Brinzolamide/Brimonidine Tartrate

SIMBRINZA (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination of a carbonic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. SIMBRINZA is a combination of brinzolamide, a carbonic anhydrase inhibitor, and brimonidine tartrate, an alpha adrenergic agonist, indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. (1)

Ophthalmic suspension containing 1% (10 mg/mL) brinzolamide and 0.2% (2 mg/mL) brimonidine tartrate. Ophthalmic suspension containing 1% (10 mg/mL) brinzolamide and 0.2% (2 mg/mL) brimonidine tartrate. (3)

Hypersensitivity to any component of this product. (4.1) Neonates and infants (under the age of two years). (4.2)

4.1 Hypersensitivity SIMBRINZA is contraindicated in patients who are hypersensitive to any component of this product.

4.2 Neonates and Infants (under the age of two years) SIMBRINZA is contraindicated in neonates and infants (under the age of two years ) [see Use in Specific Populations (8.4) ].

Potential for sulfonamide hypersensitivity reactions because of the brinzolamide component (5.1) Potential for corneal endothelium cell loss (5.2) Severe renal impairment may limit the metabolism of the brinzolamide component (5.3)

5.1 Sulfonamide Hypersensitivity Reactions SIMBRINZA contains brinzolamide, a sulfonamide, and although administered topically is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of SIMBRINZA. Fatalities have occurred due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation immediately. [see Adverse Reactions (6.2) and Patient Counseling Information (17) ].

5.2 Corneal Endothelium Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Caution should be used when prescribing SIMBRINZA to this group of patients.

5.3 Severe Renal Impairment SIMBRINZA has not been specifically studied in patients with severe renal impairment (CrCl less than 30 mL/min). Since brinzolamide and its metabolite are excreted predominantly by the kidney, SIMBRINZA is not recommended in such patients.

5.4 Acute Angle-Closure Glaucoma The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. SIMBRINZA has not been studied in patients with acute angle-closure glaucoma.

5.5 Contact Lens Wear The preservative in SIMBRINZA, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA but may be reinserted 15 minutes after instillation [see Patient Counseling Information (17) ] .

5.6 Severe Cardiovascular Disease Brimonidine tartrate, a component of SIMBRINZA, has a less than 5% mean decrease in blood pressure two hours after dosing in clinical studies; caution should be exercised in treating patients with severe cardiovascular disease.

5.7 Severe Hepatic Impairment Because brimonidine tartrate, a component of SIMBRINZA, has not been studied in patients with hepatic impairment, caution should be exercised in such patients.

5.8 Potentiation of Vascular Insufficiency Brimonidine tartrate, a component of SIMBRINZA, may potentiate syndromes associated with vascular insufficiency. SIMBRINZA should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or thromboangiitis obliterans.

5.9 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 have 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) ] .

Most common adverse reactions occurring in approximately 3% to 5% of patients included blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, eye allergy. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Alcon Laboratories, Inc. at 1-800-757-9195 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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice. SIMBRINZA In two clinical trials of three months duration 435 patients were treated with SIMBRINZA, and 915 were treated with the two individual components. The most frequently reported adverse reactions in patients treated with SIMBRINZA occurring in approximately 3% to 5% of patients in descending order of incidence were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Rates of adverse reactions reported with the individual components were comparable. Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA patients. Other adverse reactions that have been reported with the individual components during clinical trials are listed below. Brinzolamide 1% In clinical studies of brinzolamide ophthalmic suspension 1%, the most frequently reported adverse reactions reported in 5% to 10% of patients were blurred vision and bitter, sour or unusual taste. Adverse reactions occurring in 1% to 5% of patients were blepharitis, dermatitis, dry eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular keratitis, ocular pain, ocular pruritus and rhinitis. The following adverse reactions were reported at an incidence below 1%: allergic reactions, alopecia, chest pain, conjunctivitis, diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, lid margin crusting or sticky sensation, nausea, pharyngitis, tearing and urticaria. Brimonidine Tartrate 0.2% In clinical studies of brimonidine tartrate 0.2%, adverse reactions occurring in approximately 10% to 30% of the subjects, in descending order of incidence, included oral dryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus. Reactions occurring in approximately 3% to 9% of the subjects, in descending order included 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. The following adverse reactions were reported in less than 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 Brinzolamide The following adverse reactions have been identified during postapproval use of brinzolamide containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious skin and subcutaneous tissue reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) may occur with the use of brinzolamide due to the sulfonamide component [see Warnings and Precautions (5.1) and Patient Counseling Information Sulfonamide Reactions (17) ]. Brimonidine Tartrate 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, hypersensitivity, iritis, keratoconjunctivitis sicca, 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 have been reported in infants receiving brimonidine tartrate ophthalmic solutions [see Contraindications (4.2) ] .

Oral Carbonic Anhydrase Inhibitors (7.1) High-dose Salicylate Therapy (7.2) Central Nervous System Depressants (7.3) Antihypertensives/Cardiac Glycosides (7.4) Tricyclic Antidepressants (7.5) Monoamine Oxidase (MAO) Inhibitors (7.6)

7.1 Oral Carbonic Anhydrase Inhibitors There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide ophthalmic suspension 1%, a component of SIMBRINZA ophthalmic suspension. The concomitant administration of SIMBRINZA and oral carbonic anhydrase inhibitors is not recommended.

7.2 High-Dose Salicylate Therapy Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. These alterations were not reported in the clinical trials with brinzolamide ophthalmic suspension 1%. However, in patients treated with oral carbonic anhydrase inhibitors, rare instances of acid-base alterations have occurred with high-dose salicylate therapy. Therefore, the potential for such drug interactions should be considered in patients receiving SIMBRINZA.

7.3 Central Nervous System Depressants Although specific drug interaction studies have not been conducted with SIMBRINZA, the possibility of an additive or potentiating effect with Central Nervous System (CNS) depressants (alcohol, opiates, barbiturates, sedatives, or anesthetics) should be considered.

7.4 Antihypertensives/Cardiac Glycosides Because brimonidine tartrate, a component of SIMBRINZA, may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with SIMBRINZA is advised.

7.5 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 SIMBRINZA 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.

7.6 Monoamine Oxidase Inhibitors Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine tartrate 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.

8.1 Pregnancy Developmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/kg/day (20, 60, and 120 times the recommended human ophthalmic dose) produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving oral doses of 18 mg/kg/day (180 times the recommended human ophthalmic dose) during gestation were proportional to the reduced maternal weight gain, with no statistically significant effects on organ or tissue development. Increases in unossified sternebrae, reduced ossification of the skull, and unossified hyoid that occurred at 6 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. Following oral administration of 14 C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood. Developmental toxicity studies performed in rats with oral doses of 0.66 mg brimonidine base/kg revealed no evidence of harm to the fetus. Dosing at this level resulted in a plasma drug concentration approximately 100 times higher than that seen in humans at the recommended human ophthalmic dose. In animal studies, brimonidine crossed the placenta and entered into the fetal circulation to a limited extent. There are no adequate and well-controlled studies in pregnant women. SIMBRINZA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

8.2 Lactation In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral dose of 15 mg/kg/day (150 times the recommended human ophthalmic dose) were observed during lactation. No other effects were observed. However, following oral administration of 14 C-brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in the blood and plasma. In animal studies, brimonidine was excreted in breast milk. It is not known whether brinzolamide and brimonidine tartrate are excreted in human milk following topical ocular administration. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SIMBRINZA (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2%, a 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 The individual component, brinzolamide, has been studied in pediatric glaucoma patients 4 weeks to 5 years of age. The individual component, brimonidine tartrate, has been studied in pediatric patients 2 to 7 years old. Somnolence (50-83%) and decreased alertness was seen in patients 2 to 6 years old. SIMBRINZA ophthalmic suspension is contraindicated in children under the age of 2 years [see Contraindications (4.2) ].

8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and adult patients.

SIMBRINZA is comprised of two components: brinzolamide (carbonic anhydrase inhibitor) and brimonidine tartrate (alpha 2 adrenergic receptor agonist). Each of these two components decreases elevated IOP. Elevated IOP is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. The higher the level of IOP, the greater the likelihood of glaucomatous field loss and optic nerve damage. Brinzolamide inhibits carbonic anhydrase in the ciliary processes of the eye to decrease aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. Brinzolamide has a peak ocular hypotensive effect occurring at 2 to 3 hours post-dosing. 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. Brimonidine tartrate has a peak ocular hypotensive effect occurring at two hours post-dosing. The result is a reduction in intraocular pressure (IOP).