BRIMONIDINE TARTRATE

Brimonidine tartrate ophthalmic solution, 0.2% is a relatively selective alpha-2 adrenergic agonist for ophthalmic use. The chemical name of brimonidine tartrate is 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate. It has a molecular weight of 442.24 as the tartrate salt and is water soluble (34 mg/mL) at pH 6.5. The structural formula is: In solution, brimonidine tartrate ophthalmic solution, 0.2% has a clear, greenish-yellow color. It has an osmolality of 280-330 mOsml/kg and a pH of 5.6-6.6. Each mL of brimonidine tartrate ophthalmic solution, 0.2% contains: Active: brimonidine tartrate 0.2% (2 mg/mL). Preservative: benzalkonium chloride 0.005% (0.05 mg). Inactives: citric acid; polyvinyl alcohol; purified water; sodium chloride and sodium citrate. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. chemical

Brimonidine tartrate ophthalmic solution, 0.2% is indicated for lowering intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. The IOP lowering efficacy of brimonidine tartrate ophthalmic solution 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 )

The recommended dose is one drop of brimonidine tartrate ophthalmic solution, 0.2% in the affected eye(s) three times daily, approximately 8 hours apart. Brimonidine tartrate ophthalmic solution 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 )

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 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 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 )].

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 (under the age of 2 years) [see Contraindications ( 4.1 )] Most common adverse reactions occurring in approximately 10 to 30% of patients receiving brimonidine ophthalmic solution 0.2% included oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. • Adverse reactions occurring in approximately 10-30% of the subjects (in descending order): oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus. • Adverse reactions occurring in approximately 3-9% of the subjects (in descending order): corneal staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, conjunctival blanching, abnormal vision and muscular pain. • Adverse reactions reported < 3% of the patients: lid crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival discharge, depression, hypertension, anxiety, palpitations/arrhythmias, nasal dryness and syncope. 6.2 Postmarketing Experience The following reactions have been identified during postmarketing use of brimonidine tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: • Bradycardia; conjunctivitis; hypersensitivity; hypotension; iritis; keratoconjunctivitis sicca; lacrimation increased; miosis; nausea; skin reactions (including erythema, eyelid pruritus, rash, and vasodilation); and tachycardia. • Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence in infants receiving brimonidine tartrate ophthalmic solutions.

• 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 may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with brimonidine tartrate ophthalmic solution is advised. 7.2 CNS Depressants Although specific drug interaction studies have not been conducted with brimonidine tartrate ophthalmic solution, 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 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.