PEDIATRIC USE SECTION.

8.4 Pediatric Use. three-month controlled clinical study was conducted in which brinzolamide ophthalmic suspension 1% was dosed only twice day in pediatric patients weeks to years of age. Patients were not required to discontinue their IOP-lowering medication(s) until initiation of monotherapy with brinzolamide ophthalmic suspension 1%. IOP-lowering efficacy was not demonstrated in this study in which the mean decrease in elevated IOP was between and mmHg. Five out of 32 patients demonstrated an increase in corneal diameter of one millimeter.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions are blurred vision and bitter, sour or unusual taste (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 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 the rates in the clinical studies of another drug and may not reflect the rates observed in practice.In clinical studies of brinzolamide ophthalmic suspension 1%, the most frequently reported adverse reactions reported in to 10% of patients were blurred vision and bitter, sour or unusual taste. Adverse reactions occurring in 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Brinzolamide caused urinary bladder tumors in female mice at oral doses of 10 mg/kg/day and in male rats at oral doses of mg/kg/day in year studies. Brinzolamide was not carcinogenic in male mice or female rats dosed orally for up to years. The carcinogenicity appears secondary to kidney and urinary bladder toxicity. These levels of exposure cannot be achieved with topical ophthalmic dosing in humans. The following tests for mutagenic potential were negative: (1) in vivo mouse micronucleus assay; (2) in vivo sister chromatid exchange assay; and (3) Ames E. coli test. The in vitro mouse lymphoma forward mutation assay was negative in the absence of activation, but positive in the presence of microsomal activation. In reproduction studies of brinzolamide in rats, there were no adverse effects on the fertility or reproductive capacity of males or females at doses up to 18 mg/kg/day (375 times the recommended human ophthalmic dose).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye. It catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In humans, carbonic anhydrase exists as number of isoenzymes, the most active being carbonic anhydrase II (CA-II), found primarily in red blood cells (RBCs), but also in other tissues. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The result is reduction in intraocular pressure (IOP).Brinzolamide ophthalmic suspension 1% contains brinzolamide, an inhibitor of carbonic anhydrase II (CA-II). Following topical ocular administration, brinzolamide inhibits aqueous humor formation and reduces elevated intraocular pressure. Elevated intraocular pressure is major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.. 12.3 Pharmacokinetics. Following topical ocular administration, brinzolamide is absorbed into the systemic circulation. Due to its affinity for CA-II, brinzolamide distributes extensively into the RBCs and exhibits long half-life in whole blood (approximately 111 days). In humans, the metabolite N-desethyl brinzolamide is formed, which also binds to CA and accumulates in RBCs. This metabolite binds mainly to CA-I in the presence of brinzolamide. In plasma, both parent brinzolamide and N-desethyl brinzolamide concentrations are low and generally below assay quantitation limits (<10 ng/mL). Binding to plasma proteins is approximately 60%. Brinzolamide is eliminated predominantly in the urine as unchanged drug. N-Desethyl brinzolamide is also found in the urine along with lower concentrations of the N-desmethoxypropyl and O-desmethyl metabolites.An oral pharmacokinetic study was conducted in which healthy volunteers received mg capsules of brinzolamide twice per day for up to 32 weeks. This regimen approximates the amount of drug delivered by topical ocular administration of brinzolamide ophthalmic suspension 1% dosed to both eyes three times per day and simulates systemic drug and metabolite concentrations similar to those achieved with long-term topical dosing. RBC CA activity was measured to assess the degree of systemic CA inhibition. Brinzolamide saturation of RBC CA-II was achieved within weeks (RBC concentrations of approximately 20 mcM). N-Desethyl brinzolamide accumulated in RBCs to steady-state within 20 to 28 weeks reaching concentrations ranging from to 30 mcM. The inhibition of CA-II activity at steady-state was approximately 70 to 75%, which is below the degree of inhibition expected to have pharmacological effect on renal function or respiration in healthy subjects.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. In two, three-month clinical studies, brinzolamide ophthalmic suspension 1% dosed three times per day in patients with elevated intraocular pressure (IOP), produced significant reductions in IOPs (4 to mmHg). These IOP reductions are equivalent to the reductions observed with TRUSOPT (dorzolamide hydrochloride ophthalmic solution) 2% dosed three times per day in the same studies.In two clinical studies in patients with elevated intraocular pressure, brinzolamide ophthalmic suspension 1% was associated with less stinging and burning upon instillation than TRUSOPT 2%.

DESCRIPTION SECTION.

11 DESCRIPTION. Brinzolamide ophthalmic suspension 1% contains carbonic anhydrase inhibitor formulated for multidose topical ophthalmic use. Brinzolamide is described chemically as: (R)-(+)-4-Ethylamino-2-(3-methoxypropyl)-3,4-dihydro-2H-thieno [3,2-e]-1,2-thiazine-6-sulfonamide-1,1- dioxide. Its empirical formula is C12H21N3O5S3, and its structural formula is: Brinzolamide has molecular weight of 383.5 and melting point of about 131C. It is white powder, which is insoluble in water, very soluble in methanol and soluble in ethanol.Brinzolamide ophthalmic suspension 1% is supplied as sterile, aqueous suspension of brinzolamide which has been formulated to be readily suspended and slow settling, following shaking. It has pH of approximately 7.5 and an osmolality of 300 mOsm/kg.Each mL of brinzolamide ophthalmic suspension 1% contains: Active ingredient: brinzolamide 10 mg. Preservative: Benzalkonium chloride 0.1 mg. Inactives: mannitol, carbomer 974P, tyloxapol, edetate disodium, sodium chloride, purified water, with hydrochloric acid and/or sodium hydroxide to adjust pH.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dose is one drop of brinzolamide ophthalmic suspension 1% in the affected eye(s) three times daily. Brinzolamide ophthalmic suspension 1% may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten (10) minutes apart.. oInstill one drop in the affected eye(s) three times daily (2). oIf more than one topical ophthalmic drug is being used, the drugs should be administered at least ten (10) minutes apart (2).. oInstill one drop in the affected eye(s) three times daily (2). oIf more than one topical ophthalmic drug is being used, the drugs should be administered at least ten (10) minutes apart (2).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oThere is potential additive effect of the known systemic effects of carbonic anhydrase inhibition in patients receiving both oral and topical carbonic anhydrase inhibitors (7.1). oRare instances of acid-base alterations have occurred with high-dose salicylate therapy (7.2).. oThere is potential additive effect of the known systemic effects of carbonic anhydrase inhibition in patients receiving both oral and topical carbonic anhydrase inhibitors (7.1). oRare instances of acid-base alterations have occurred with high-dose salicylate therapy (7.2).. 7.1 Oral Carbonic Anhydrase Inhibitors. There is 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%. The concomitant administration of brinzolamide ophthalmic suspension 1% 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. 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 brinzolamide ophthalmic suspension 1%.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.1 Sulfonamide Reactions. Advise patients that if serious or unusual ocular or systemic reactions or signs of hypersensitivity occur, they should discontinue the use of the product and consult their physician.. 17.2 Temporary Blurred Vision. Vision may be temporarily blurred following dosing with brinzolamide ophthalmic suspension 1%. Advise patients to exercise care in operating machinery or driving motor vehicle.. 17.3 Avoiding Contamination of the Product. Instruct patients to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures or other surfaces, since the product 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.. 17.4 Intercurrent Ocular Conditions. Advise 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.. 17.5 Concomitant Topical Ocular Therapy. If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart.. 17.6 Contact Lens Wear. The preservative in brinzolamide ophthalmic suspension 1%, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of brinzolamide ophthalmic suspension 1%, but may be reinserted 15 minutes after instillation.TRUSOPT is registered trademark of Merck Co., Inc.Manufactured byAlcon Laboratories, Inc.Fort Worth, Texas 76134 forSandoz Inc.Princeton, NJ 08540T2017-74November 2015.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Carbonic anhydrase (CA) is an enzyme found in many tissues of the body including the eye. It catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In humans, carbonic anhydrase exists as number of isoenzymes, the most active being carbonic anhydrase II (CA-II), found primarily in red blood cells (RBCs), but also in other tissues. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The result is reduction in intraocular pressure (IOP).Brinzolamide ophthalmic suspension 1% contains brinzolamide, an inhibitor of carbonic anhydrase II (CA-II). Following topical ocular administration, brinzolamide inhibits aqueous humor formation and reduces elevated intraocular pressure. Elevated intraocular pressure is major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Brinzolamide caused urinary bladder tumors in female mice at oral doses of 10 mg/kg/day and in male rats at oral doses of mg/kg/day in year studies. Brinzolamide was not carcinogenic in male mice or female rats dosed orally for up to years. The carcinogenicity appears secondary to kidney and urinary bladder toxicity. These levels of exposure cannot be achieved with topical ophthalmic dosing in humans. The following tests for mutagenic potential were negative: (1) in vivo mouse micronucleus assay; (2) in vivo sister chromatid exchange assay; and (3) Ames E. coli test. The in vitro mouse lymphoma forward mutation assay was negative in the absence of activation, but positive in the presence of microsomal activation. In reproduction studies of brinzolamide in rats, there were no adverse effects on the fertility or reproductive capacity of males or females at doses up to 18 mg/kg/day (375 times the recommended human ophthalmic dose).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following topical ocular administration, brinzolamide is absorbed into the systemic circulation. Due to its affinity for CA-II, brinzolamide distributes extensively into the RBCs and exhibits long half-life in whole blood (approximately 111 days). In humans, the metabolite N-desethyl brinzolamide is formed, which also binds to CA and accumulates in RBCs. This metabolite binds mainly to CA-I in the presence of brinzolamide. In plasma, both parent brinzolamide and N-desethyl brinzolamide concentrations are low and generally below assay quantitation limits (<10 ng/mL). Binding to plasma proteins is approximately 60%. Brinzolamide is eliminated predominantly in the urine as unchanged drug. N-Desethyl brinzolamide is also found in the urine along with lower concentrations of the N-desmethoxypropyl and O-desmethyl metabolites.An oral pharmacokinetic study was conducted in which healthy volunteers received mg capsules of brinzolamide twice per day for up to 32 weeks. This regimen approximates the amount of drug delivered by topical ocular administration of brinzolamide ophthalmic suspension 1% dosed to both eyes three times per day and simulates systemic drug and metabolite concentrations similar to those achieved with long-term topical dosing. RBC CA activity was measured to assess the degree of systemic CA inhibition. Brinzolamide saturation of RBC CA-II was achieved within weeks (RBC concentrations of approximately 20 mcM). N-Desethyl brinzolamide accumulated in RBCs to steady-state within 20 to 28 weeks reaching concentrations ranging from to 30 mcM. The inhibition of CA-II activity at steady-state was approximately 70 to 75%, which is below the degree of inhibition expected to have pharmacological effect on renal function or respiration in healthy subjects.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category CDevelopmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, and mg/kg/day (20, 62, and 125 times the recommended human ophthalmic dose) produced maternal toxicity at mg/kg/day and significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at and mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving oral doses of 18 mg/kg/day (375 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 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. Following oral administration of 14C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood. There are no adequate and well-controlled studies in pregnant women. Brinzolamide ophthalmic suspension 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

SPL UNCLASSIFIED SECTION.

5.1 Sulfonamide Hypersensitivity Reactions. Brinzolamide ophthalmic suspension 1% is sulfonamide and although administered topically it is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of brinzolamide ophthalmic suspension 1%. Fatalities have occurred, although rarely, 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 sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Category CDevelopmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, and mg/kg/day (20, 62, and 125 times the recommended human ophthalmic dose) produced maternal toxicity at mg/kg/day and significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at and mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving oral doses of 18 mg/kg/day (375 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 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. Following oral administration of 14C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood. There are no adequate and well-controlled studies in pregnant women. Brinzolamide ophthalmic suspension 1% should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. 8.3 Nursing Mothers. In study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral dose of 15 mg/kg/day (312 times the recommended human ophthalmic dose) were seen during lactation. No other effects were observed. However, following oral administration of 14C-brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in the blood and plasma.It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from brinzolamide ophthalmic suspension 1%, 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. three-month controlled clinical study was conducted in which brinzolamide ophthalmic suspension 1% was dosed only twice day in pediatric patients weeks to years of age. Patients were not required to discontinue their IOP-lowering medication(s) until initiation of monotherapy with brinzolamide ophthalmic suspension 1%. IOP-lowering efficacy was not demonstrated in this study in which the mean decrease in elevated IOP was between and mmHg. Five out of 32 patients demonstrated an increase in corneal diameter of one millimeter.. 8.5 Geriatric Use. No overall differences in safety or effectiveness have been observed between elderly and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oSulfonamide hypersensitivity reactions (5.1). oCorneal edema may occur in patients with low endothelial cell counts (5.2).. oSulfonamide hypersensitivity reactions (5.1). oCorneal edema may occur in patients with low endothelial cell counts (5.2).. 5.1 Sulfonamide Hypersensitivity Reactions. Brinzolamide ophthalmic suspension 1% is sulfonamide and although administered topically it is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of brinzolamide ophthalmic suspension 1%. Fatalities have occurred, although rarely, 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 sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.. 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 brinzolamide ophthalmic suspension 1% to this group of patients.. 5.3 Severe Renal Impairment Brinzolamide ophthalmic suspension 1% has not been studied in patients with severe renal impairment (CrCl <30 mL/min). Because brinzolamide ophthalmic suspension 1% and its metabolite are excreted predominantly by the kidney, brinzolamide ophthalmic suspension 1% 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. Brinzolamide ophthalmic suspension 1% has not been studied in patients with acute angle-closure glaucoma.. 5.5 Contact Lens Wear. The preservative in brinzolamide ophthalmic suspension 1%, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of brinzolamide ophthalmic suspension 1%, but may be reinserted 15 minutes after instillation.