VA Class:OP109

ATC Class:S01EC04

AHFS Class:

• Carbonic Anhydrase Inhibitors 52:40.12

Generic Name(s):

• Brinzolamide

Chemical Name:

• ( R )-4-(Ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2 H -thieno[3,2- e ]-1,2-thiazine-6-sulfonamide 1,1-dioxide

Molecular Formula:

• C₁₂H₂₁N₃O₅S₃

Brinzolamide is a carbonic anhydrase inhibitor.2,4,6

Ocular Hypertension and Glaucoma

Ophthalmic suspensions containing brinzolamide alone or in fixed combination with brimonidine tartrate are used topically to reduce elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.1,3,4,5,6,8,10

Elevated IOP in patients with glaucoma can be reduced by medical treatment, laser therapy, and/or incisional glaucoma surgery; treatment with a topical ocular hypotensive agent frequently is the initial intervention for primary open-angle glaucoma.130 Selection of an initial ocular hypotensive agent is influenced by the extent of the required reduction in IOP, coexisting medical conditions, and the characteristics of the individual drugs (e.g., dosing frequency, adverse effect profile, cost).130,132 With single-agent regimens, the reduction in IOP is approximately 25-33% with topical prostaglandin analogs; 20-25% with topical β-adrenergic blocking agents, α-adrenergic agonists, or miotic (parasympathomimetic) agents; 20-30% with oral carbonic anhydrase inhibitors; 18% with topical rho kinase inhibitors; and 15-20% with topical carbonic anhydrase inhibitors.130,131 In the absence of other considerations (e.g., contraindications, cost considerations, intolerance, adverse effects, patient refusal), a prostaglandin analog frequently is considered for initial therapy because of the relatively greater activity, once-daily administration, and low frequency of systemic adverse effects with this drug class; however, ocular adverse effects can occur.130,131,132,134

IOP should be reduced toward a target level that the clinician believes will slow disease progression and avoid visual field losses that would substantially reduce quality of life during the patient's lifetime.130,132 The target level is an estimate and should be individualized based on such factors as the extent of optic nerve damage and/or visual field loss, the baseline IOP at which damage occurred, rate of progression, life expectancy, and other considerations.130,132 Reducing the pretreatment IOP by 25% or more has been shown to slow progression of primary open-angle glaucoma.130,131 The target IOP should be adjusted up or down as needed over the course of the disease.130,131,132 If the target IOP is not achieved with single-agent therapy, alternative or additional ocular hypotensive agents may be selected depending on the patient's response to the initial drug.130 Combination therapy with drugs from different therapeutic classes often is required to achieve adequate control of IOP.131,133

Clinical Experience

Safety and efficacy of brinzolamide were evaluated in several randomized active- and placebo-controlled studies.1,3,5,6,8 In these studies, brinzolamide 1% administered 3 times daily was as effective as dorzolamide 2% administered 3 times daily in reducing elevated IOP in patients with open-angle glaucoma or ocular hypertension, resulting in reductions in IOP of approximately 4-5 mm Hg; however, brinzolamide appeared to cause less stinging and burning upon topical application to the eye.1,3,6,8 Brinzolamide 1% administered 2 or 3 times daily was less effective than timolol 0.5% administered twice daily in reducing IOP.5 Tolerance to brinzolamide apparently does not occur; the reduction in IOP has been maintained over at least 18 months of brinzolamide therapy.5

In clinical studies evaluating topical brinzolamide 1% in fixed combination with brimonidine tartrate 0.2% in patients with open-angle glaucoma or ocular hypertension, the IOP-lowering effect of the fixed-combination ophthalmic suspension administered 3 times daily was 1-3 mm Hg greater than that of either drug administered at the same dosage as monotherapy throughout 3 months of treatment.10

When topical brinzolamide is used in conjunction with a topical β-adrenergic blocking agent (e.g., timolol), the IOP-lowering effects of these agents may be additive.4,6 In one study in patients with open-angle glaucoma or ocular hypertension in whom IOP was not adequately controlled with timolol alone, addition of brinzolamide to timolol therapy resulted in further decreases in IOP.4,6

Brinzolamide is applied topically to the eye as an ophthalmic suspension.1 Brinzolamide also is commercially available in fixed combination with brimonidine tartrate for topical application to the eye as an ophthalmic suspension.10 The suspensions should be shaken well prior to use.1,10 Care should be taken to avoid contamination of the suspension.1,10 (See Bacterial Keratitis under Cautions: Warnings/Precautions.)

Ophthalmic suspensions containing brinzolamide alone or in fixed combination with brimonidine contain benzalkonium chloride, which may be absorbed by soft contact lenses.1,10 Contact lenses should be removed prior to administration of each dose of these ophthalmic suspensions, but may be reinserted 15 minutes after the dose.1,10

The manufacturer states that other ophthalmic preparations should be administered at least 10 minutes apart from brinzolamide ophthalmic suspension and at least 5 minutes apart from the fixed-combination ophthalmic suspension containing brinzolamide and brimonidine tartrate.1,10

Dosage

For the treatment of open-angle glaucoma or ocular hypertension in adults, the usual dosage of brinzolamide is 1 drop of a 1% ophthalmic suspension in the affected eye(s) 3 times daily.1

If the target intraocular pressure (IOP) is not achieved, alternative or additional ocular hypotensive agents may be required.130,131,133 (See Uses: Ocular Hypertension and Glaucoma.) When brinzolamide is used in fixed combination with brimonidine tartrate, the usual adult dosage is 1 drop of an ophthalmic suspension containing brinzolamide 1% and brimonidine tartrate 0.2% in the affected eye(s) 3 times daily.10 Because of the potential for additive systemic effects, combined use of topical brinzolamide and an oral carbonic anhydrase inhibitor (e.g., acetazolamide, dichlorphenamide, methazolamide) is not recommended by the manufacturer.1

Special Populations

The manufacturer makes no special population dosage recommendations at this time.1 Topical brinzolamide has not been evaluated in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/minute).1 Because brinzolamide and its metabolite are eliminated mainly by the kidneys, the manufacturer states that topical ocular use of the drug in patients with severe renal impairment is not recommended.1

Contraindications

Brinzolamide is contraindicated in patient with known hypersensitivity to the drug or any ingredient in the formulation.1

Warnings/Precautions

Sensitivity Reactions

Sulfonamide Sensitivity Reactions

Serious, sometimes fatal, adverse events (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, other blood dyscrasias) associated with sulfonamide therapy are possible.1 Sensitization may recur when a sulfonamide is readministered, regardless of the route of administration.1 Brinzolamide therapy should be discontinued if serious reactions or signs or symptoms of hypersensitivity occur.1

Use of Fixed Combinations

When brinzolamide is used in fixed combination with brimonidine tartrate, the cautions, precautions, contraindications, and drug interactions associated with each drug in the fixed combination should be considered.10

Corneal Endothelium

Carbonic anhydrase activity has been observed in the cytoplasm and around the plasma membranes of the corneal endothelium.1 Topical brinzolamide should be used with caution in patients with low endothelial cell counts, since these patients are at increased risk for development of corneal edema.1

Angle-closure Glaucoma

Brinzolamide has not been studied in patients with acute angle-closure glaucoma.1 Acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents.1

Bacterial Keratitis

Bacterial keratitis has been reported with the use of multiple-dose containers of topical ophthalmic preparations.10 These containers had been inadvertently contaminated by patients who, in most cases, had concurrent corneal disease or a disruption of the ocular epithelial surface.10

Improper handling of ophthalmic preparations can result in contamination of the preparation by common bacteria known to cause ocular infections.1,10 Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic preparations.1,10 (See Advice to Patients.)

Contact Lenses

Ophthalmic suspensions containing brinzolamide alone or in fixed combination with brimonidine tartrate contain benzalkonium chloride, which may be absorbed by soft contact lenses.1,10 Contact lenses should be removed prior to administration of each dose of these ophthalmic suspensions, but may be reinserted 15 minutes after the dose.1,10

Specific Populations

Pregnancy

Following oral administration of radiolabeled brinzolamide in rats, radioactivity crossed the placenta and was detected in fetal circulation and tissues.1 In studies in rats, no drug-related malformations or effects on organ or tissue development were observed, and reductions in fetal body weight were proportional to reductions in maternal weight gain.1 In developmental toxicity studies in rabbits, a slight increase in the number of fetal variations (e.g., accessory skull bones) was observed.1

There are no adequate and well-controlled studies of brinzolamide to date in pregnant women.1 Brinzolamide should be used during pregnancy only if potential benefits to the woman justify the potential risk to the fetus.1

Lactation

Brinzolamide is distributed into milk in rats following oral administration.1,2 It is not known whether brinzolamide is distributed into human milk following topical application to the eye.1 A decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

Pediatric Use

Safety and efficacy of topical ophthalmic brinzolamide have not been established in children.1,9 A 3-month controlled clinical trial in 32 pediatric patients 4 weeks to 5 years of age failed to demonstrate intraocular pressure (IOP)-lowering efficacy of twice-daily topical administration of brinzolamide 1%.1 Patients were not required to discontinue their current IOP-lowering therapy until initiation of monotherapy with brinzolamide.1 The mean decrease in elevated IOP with brinzolamide therapy was 0-2 mm Hg.1 An increase in corneal diameter of 1 mm was observed in 5 patients.1

Geriatric Use

No overall differences in safety and efficacy of topical ophthalmic brinzolamide have been observed between geriatric patients and younger adults.1

Renal Impairment

Brinzolamide has not been studied in patients with severe renal impairment (creatinine clearance less than 30 mL/minute).1 Use of the drug is not recommended in such patients, since brinzolamide and its metabolite are excreted mainly by the kidneys.1

Common Adverse Effects

Adverse effects reported in approximately 1-10% of patients receiving brinzolamide include blurred vision, taste abnormality (bitter, sour, or unusual taste), blepharitis, dermatitis, dry eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular keratitis, ocular pain, ocular pruritus, and rhinitis.1

Oral Carbonic Anhydrase Inhibitors

Additive systemic effects resulting from carbonic anhydrase inhibition are possible when topical ophthalmic brinzolamide is used concomitantly with an oral carbonic anhydrase inhibitor; such concomitant use is not recommended.1

Salicylates

Acid-base disturbances produced by oral carbonic anhydrase inhibitors have been associated with toxicity in some patients receiving high-dose salicylates.1 (See Drug Interactions in the Carbonic Anhydrase Inhibitors General Statement 52:10 and Drug Interactions: Acidifying and Alkalinizing Agents, in the Salicylates General Statement 28:08.04.24.) Although acid-base and electrolyte disturbances were not reported in clinical trials in patients receiving brinzolamide ophthalmic suspension, the possibility of toxicity in patients receiving concomitant therapy with topical ophthalmic brinzolamide and high-dose salicylates should be considered.1

Description

Brinzolamide is a carbonic anhydrase inhibitor.1,2,3,4,5,6 Similar to other carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, dorzolamide, methazolamide), brinzolamide is a nonbacteriostatic sulfonamide derivative.1 All these agents contain an unsubstituted sulfamyl group.1,2,6 Brinzolamide is pharmacologically related to other carbonic anhydrase inhibitors.1,2,6,7 Although the exact mechanism of action by which carbonic anhydrase inhibitors lower intraocular pressure (IOP) has not been fully elucidated, fluorophotometric studies suggest that reduced aqueous humor formation is the principal effect.1,2,5,7 Topical brinzolamide can produce mean IOP reductions of about 16-19%.3,8

Brinzolamide is a highly specific inhibitor of carbonic anhydrase II (CA-II), the main carbonic anhydrase isoenzyme involved in aqueous humor secretion.1,2,3 Inhibition of carbonic anhydrase in the ciliary process of the eye decreases the rate of aqueous humor secretion and IOP by slowing bicarbonate formation and reducing sodium and fluid transport.1,2

Some systemic absorption occurs following topical administration of brinzolamide to the eye.1,2 Following long-term administration of topical brinzolamide, the drug accumulates in erythrocytes as a result of CA-II binding and exhibits a half-life in whole blood of approximately 111 days.1 In addition, the N -desethyl metabolite accumulates in erythrocytes as a result of binding to carbonic anhydrase.1 However, sufficient CA-II activity remains so that adverse effects resulting from systemic carbonic anhydrase inhibition are not observed.1,5 Following topical application to the eye, plasma concentrations of both the parent drug and N -desethyl metabolite generally are below the quantitation limits of the assay.1 Brinzolamide is eliminated mainly in urine as unchanged drug; the N -desethyl metabolite also is recovered in urine along with lower concentrations of N -desmethoxypropyl and O -desmethyl metabolites.1

Advice to Patients

Risk of adverse reactions, including sensitivity reactions.1 Importance of discontinuing therapy and consulting clinician if serious or unusual ocular or systemic reactions or signs of sensitivity occur.1

Risk of temporary blurring of vision following topical application to the eye; importance of exercising caution if operating machinery or driving a motor vehicle.1

Importance of learning and adhering to proper administration techniques to avoid contamination of the suspension with common bacteria that can cause ocular infections (e.g., bacterial keratitis).1 Patients should be instructed that the tip of the dispensing container should not touch the eye, surrounding structures, or any other surface.1 Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic preparations.1 Importance of always replacing the container cap immediately after use and of not using suspensions that are cloudy or discolored or are past the labeled expiration date.10

Importance of advising patients to immediately contact their clinician for advice regarding continued use of the current multidose container if they experience an intercurrent ocular condition (e.g., trauma, infection) or require ocular surgery.1

Importance of shaking the ophthalmic suspension well prior to each use.1,10

Importance of administering other ophthalmic preparations at least 10 minutes apart from brinzolamide ophthalmic suspension and at least 5 minutes apart from brinzolamide and brimonidine tartrate ophthalmic suspension.1,10

Importance of removing contact lenses prior to administering a dose of brinzolamide ophthalmic suspension or brinzolamide and brimonidine tartrate ophthalmic suspension and of delaying reinsertion of the lenses for at least 15 minutes after the dose, since benzalkonium chloride in the preparation may be absorbed by soft contact lenses.1,10

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Alcon. Azopt^® (brinzolamide) ophthalmic suspension 1% prescribing information. Fort Worth, TX; 2015 Nov.

2. DeSantis L. Preclinical overview of brinzolamide. Surv Ophthalmol . 2000; 44(Suppl 2):119-29.

3. Silver LH and the Brinzolamide Primary Therapy Study Group. Clinical efficacy and safety of brinzolamide (Azopt®), a new topical carbonic anhydrase inhibitor for primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol . 1998; 126:400-8. [PubMed 9744373]

4. Shin D and the Brinzolamide Adjunctive Therapy Study Group. Adjunctive therapy with brinzolamide 1% ophthalmic suspension (Azopt^®) in patients with open-angle glaucoma or ocular hypertension maintained on timolol therapy. Surv Ophthalmol . 2000; 44(Suppl 2):163-8.

5. March WF, Ochsner KI and the Brinzolamide Long-Term Therapy Study Group. The long-term safety and efficacy of brinzolamide 1.0% (Azopt) in patients with primary open-angle glaucoma or ocular hypertension. Am J Ophthalmol . 2000; 129:136-43. [PubMed 10682964]

6. Anon. Brinzolamide-a new topical carbonic anhydrase inhibitor for glaucoma. Med Lett Drugs Ther . 1998; 40:95-6. [PubMed 9774966]

7. Ingram CJ, Brubaker RF. Effect of brinzolamide and dorzolamide on aqueous humor flow in human eyes. Am J Ophthalmol . 1999; 128:292-6. [PubMed 10511022]

8. Sall K and the Brinzolamide Primary Therapy Study Group. The efficacy and safety of brinzolamide 1% ophthalmic suspension (Azopt®) as a primary therapy in patients with open-angle glaucoma or ocular hypertension. Surv Ophthalmol . 2000; 44(Suppl 2):155-62.

9. Alcon, Fort Worth, TX: Personal communication.

10. Alcon. Simbrinza^® (brinzolamide and brimonidine tartrate) ophthalmic suspension prescribing information. Fort Worth, TX; 2015 Nov.

130. Prum BE Jr, Rosenberg LF, Gedde SJ et al. Primary open-angle glaucoma preferred practice pattern^® guideline [published corrigendum appears in Ophthalmology . 2018; 125: 949]. San Francisco, CA: American Academy of Ophthalmology; 2015. From the American Academy of Ophthalmology website. [Web]

131. Liebmann JM, Lee JK. Current therapeutic options and treatments in development for the management of primary open-angle glaucoma. Am J Manag Care . 2017; 23(15 Suppl):S279-S292. [PubMed 29164845]

132. Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a review. JAMA . 2014; 311:1901-11. [PubMed 24825645]

133. Gupta D, Chen PP. Glaucoma. Am Fam Physician . 2016; 93:668-74. [PubMed 27175839]

134. Inoue K. Managing adverse effects of glaucoma medications. Clin Ophthalmol . 2014; 8:903-13. [PubMed 24872675]