ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 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 years) [see Contraindications (4.1)]. 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 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 Akorn, Inc., at 1-800-932-5676 or the 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 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% to 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% to 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.. Adverse reactions occurring in approximately 10% to 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% to 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 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 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.. 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No 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 1.0 mg/kg/day in rats achieved ~77 and 118 times, respectively, the plasma Cmax drug concentration estimated in humans treated with one drop brimonidine tartrate ophthalmic solution 0.2% into both eyes times per day.Brimonidine 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.A 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, estimated as approximately 200 times the systemic exposure (AUC) following the maximum recommended human ophthalmic dose of brimonidine tartrate ophthalmic solution 0.5%.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Brimonidine tartrate ophthalmic solution 0.2% 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 0.2% solution, plasma concentrations peaked within to hours and declined with systemic half-life of approximately hours.. DistributionThe protein binding of brimonidine has not been studied.. MetabolismIn 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.In comparative clinical studies with timolol 0.5%, lasting up to one year, the IOP lowering effect of brimonidine tartrate ophthalmic solution was approximately to mm Hg compared with approximately mm Hg for timolol. In these studies, both patient groups were dosed BID; however, due to the duration of action of brimonidine tartrate ophthalmic solution, it is recommended that brimonidine tartrate ophthalmic solution be dosed TID. Eight percent of subjects were discontinued from studies due to inadequately controlled intraocular pressure, which in 30% of these patients occurred during the first month of therapy. Approximately 20% were discontinued due to adverse experiences.

DESCRIPTION SECTION.

11 DESCRIPTION. Brimonidine tartrate ophthalmic solution 0.2%, sterile, is relatively selective alpha-2 adrenergic receptor agonist (topical intraocular pressure lowering agent).The structural formula of brimonidine tartrate is:5-Bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate; MW= 442.24In solution, brimonidine tartrate ophthalmic solution 0.2% has clear, greenish-yellow color. It has an osmolality of 280 to 330 mOsml/kg and pH of 5.6 to 6.6.Each mL of brimonidine tartrate ophthalmic solution contains the active ingredient brimonidine tartrate 0.2% (2 mg/mL) with the inactive ingredients benzalkonium chloride 0.005% (0.05 mg/mL) as preservative; citric acid; polyvinyl alcohol; sodium chloride; sodium citrate; and water for injection. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH.. Structural Formula.

DRUG INTERACTIONS SECTION.

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). 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.

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 Contact LensesAdvise patients that contact lenses should be removed prior to instillation of brimonidine tartrate ophthalmic solution and may be reinserted 15 minutes following its administration.. 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.AKORNManufactured by: Akorn, Inc. Lake Forest, IL 60045BT00N Rev. 10/16.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No 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 1.0 mg/kg/day in rats achieved ~77 and 118 times, respectively, the plasma Cmax drug concentration estimated in humans treated with one drop brimonidine tartrate ophthalmic solution 0.2% into both eyes times per day.Brimonidine 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.A 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, estimated as approximately 200 times the systemic exposure (AUC) following the maximum recommended human ophthalmic dose of brimonidine tartrate ophthalmic solution 0.5%.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Brimonidine tartrate ophthalmic solution is contraindicated in children under the age of years [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. The safety and effectiveness of brimonidine tartrate have not been studied in children below the age of years.In well-controlled clinical study conducted in pediatric glaucoma patients (ages to years) the most commonly observed adverse reactions with brimonidine tartrate ophthalmic solution 0.2% dosed three times daily were somnolence (50% to 83% in patients ages to years) and decreased alertness. In pediatric patients years of age (greater than 20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of patients on brimonidine tartrate ophthalmic solution 0.2% discontinued from the study due to somnolence.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category B: Teratogenicity studies have been performed in animals.Brimonidine tartrate was not teratogenic when given orally during gestation days through 15 in rats and days through 18 in rabbits. The highest doses of brimonidine tartrate in rats (2.5 mg/kg/day) and rabbits (5 mg/kg/day) achieved AUC exposure values 375-fold higher or 19-fold higher, respectively, than similar values estimated in humans treated with brimonidine tartrate ophthalmic solution 0.2%, one drop in one eye, twice 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 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Use with caution in children >= years of age. (8.4). 8.1 Pregnancy. Pregnancy Category B: Teratogenicity studies have been performed in animals.Brimonidine tartrate was not teratogenic when given orally during gestation days through 15 in rats and days through 18 in rabbits. The highest doses of brimonidine tartrate in rats (2.5 mg/kg/day) and rabbits (5 mg/kg/day) achieved AUC exposure values 375-fold higher or 19-fold higher, respectively, than similar values estimated in humans treated with brimonidine tartrate ophthalmic solution 0.2%, one drop in one eye, twice 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 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.. 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 tartrate ophthalmic solution in nursing infants, 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. Brimonidine tartrate ophthalmic solution is contraindicated in children under the age of years [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. The safety and effectiveness of brimonidine tartrate have not been studied in children below the age of years.In well-controlled clinical study conducted in pediatric glaucoma patients (ages to years) the most commonly observed adverse reactions with brimonidine tartrate ophthalmic solution 0.2% dosed three times daily were somnolence (50% to 83% in patients ages to years) and decreased alertness. In pediatric patients years of age (greater than 20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of 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.. 8.6 Special Populations. Brimonidine tartrate ophthalmic solution has not been studied in patients with hepatic impairment.Brimonidine tartrate ophthalmic solution has not been studied in patients with renal impairment. The effect of dialysis on brimonidine pharmacokinetics in patients with renal failure is not known.

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 [see Patient Counseling Information (17)].. 5.4 Use with Contact Lenses. The preservative in brimonidine tartrate ophthalmic solution, benzalkonium chloride, may be absorbed by soft contact lenses. Patients wearing soft contact lenses should be instructed to wait at least 15 minutes after instilling brimonidine tartrate ophthalmic solution to insert soft contact lenses.