Brimonidine Tartrate/Timolol Maleate

Warnings and Precautions ( 5.10 , 5.12 ) 3/2026

1 INDICATIONS AND USAGE Brimonidine tartrate and timolol maleate ophthalmic solution is indicated for the reduction of elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to inadequately controlled IOP. The IOP-lowering of brimonidine tartrate and timolol maleate ophthalmic solution dosed twice a day was slightly less than that seen with the concomitant administration of 0.5% timolol maleate ophthalmic solution dosed twice a day and 0.2% brimonidine tartrate ophthalmic solution dosed three times per day. Brimonidine tartrate and timolol maleate ophthalmic solution is a combination of brimonidine tartrate, an alpha-adrenergic receptor agonist, and timolol maleate, a beta-adrenergic receptor inhibitor, indicated for the reduction of elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to inadequately controlled IOP. The IOP-lowering of brimonidine tartrate and timolol maleate ophthalmic solution dosed twice a day was slightly less than that seen with the concomitant administration of timolol maleate ophthalmic solution, 0.5% dosed twice a day and brimonidine tartrate ophthalmic solution, 0.2% dosed three times per day. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dose is one drop of brimonidine tartrate/timolol maleate ophthalmic solution in the affected eye(s) twice daily approximately 12 hours apart. 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), twice daily approximately 12 hours apart. ( 2 )

3 DOSAGE FORMS AND STRENGTHS Solution containing 2 mg/mL brimonidine tartrate and 5 mg/mL timolol (6.8 mg/mL timolol maleate). Solution containing 2 mg/mL brimonidine tartrate and 5 mg/mL timolol. ( 3 )

4 CONTRAINDICATIONS • Bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease. ( 4.1 , 5.1 , 5.3 ) • Sinus bradycardia, atrioventricular block, overt cardiac failure, cardiogenic shock. ( 4.2 , 5.2 ) • Neonates and infants (pediatric patients younger than 2 years old). ( 4.3 ) • Hypersensitivity to any component of this product. ( 4.4 ) 4.1 Reactive Airway Disease Including Asthma, COPD Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in patients with reactive airway disease including bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease [see Warnings and Precautions ( 5.1 , 5.3 )] . 4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in patients with sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure [see Warnings and Precautions ( 5.2 )] ; cardiogenic shock. 4.3 Neonates and Infants (Pediatric Patients Younger than 2 Years Old) Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in neonates and infants (pediatric patients younger than 2 years old) [see Use in Specific Populations ( 8.4 )] . 4.4 Hypersensitivity Reactions Local hypersensitivity reactions have occurred following the use of different components of brimonidine tartrate and timolol maleate ophthalmic solution. Brimonidine tartrate and timolol maleate ophthalmic solution is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this medication in the past.

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Hypersensitivity Reactions [see Contraindications ( 4.4 )] • Potential for Severe Respiratory or Cardiac Reactions [see Warnings and Precautions ( 5.1 )] • Cardiac Failure [see Warnings and Precautions ( 5.2 )] • Potentiation of Vascular Insufficiency [see Warnings and Precautions ( 5.4 )] • Increased Reactivity to Allergens [see Warnings and Precautions ( 5.5 )] • Potentiation of Muscle Weakness [see Warnings and Precautions ( 5.6 )] • Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus [see Warnings and Precautions ( 5.7 )] • Masking of Thyrotoxicosis [see Warnings and Precautions ( 5.8 )] • Ocular Hypersensitivity [see Warnings and Precautions ( 5.9 )] • Contamination of Topical Ophthalmic Products after Use [see Warnings and Precautions ( 5.10 )] • Impairment of Beta-adrenergically Mediated Reflexes During Surgery [see Warnings and Precautions ( 5.11 )] Most common adverse reactions occurring in approximately 5% to 15% of patients included allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, and stinging. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Brimonidine Tartrate and Timolol Maleate Ophthalmic Solution In clinical trials of 12 months duration with brimonidine tartrate and timolol maleate ophthalmic solution, the most frequent reactions associated with its use occurring in approximately 5% to 15% of the patients included: allergic conjunctivitis, conjunctival folliculosis, conjunctival hyperemia, eye pruritus, ocular burning, and stinging. The following adverse reactions were reported in 1% to 5% of patients: asthenia, blepharitis, corneal erosion, depression, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid erythema, eyelid pruritus, foreign body sensation, headache, hypertension, oral dryness, somnolence, superficial punctate keratitis, and visual disturbance. Other adverse reactions that have been reported with the individual components are listed below. Brimonidine Tartrate (0.1% to 0.2%) Abnormal taste, allergic reaction, blepharoconjunctivitis, blurred vision, bronchitis, cataract, conjunctival blanching, conjunctival edema, conjunctival hemorrhage, conjunctivitis, cough, dizziness, dyspepsia, dyspnea, fatigue, flu syndrome, follicular conjunctivitis, gastrointestinal disorder, hypercholesterolemia, hypotension, infection (primarily colds and respiratory infections), hordeolum, insomnia, keratitis, lid crusting, lid disorder, muscular pain, nasal dryness, ocular allergic reaction, pharyngitis, photophobia, rash, rhinitis, sinus infection, sinusitis, superficial punctate keratopathy, tearing, upper respiratory symptoms, visual field defect, vitreous detachment, vitreous disorder, vitreous floaters, and worsened visual acuity. Timolol (Ocular Administration) • Body as a whole : chest pain • Cardiovascular : Arrhythmia, bradycardia, cardiac arrest, cardiac failure, cerebral ischemia, cerebral vascular accident, claudication, cold hands and feet, edema, heart block, palpitation, pulmonary edema, Raynaud’s phenomenon, syncope, and worsening of angina pectoris • Digestive : anorexia, diarrhea, nausea • Immunologic : Systemic lupus erythematosus • Nervous System/Psychiatric : Increase in signs and symptoms of myasthenia gravis, insomnia, nightmares, paresthesia, behavioral changes and psychic disturbances including confusion, hallucinations, anxiety, disorientation, nervousness, and memory loss • Skin : Alopecia …

7 DRUG INTERACTIONS • Antihypertensives/cardiac glycosides may lower blood pressure. ( 7.1 ) • Concomitant use with systemic beta-blockers may potentiate systemic beta-blockade. ( 7.2 ) • Oral or intravenous calcium antagonists may cause atrioventricular conduction disturbances, left ventricular failure, and hypotension. ( 7.3 ) • Catecholamine-depleting drugs may have additive effects and produce hypotension and/or marked bradycardia. ( 7.4 ) • Use with CNS depressants may result in an additive or potentiating effect. ( 7.5 ) • Digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. ( 7.6 ) • CYP2D6 inhibitors may potentiate systemic beta-blockade. ( 7.7 ) • Tricyclic antidepressants may potentially blunt the hypotensive effect of systemic clonidine. ( 7.8 ) • Monoamine oxidase inhibitors may result in increased hypotension. ( 7.9 ) 7.1 Antihypertensives/Cardiac Glycosides Because brimonidine tartrate and timolol maleate ophthalmic solution may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with brimonidine tartrate and timolol maleate ophthalmic solution is advised. 7.2 Beta-adrenergic Blocking Agents Patients who are receiving a beta-adrenergic blocking agent either orally or intravenously and brimonidine tartrate and timolol maleate ophthalmic solution should be observed for potential additive effects of beta-blockade, both systemic and on intraocular pressure. The concomitant use of two topical beta-adrenergic blocking agents is not recommended. 7.3 Calcium Antagonists Caution should be used in the co-administration of beta-adrenergic blocking agents, such as brimonidine tartrate and timolol maleate ophthalmic solution, and oral or intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should be avoided. 7.4 Catecholamine-depleting Drugs Close observation of the patient is recommended when a beta blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may result in vertigo, syncope, or postural hypotension. 7.5 CNS Depressants Although specific drug interaction studies have not been conducted with brimonidine tartrate and timolol maleate ophthalmic solution, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics) should be considered. 7.6 Digitalis and Calcium Antagonists The concomitant use of beta-adrenergic blocking agents with digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. 7.7 CYP2D6 Inhibitors Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and timolol. 7.8 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 and timolol maleate ophthalmic solution in humans can lead to resulting interference with the IOP-lowering effect. Caution, however, is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines. 7.9 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, however, 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 and timolol maleate ophthalmic solution in pregnant women. Limited available data from postmarketing safety reports and published literature reviews with brimonidine tartrate and timolol maleate ophthalmic solution use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data) . In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. Oral administration of brimonidine tartrate or timolol maleate to pregnant rats and rabbits during organogenesis at dose exposures 580 and 37 times the recommended human ophthalmic dose (RHOD) resulted in no adverse developmental effects (see Data) . Oral administration of timolol maleate to mice, rats, and rabbits during organogenesis at dose exposures up to 4,200 times the RHOD resulted in no evidence of fetal malformations (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. 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 the breastfed infant Animal Data Embryofetal development studies were conducted with oral administration of brimonidine tartrate during organogenesis in rats (gestation days 6 to 15) and rabbits (gestation days 6 to 18). No adverse developmental effects were observed in rats up to 2.5 mg/kg/day and rabbits up to 5 mg/kg/day. These doses represent exposures 580 and 37 times higher, respectively, than the recommended human ophthalmic dose (RHOD) of brimonidine tartrate and timolol maleate ophthalmic solution at 1 drop in both eyes twice daily. Orally administered brimonidine crossed the placenta in pregnant rats and entered the fetal circulation to a limited extent. Embryofetal development studies conducted with timolol during organogenesis in mice, rats, and rabbits at oral doses up to 50 mg/kg/day [4,200 times the maximum recommended human ophthalmic dose of 0.012 mg/kg/day on a mg/kg basis (MRHOD)] demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 mg/kg/day (83,000 times the MRHOD) were maternotoxic in mice and resulted in an increased number of fetal resorptions. Increased fetal resorptions were also seen in rabbits at doses 8,300 times the MRHOD without apparent maternotoxicity. 8.2 Lactation Risk Summary Timolol has been detected in human milk following oral and ophthalmic drug administration. It is not known whether brimonidine tartrate is excreted in human milk. In animal studies, brimonidine tartrate has been shown to be excreted in breast milk. Because of the potential for serious adverse reactions in the breastfed infant, including central nervous system depression and apnea, brimonidine tartrate and timolol maleate ophthalmic solution is not recommended for use during lactation. Data Animal Data After a single oral dose of 14C-labeled brimonidine tartrate to lactating rats, brimonidine tartrate and trace metabolites were detected in milk after 30 minutes. There was 30% higher milk concentration compared to maternal plasma concentration 30 minutes af …

12.1 Mechanism of Action Brimonidine tartrate and timolol maleate ophthalmic solution is comprised of two components: brimonidine tartrate and timolol. Each of these two components decreases elevated intraocular pressure, whether or not associated with glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. The higher the level of intraocular pressure, the greater the likelihood of glaucomatous field loss and optic nerve damage. Brimonidine tartrate and timolol maleate ophthalmic solution is a relatively selective alpha-2 adrenergic receptor agonist with a non-selective beta-adrenergic receptor inhibitor. Both brimonidine and timolol have a rapid onset of action, with peak ocular hypotensive effect seen at two hours post-dosing for brimonidine and one to two hours for timolol. 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. Timolol maleate is a beta 1 and beta 2 adrenergic receptor inhibitor that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity.

11 DESCRIPTION Brimonidine Tartrate and Timolol Maleate Ophthalmic Solution 0.2%/0.5%, sterile, contains brimonidine tartrate, a relatively selective alpha-2 adrenergic receptor agonist, and timolol maleate, a non-selective beta-adrenergic receptor inhibitor (topical intraocular pressure lowering agent) for topical ophthalmic use. The structural formulae are: Brimonidine tartrate: 5-bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate; MW= 442.22 Timolol maleate: (-)-1-( tert -butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)-oxy]-2-propanol maleate (1:1) (salt); MW= 432.49 as the maleate salt In solution, Brimonidine Tartrate and Timolol Maleate Ophthalmic Solution has a clear, greenish-yellow color. It has an osmolality of 260-330 mOsmol/kg and a pH during its shelf life of 6.5-7.3. Brimonidine tartrate appears as a white, or slightly yellowish, or slightly brownish powder and is soluble in water and practically insoluble in anhydrous ethanol and toluene. Timolol maleate appears as a white to practically white powder and is soluble in water, methanol, and alcohol, sparingly soluble in chloroform and propylene glycol and insoluble in ether and cyclohexane. Each mL of Brimonidine Tartrate and Timolol Maleate Ophthalmic Solution contains the active ingredients brimonidine tartrate 0.2% and timolol 0.5% (6.8 mg/mL timolol maleate) with the inactive ingredients benzalkonium chloride 0.005%; sodium phosphate, monobasic; sodium phosphate, dibasic; water for injection; and hydrochloric acid and/or sodium hydroxide to adjust pH. structure structure1

10 OVERDOSAGE There have been reports of inadvertent overdosage with timolol ophthalmic solution resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest. With the exception of hypotension, very limited information exists on accidental ingestion of brimonidine in adults. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine ophthalmic solutions 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.