15%). Brimonidine tartrate appears as an off-white to pale-yellow powder and is soluble in both water (0.6 mg/mL) and in the product vehicle (1.4 mg/mL) at pH 7.7. Each mL of brimonidine tartrate ophthalmic solution 0.1% and 0.15% contains the active ingredient brimonidine tartrate 0.1% (1 mg/mL) or 0.15% (1.5 mg/mL) with the inactive ingredients sodium carboxymethylcellulose; sodium borate; boric acid; sodium chloride; potassium chloride; calcium chloride; magnesium chloride; PURITE ® 0.005% (0.05 mg/mL) as a preservative; purified water; and hydrochloric acid and/or sodium hydroxide to adjust pH. The structural formula of brimonidine tartrate.

10 OVERDOSAGE Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse reaction reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine tartrate ophthalmic solution as part of medical treatment of congenital glaucoma or by accidental oral ingestion (see USE IN SPECIFIC POPULATIONS , 8.4). Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained. 5-Bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate; MW= 442.24 In solution, brimonidine tartrate ophthalmic solution has a clear, greenish-yellow color. It has an osmolality of 250-350 mOsmol/kg and a pH of 7.4-8.0. Brimonidine tartrate appears as a pale yellow colored powder to wheatish colored powder and is soluble in water at pH 7.4 to 8.0. Each mL of brimonidine tartrate ophthalmic solution contains the active ingredient brimonidine tartrate 0.1% (1 mg/mL) with the inactive ingredients sodium carboxymethylcellulose; sodium borate; boric acid; sodium chloride; potassium chloride; calcium chloride; magnesium chloride; iPRES 25 - Stablized Oxychloro Complex (0.005%) 0.05 mg/mL as a preservative; water for injection; and hydrochloric acid and/or sodium hydroxide to adjust pH.

16 HOW SUPPLIED/STORAGE AND HANDLING Brimonidine tartrate ophthalmic solution, 0.2% is supplied sterile, in white opaque LDPE plastic bottles and natural nozzle with purple tear-off HDPE caps as follows: 5 mL in 5mL bottle NDC 14445-400-05 10 mL in 10 mL bottle NDC 14445-400-10 15 mL in 15 mL bottle NDC 14445-400-15. STORAGE: Store between 20°- 25°C (68°- 77°F) [See USP Controlled Room Temperature]. KEEP OUT OF THE REACH OF CHILDREN. TEAR AND DISCARD RING BEFORE USE Do not use if tear-off ring is broken or missing.