Brimonidine Tartrate ophthalmic solution, 0.15%

1 INDICATIONS AND USAGE Brimonidine tartrate ophthalmic solution, 0.15% is an alpha adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Brimonidine Tartrate Ophthalmic Solution is an alpha adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.

2 DOSAGE AND ADMINISTRATION The recommended dose is one drop of brimonidine tartrate ophthalmic solution 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.

4 CONTRAINDICATIONS • 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). 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.

5 WARNINGS AND PRECAUTIONS • Potentiation of vascular insufficiency. ( 5.1 ) 5.1 Potentiation of Vascular Insufficiency Brimonidine tartrate ophthalmic solution may potentiate syndromes associated with vascular insufficiency. Brimonidine tartrate ophthalmic solution should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans. 5.2 Severe Cardiovascular Disease Although brimonidine tartrate ophthalmic solution had minimal effect on the blood pressure of patients in clinical studies, caution should be exercised in treating patients with severe cardiovascular disease. 5.3 Contamination of Topical Ophthalmic Products After Use There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface (see PATIENT COUNSELING INFORMATION , 17).

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 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.

6 ADVERSE REACTIONS Most common adverse reactions occurring in approximately 5% to 20% of patients receiving brimonidine ophthalmic solution (0.1%-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 Alembic Pharmaceuticals, Inc. at 1-866-210-9797 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 10-20% of the subjects receiving brimonidine ophthalmic solution (0.1-0.2%) included: allergic conjunctivitis, conjunctival hyperemia, and eye pruritus. Adverse reactions occurring in approximately 5-9% included: burning sensation, conjunctival folliculosis, hypertension, ocular allergic reaction, oral dryness, and visual disturbance. Adverse reactions occurring in approximately 1-4% of the subjects receiving brimonidine ophthalmic solution (0.1-0.2%) 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 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, depression, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), syncope, and tachycardia. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions.

8.1 Pregnancy Pregnancy Category B: Teratogenicity studies have been performed in animals. Brimonidine tartrate was not teratogenic when given orally during gestation days 6 through 15 in rats and days 6 through 18 in rabbits. The highest doses of brimonidine tartrate in rats (2.5 mg/kg/day) and rabbits (5.0 mg/kg/day) achieved AUC exposure values 360- and 20-fold higher, or 260- and 15-fold higher, respectively, than similar values estimated in humans treated with brimonidine tartrate ophthalmic solution 0.15%,1 drop in both eyes three times daily. There are no adequate and well-controlled studies in pregnant women; however, in animal studies,brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. Because animal reproduction studies are not always predictive of human response, brimonidine tartrate ophthalmic solution should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.