ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling:oPotentiation of Vascular Insufficiency [see Warnings and Precautions (5.1)]oSevere Cardiovascular Disease [see Warnings and Precautions (5.2)]oContamination of Topical Ophthalmic Products after Use [see Warnings and Precautions (5.3)]oNeonates and Infants (Pediatric Patients Younger than Years Old) [see Contraindications (4.1)]. oPotentiation of Vascular Insufficiency [see Warnings and Precautions (5.1)]. oSevere Cardiovascular Disease [see Warnings and Precautions (5.2)]. oContamination of Topical Ophthalmic Products after Use [see Warnings and Precautions (5.3)]. oNeonates and Infants (Pediatric Patients Younger than Years Old) [see Contraindications (4.1)]. 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 Sandoz Inc. at 1-800-525-8747 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. 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.oBradycardia, depression, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), syncope, and tachycardia.oApnea, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions.. oBradycardia, depression, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), syncope, and tachycardia.. oApnea, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisNo compound-related carcinogenic effects were observed in either mice or rats following 21-month and 24- month study, respectively. In these studies, dietary administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and mg/kg/day in rats achieved approximately 150 and 120 times or 93 and 76 times the recommended human ophthalmic dose (RHOD) based on Cmax respectively for brimonidine tartrate 0.1% or 0.15%.MutagenesisBrimonidine tartrate was not mutagenic or clastogenic in series of in vitro and in vivo studies including the Ames bacterial reversion test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and three in vivo studies in CD-1 mice: host-mediated assay, cytogenetic study, and dominant lethal assay.Impairment of FertilityA reproduction and fertility study in rats with brimonidine tartrate demonstrated no adverse effect on male or female fertility at oral doses up to mg/kg (approximately 250 or 180 times the recommended human ophthalmic dose [RHOD] based on estimated AUC) respectively for brimonidine tartrate 0.1% and 0.15%.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Brimonidine tartrate ophthalmic solution is relatively selective alpha-2 adrenergic receptor agonist with peak ocular hypotensive effect occurring at two hours post-dosing. Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has dual mechanism of action by reducing aqueous humor production and increasing uveoscleral outflow. 12.3 Pharmacokinetics AbsorptionAfter ocular administration of either 0.1% or 0.2% solution, plasma concentrations peaked within 0.5 to 2.5 hours and declined with systemic half-life of approximately hours. DistributionBrimonidine was approximately 29% bound to plasma proteins in healthy subjects.. EliminationMetabolismIn humans, brimonidine is extensively metabolized by the liver. ExcretionUrinary excretion is the major route of elimination of brimonidine and its metabolites. Approximately 87% of an orally-administered radioactive dose of brimonidine was eliminated within 120 hours, with 74% found in the urine.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES Elevated IOP presents major risk factor in glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss. Brimonidine tartrate has the action of lowering intraocular pressure with minimal effect on cardiovascular and pulmonary parameters. Clinical studies were conducted to evaluate the safety, efficacy, and acceptability of brimonidine tartrate ophthalmic solution 0.15% compared with brimonidine tartrate ophthalmic solution administered three-times-daily in patients with open-angle glaucoma or ocular hypertension. Those results indicated that brimonidine tartrate ophthalmic solution 0.15% is comparable in IOP lowering effect to brimonidine tartrate ophthalmic solution 0.2%, and effectively lowers IOP in patients with open-angle glaucoma or ocular hypertension by approximately to mmHg.A clinical study was conducted to evaluate the safety, efficacy, and acceptability of brimonidine tartrate ophthalmic solution, 0.1% compared with brimonidine tartrate ophthalmic solution, 0.2% administered three-times-daily in patients with open-angle glaucoma or ocular hypertension. Those results indicated that brimonidine tartrate ophthalmic solution 0.1% is equivalent in IOP lowering effect to brimonidine tartrate ophthalmic solution 0.2%, and effectively lowers IOP in patients with open-angle glaucoma or ocular hypertension by approximately to mmHg.

DESCRIPTION SECTION.

11 DESCRIPTION Brimonidine tartrate ophthalmic solution, 0.1%, sterile, is relatively selective alpha-2 adrenergic receptor agonist for topical ophthalmic use. The structural formula of brimonidine tartrate is: 5-Bromo-6-(2-Imidazolin-2-ylamino)quinoxaline Tartrate; MW 442.22In solution, brimonidine tartrate ophthalmic solution, 0.1% has clear, greenish-yellow color. It has an osmolality of 255 to 300 mOsmol/kg and pH of 7.5 to 7.8. Brimonidine tartrate appears as an white to off-white, pale yellow to 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% contains: Active ingredient: brimonidine tartrate 0.1% (1 mg/mL). Preservative: sodium chlorite 0.005% (0.05 mg/mL). Inactives: boric acid; calcium chloride; magnesium chloride; potassium chloride; sodium borate; sodium carboxymethylcellulose; sodium chloride and purified water. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. structure.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oAntihypertensives/cardiac glycosides may lower blood pressure. (7.1) oUse with CNS depressants may result in an additive or potentiating effect. (7.2) oTricyclic antidepressants may potentially blunt the hypotensive effect of systemic clonidine. (7.3) oMonoamine oxidase inhibitors may result in increased hypotension. (7.4) oAntihypertensives/cardiac glycosides may lower blood pressure. (7.1) oUse with CNS depressants may result in an additive or potentiating effect. (7.2) oTricyclic antidepressants may potentially blunt the hypotensive effect of systemic clonidine. (7.3) oMonoamine 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Handling the ContainerInstruct patients that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Warnings and Precautions (5.3)]. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle.When to Seek Physician AdviceAdvise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physicians advice concerning the continued use of the present multidose container.Use with Other Ophthalmic DrugsAdvise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart.Potential for Decreased Mental AlertnessAs with other similar medications, brimonidine tartrate ophthalmic solution may cause fatigue and/or drowsiness in some patients. Caution patients who engage in hazardous activities of the potential for decrease in mental alertness.Manufactured by Alcon Laboratories, Inc.Fort Worth, TX 76134 for Sandoz Inc.Princeton, NJ 08540Rev. October 2025300074220-1025.

LACTATION SECTION.

8.2 Lactation Risk SummaryIt 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 in nursing infants, brimonidine tartrate ophthalmic solution is not recommended for use during lactation.DataAnimal DataAfter single oral dose of 14C-labeled brimonidine tartrate to lactating rats, brimonidine and metabolites were detected in milk. After male and female rats received single oral dose of 14C-brimonidine tartrate, brimonidine crossed the blood-brain barrier. Radiolabel was detected in the cerebellum, cerebrum, and spinal cord.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisNo compound-related carcinogenic effects were observed in either mice or rats following 21-month and 24- month study, respectively. In these studies, dietary administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and mg/kg/day in rats achieved approximately 150 and 120 times or 93 and 76 times the recommended human ophthalmic dose (RHOD) based on Cmax respectively for brimonidine tartrate 0.1% or 0.15%.MutagenesisBrimonidine tartrate was not mutagenic or clastogenic in series of in vitro and in vivo studies including the Ames bacterial reversion test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and three in vivo studies in CD-1 mice: host-mediated assay, cytogenetic study, and dominant lethal assay.Impairment of FertilityA reproduction and fertility study in rats with brimonidine tartrate demonstrated no adverse effect on male or female fertility at oral doses up to mg/kg (approximately 250 or 180 times the recommended human ophthalmic dose [RHOD] based on estimated AUC) respectively for brimonidine tartrate 0.1% and 0.15%.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Brimonidine tartrate ophthalmic solution is contraindicated in pediatric patients younger than years old [see Contraindications (4.1)]. During postmarketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine. In well-controlled clinical study conducted in pediatric glaucoma patients aged to years old, the most commonly observed adverse reactions with brimonidine tartrate ophthalmic solution 0.2% dosed three times daily were somnolence (50% to 83% in pediatric patients aged to years old) and decreased alertness. In pediatric patients aged years and older (greater than 20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of pediatric patients on brimonidine tartrate ophthalmic solution 0.2% discontinued from the study due to somnolence.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryThere are no adequate and well-controlled studies with brimonidine tartrate ophthalmic solution 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 limited extent (see Data). 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.DataHuman DataLimited available data from postmarketing safety reports and published literature with topical use of brimonidine ophthalmic solution in pregnant women are insufficient to inform drug-associated risk of pregnancy-related adverse outcomes including miscarriage, stillbirth, congenital anomaly, and events experienced by offspring while breastfeeding.Animal DataEmbryofetal studies were conducted in pregnant rabbits administered brimonidine tartrate by daily oral gavage on gestation days to 18, to target the period of organogenesis. Brimonidine caused miscarriage at 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 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 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 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 single oral dose of 14C-brimonidine tartrate, brimonidine and metabolites crossed the placenta and were detectable in fetal blood and organs.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Use with caution in pediatric patients aged years and older. (8.4) 8.1 Pregnancy Risk SummaryThere are no adequate and well-controlled studies with brimonidine tartrate ophthalmic solution 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 limited extent (see Data). 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.DataHuman DataLimited available data from postmarketing safety reports and published literature with topical use of brimonidine ophthalmic solution in pregnant women are insufficient to inform drug-associated risk of pregnancy-related adverse outcomes including miscarriage, stillbirth, congenital anomaly, and events experienced by offspring while breastfeeding.Animal DataEmbryofetal studies were conducted in pregnant rabbits administered brimonidine tartrate by daily oral gavage on gestation days to 18, to target the period of organogenesis. Brimonidine caused miscarriage at 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 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 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 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 single oral dose of 14C-brimonidine tartrate, brimonidine and metabolites crossed the placenta and were detectable in fetal blood and organs.. 8.2 Lactation Risk SummaryIt 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 in nursing infants, brimonidine tartrate ophthalmic solution is not recommended for use during lactation.DataAnimal DataAfter single oral dose of 14C-labeled brimonidine tartrate to lactating rats, brimonidine and metabolites were detected in milk. After male and female rats received single oral dose of 14C-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 is contraindicated in pediatric patients younger than years old [see Contraindications (4.1)]. During postmarketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine. In well-controlled clinical study conducted in pediatric glaucoma patients aged to years old, the most commonly observed adverse reactions with brimonidine tartrate ophthalmic solution 0.2% dosed three times daily were somnolence (50% to 83% in pediatric patients aged to years old) and decreased alertness. In pediatric patients aged years and older (greater than 20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of pediatric patients on brimonidine tartrate ophthalmic solution 0.2% discontinued from the study due to somnolence. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and other adult patients.

WARNINGS AND PRECAUTIONS SECTION.

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, Raynauds 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 concurrent corneal disease or disruption of the ocular epithelial surface. Do not touch the tip of the dispensing container to the eye or surrounding structures. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Patient Counseling Information (17)].