DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. The recommended dose is one drop of AZOPT in the affected eye(s) times daily. AZOPT may be used concomitantly with other topical ophthalmic drug products to lower IOP. If more than one topical ophthalmic drug is being used, the drugs should be administered at least 10 minutes apart.. Instill one drop in the affected eye(s) times daily. (2) If more than one topical ophthalmic drug is being used, the drugs should be administered at least 10 minutes apart. (2). Instill one drop in the affected eye(s) times daily. (2) If more than one topical ophthalmic drug is being used, the drugs should be administered at least 10 minutes apart. (2).

ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. Most common adverse reactions (incidence to 10%) are blurred vision and bitter, sour, or unusual taste. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical 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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice.In clinical studies of AZOPT, 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisBrinzolamide 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.MutagenesisThe 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.Impairment of FertilityIn 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 RHOD based on mg/kg).

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Carbonic anhydrase 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, 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 IOP.AZOPT contains brinzolamide, an inhibitor of carbonic anhydrase II. Following topical ocular administration, brinzolamide inhibits aqueous humor formation and reduces elevated IOP. Elevated IOP is major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.. 12.3Pharmacokinetics. Following topical ocular administration, brinzolamide is absorbed into the systemic circulation. Due to its affinity for carbonic anhydrase 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 carbonic anhydrase and accumulates in RBCs. This metabolite binds mainly to carbonic anhydrase in the presence of brinzolamide. In plasma, both parent brinzolamide and N-desethyl brinzolamide concentrations are low and generally below assay quantitation limits (less than 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 AZOPT dosed to both eyes times per day and simulates systemic drug and metabolite concentrations similar to those achieved with long-term topical dosing. Red blood cell carbonic anhydrase activity was measured to assess the degree of systemic carbonic anhydrase inhibition. Brinzolamide saturation of RBC carbonic anhydrase 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 carbonic anhydrase 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 TRIALS EXPERIENCE SECTION.

6.1Clinical 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 the rates in the clinical trials of another drug and may not reflect the rates observed in practice.In clinical studies of AZOPT, 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.

DESCRIPTION SECTION.

11DESCRIPTION. AZOPT 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 g/mol and melting point of about 131C. It is white powder, which is insoluble in water, very soluble in methanol and soluble in ethanol.AZOPT 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 AZOPT contains: Active ingredient: brinzolamide 10 mg; Preservative: Benzalkonium chloride 0.1 mg; Inactives: carbomer 974P, edetate disodium, mannitol, hydrochloric acid and/or sodium hydroxide to adjust pH, purified water, sodium chloride, and tyloxapol.. chemical.

DRUG INTERACTIONS SECTION.

7DRUG INTERACTIONS. There 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) Rare instances of acid-base alterations have occurred with high-dose salicylate therapy. (7.2). There 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) Rare instances of acid-base alterations have occurred with high-dose salicylate therapy. (7.2). 7.1Oral 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 AZOPT. The concomitant administration of AZOPT and oral carbonic anhydrase inhibitors is not recommended.. 7.2High-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 AZOPT.

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. Sulfonamide Hypersensitivity ReactionsAdvise 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 [see Warnings and Precautions (5.1)].Temporary Blurred VisionVision may be temporarily blurred following dosing with AZOPT. Advise patients to exercise care in operating machinery or driving motor vehicle.Avoiding Contamination of the ProductInstruct 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.Intercurrent Ocular ConditionsAdvise 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 multi-dose container.Concomitant Topical Ocular TherapyIf more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart.Contact Lens WearThe preservative in AZOPT, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of AZOPT, but may be reinserted 15 minutes after instillation.TRUSOPT is registered trademark of Merck Co., Inc.Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936(C) NovartisT2021-86.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. Carbonic anhydrase 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, 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 IOP.AZOPT contains brinzolamide, an inhibitor of carbonic anhydrase II. Following topical ocular administration, brinzolamide inhibits aqueous humor formation and reduces elevated IOP. Elevated IOP is major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.

NONCLINICAL TOXICOLOGY SECTION.

13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisBrinzolamide 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.MutagenesisThe 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.Impairment of FertilityIn 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 RHOD based on mg/kg).

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. Following topical ocular administration, brinzolamide is absorbed into the systemic circulation. Due to its affinity for carbonic anhydrase 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 carbonic anhydrase and accumulates in RBCs. This metabolite binds mainly to carbonic anhydrase in the presence of brinzolamide. In plasma, both parent brinzolamide and N-desethyl brinzolamide concentrations are low and generally below assay quantitation limits (less than 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 AZOPT dosed to both eyes times per day and simulates systemic drug and metabolite concentrations similar to those achieved with long-term topical dosing. Red blood cell carbonic anhydrase activity was measured to assess the degree of systemic carbonic anhydrase inhibition. Brinzolamide saturation of RBC carbonic anhydrase 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 carbonic anhydrase 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.

8.1Pregnancy. Risk SummaryThere are no adequate and well-controlled studies in pregnant women to inform drug-associated risk.In reproductive toxicity studies, brinzolamide administered orally to rats induced fetal toxicity at 375-times the recommended human ophthalmic dose (RHOD) based on mg/kg. In rabbits, no fetal toxicity was observed following oral administration (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4%, and of miscarriage is 15% to 20%, of clinically recognized pregnancies.DataAnimal DataEmbryo-fetal studies were conducted in pregnant rats administered 0, 2, 6, or 18 mg/kg/day brinzolamide by oral gavage on gestation days to 17, to target the period of organogenesis. Decreased fetal body weight with reduced skeletal ossification were observed at 18 mg/kg/day (375 times the RHOD based on mg/kg). The no-observed-adverse-effect-level (NOAEL) for fetal toxicity was mg/kg/day (125 times the RHOD). Decreased maternal weight gain was observed at 18 mg/kg/day. The NOAEL for maternal toxicity was mg/kg/day (125 times the RHOD). Embryo-fetal studies were conducted in pregnant rabbits administered 0, 1, 3, or mg/kg/day of brinzolamide by oral gavage on gestation days to 18, to target the period of organogenesis. No treatment-related fetal effects were observed at any dose. The NOAEL for fetal toxicity was mg/kg/day (125 times the RHOD based on mg/kg). Maternal weight loss during pregnancy was observed at mg/kg/day (63 times the RHOD) and above. The NOAEL for maternal toxicity was mg/kg/day (21 times the RHOD).A peri-/postnatal study was conducted in rats administered brinzolamide by oral gavage from gestation day 16 through lactation day 20. Decreased pup body weight was observed at 15 mg/kg/day (313 times the RHOD based on mg/kg). The NOAEL for developmental toxicity was mg/kg/day (104 times the RHOD). 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.

SPL UNCLASSIFIED SECTION.

5.1Sulfonamide Hypersensitivity Reactions. AZOPT 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 AZOPT. 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 readministered 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.

8USE IN SPECIFIC POPULATIONS. 8.1Pregnancy. Risk SummaryThere are no adequate and well-controlled studies in pregnant women to inform drug-associated risk.In reproductive toxicity studies, brinzolamide administered orally to rats induced fetal toxicity at 375-times the recommended human ophthalmic dose (RHOD) based on mg/kg. In rabbits, no fetal toxicity was observed following oral administration (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4%, and of miscarriage is 15% to 20%, of clinically recognized pregnancies.DataAnimal DataEmbryo-fetal studies were conducted in pregnant rats administered 0, 2, 6, or 18 mg/kg/day brinzolamide by oral gavage on gestation days to 17, to target the period of organogenesis. Decreased fetal body weight with reduced skeletal ossification were observed at 18 mg/kg/day (375 times the RHOD based on mg/kg). The no-observed-adverse-effect-level (NOAEL) for fetal toxicity was mg/kg/day (125 times the RHOD). Decreased maternal weight gain was observed at 18 mg/kg/day. The NOAEL for maternal toxicity was mg/kg/day (125 times the RHOD). Embryo-fetal studies were conducted in pregnant rabbits administered 0, 1, 3, or mg/kg/day of brinzolamide by oral gavage on gestation days to 18, to target the period of organogenesis. No treatment-related fetal effects were observed at any dose. The NOAEL for fetal toxicity was mg/kg/day (125 times the RHOD based on mg/kg). Maternal weight loss during pregnancy was observed at mg/kg/day (63 times the RHOD) and above. The NOAEL for maternal toxicity was mg/kg/day (21 times the RHOD).A peri-/postnatal study was conducted in rats administered brinzolamide by oral gavage from gestation day 16 through lactation day 20. Decreased pup body weight was observed at 15 mg/kg/day (313 times the RHOD based on mg/kg). The NOAEL for developmental toxicity was mg/kg/day (104 times the RHOD). 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.. 8.2Lactation. Risk SummaryThere are no data on the presence of brinzolamide in human milk, the effects on the breastfed infant, or the effects on milk production. Brinzolamide has been detected in the milk of lactating rats.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for AZOPT and any potential adverse effects on the breast-fed child from AZOPT.. 8.4Pediatric Use. 3-month controlled clinical study was conducted in which AZOPT 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 AZOPT. IOP-lowering efficacy was not demonstrated in this study in which the mean decrease in elevated IOP was between mmHg and mmHg. Five out of 32 patients demonstrated an increase in corneal diameter of one millimeter.. 8.5Geriatric Use. No overall differences in safety or effectiveness have been observed between elderly and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Sulfonamide hypersensitivity reactions. (5.1) Corneal edema may occur in patients with low endothelial cell counts. (5.2). Sulfonamide hypersensitivity reactions. (5.1) Corneal edema may occur in patients with low endothelial cell counts. (5.2). 5.1Sulfonamide Hypersensitivity Reactions. AZOPT 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 AZOPT. 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 readministered 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 AZOPT to this group of patients.. 5.3 Severe Renal Impairment. AZOPT has not been studied in patients with severe renal impairment [creatinine clearance (CrCl) less than 30 mL/min]. Because AZOPT and its metabolite are excreted predominantly by the kidney, AZOPT is not recommended in such patients.. 5.4Acute Angle-Closure Glaucoma. The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. AZOPT has not been studied in patients with acute angle-closure glaucoma.. 5.5 Risk of Contamination. 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.. 5.6Contact Lens Wear. The preservative in AZOPT, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of AZOPT, but may be reinserted 15 minutes after instillation.