CLASSES

Carbonic Anhydrase Inhibitors, Ophthalmic

DEA CLASS

Rx

DESCRIPTION

Ophthalmic carbonic anhydrase inhibitor; used for ocular hypertension or open-angle glaucoma.

COMMON BRAND NAMES

Azopt

HOW SUPPLIED

Azopt/Brinzolamide Ophthalmic Susp: 1%

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

3 drops/day ophthalmic solution in each affected eye.

3 drops/day ophthalmic solution in each affected eye.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Use brinzolamide with caution in patients with hepatic disease; data are lacking.

CrCl < 30 mL/min: Use is not recommended.

ADMINISTRATION

Brinzolamide is for ophthalmic use only.
Instruct patient on proper instillation of the ophthalmic suspension.
Shake well prior to using.
Wash hands before and after use.
To avoid contamination, do not touch the tip of the dropper to the eye, fingertips, or other surfaces.
If more than 1 ophthalmic drug is to be administered, the 2 drugs should be administered at least 10 minutes apart.
Contact lenses should be removed prior to instilling the ophthalmic suspension; they can be reinserted after 15 minutes.

STORAGE

Azopt:
- Store between 39 to 86 degrees F
- Store in a cool, dry place

CONTRAINDICATIONS / PRECAUTIONS

Brinzolamide is contraindicated in patients with hypersensitivity to any component of the product. Also, brinzolamide is a chemical sulfonamide possessing a structure and pharmacologic activity distinct from the bacteriostatic sulfonamides. Rarely, sulfonamides of any type can produce allergic reactions, some of which may be severe. Use brinzolamide with caution, if at all, in patients with a history of sulfonamide hypersensitivity. Brinzolamide is absorbed systemically and may cause the same types of adverse reactions that are attributable to sulfonamides. Fatalities have occurred, although rarely, due to severe reactions to sulfonamides. Sensitization may recur when a sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, brinzolamide should be discontinued.

Brinzolamide should be used cautiously in patients with renal impairment. Brinzolamide has not been studied in patients with severe renal disease (CrCl < 30 mL/min) and is not recommended in such patients because brinzolamide and its metabolites are excreted predominantly by the kidney.

Brinzolamide has not been studied in patients with hepatic disease. Use brinzolamide with caution in these patients.

Brinzolamide has not been studied in patients with acute closed-angle glaucoma. Management of patients with acute closed-angle glaucoma requires therapeutic interventions in addition to ocular hypotensive agents.

There are no adequate and well-controlled studies evaluating the use of brinzolamide during human pregnancy. In animal embryo-fetal studies, decreased fetal body weight with reduced skeletal ossification were observed in the off-spring of rats administered oral brinzolamide doses of 18 mg/kg/day [375-times the recommended human ophthalmic dose (RHOD) based on mg/kg]. In rabbits, no treatment-related fetal effects were observed at doses up to 6 mg/kg/day (up to 125-times the RHOD). The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in rats and rabbits was 6 mg/kg/day (125-times the RHOD). To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration. 

There are no data regarding the presence of brinzolamide in human milk, the effects on the breast-fed infant, or the effects on milk production. To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration. It may be prudent to consider an alternative glaucoma therapy in a mother who is breast-feeding, such as dorzolamide and acetazolamide. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

The safety and effectiveness of brinzolamide in children have not been established.

Brinzolamide is formulated with the preservative benzalkonium chloride, which may be absorbed by soft contact lenses. Users of soft contact lenses should not administer brinzolamide while wearing the lenses. Contact lenses may be reinserted 15 minutes after instillation.

ADVERSE REACTIONS

keratitis / Delayed / 1.0-5.0
keratoconjunctivitis / Early / 0-1.0
agranulocytosis / Delayed / Incidence not known
toxic epidermal necrolysis / Delayed / Incidence not known
aplastic anemia / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
hepatic necrosis / Delayed / Incidence not known

blurred vision / Early / 5.0-10.0
hyperemia / Delayed / 1.0-5.0
blepharitis / Early / 1.0-5.0
keratopathy / Delayed / 0-1.0
conjunctivitis / Delayed / 0-1.0
dyspnea / Early / 0-1.0
hypertonia / Delayed / 0-1.0
chest pain (unspecified) / Early / 0-1.0

dysgeusia / Early / 5.0-10.0
ocular pruritus / Rapid / 1.0-5.0
foreign body sensation / Rapid / 1.0-5.0
ocular irritation / Rapid / 1.0-5.0
rhinitis / Early / 1.0-5.0
xerophthalmia / Early / 1.0-5.0
headache / Early / 1.0-5.0
ocular pain / Early / 1.0-5.0
lacrimation / Early / 0-1.0
diplopia / Early / 0-1.0
xerostomia / Early / 0-1.0
dyspepsia / Early / 0-1.0
nausea / Early / 0-1.0
diarrhea / Early / 0-1.0
pharyngitis / Delayed / 0-1.0
dizziness / Early / 0-1.0
alopecia / Delayed / Incidence not known
urticaria / Rapid / Incidence not known

DRUG INTERACTIONS

There are no drug interactions associated with Brinzolamide products.

PREGNANCY AND LACTATION

There are no adequate and well-controlled studies evaluating the use of brinzolamide during human pregnancy. In animal embryo-fetal studies, decreased fetal body weight with reduced skeletal ossification were observed in the off-spring of rats administered oral brinzolamide doses of 18 mg/kg/day [375-times the recommended human ophthalmic dose (RHOD) based on mg/kg]. In rabbits, no treatment-related fetal effects were observed at doses up to 6 mg/kg/day (up to 125-times the RHOD). The no-observed-adverse-effect-level (NOAEL) for fetal toxicity in rats and rabbits was 6 mg/kg/day (125-times the RHOD). To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration. 

There are no data regarding the presence of brinzolamide in human milk, the effects on the breast-fed infant, or the effects on milk production. To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration. It may be prudent to consider an alternative glaucoma therapy in a mother who is breast-feeding, such as dorzolamide and acetazolamide. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

MECHANISM OF ACTION

Brinzolamide inhibits carbonic anhydrase II (CA-II). Carbonic anhydrase catalyzes the reversible reaction involving hydration of carbon dioxide and dehydration of carbonic acid. Many body tissues contain carbonic anhydrase; CA-II is the isozyme that plays a key role in controlling aqueous humor production and pressure in the eye. Carbonic anhydrase II is found in the ciliary body of the eye and works by decreasing bicarbonate ion concentrations in ocular fluid. This results in decreased aqueous humor secretion and subsequently a reduction in intraocular pressure (IOP). Carbonic anhydrase II is also present in red blood cells and other cells that secrete hydrogen or hydrogen compounds. Brinzolamide appears to have no clinically significant biochemical or hematologic effects when administered topically to the eye.

PHARMACOKINETICS

Brinzolamide is administered topically as an ophthalmic suspension.
 
Following administration, brinzolamide is absorbed into the systemic circulation. Brinzolamide distributes extensively into erythrocytes and exhibits a long half-life in whole blood (about 111 days) due to its affinity for carbonic anhydrase type II (CA-II). Approximately 60% of brinzolamide in plasma is protein bound. Brinzolamide is metabolized to N-desethyl brinzolamide which also binds to carbonic anhydrase and accumulates in erythrocytes. In the presence of brinzolamide, this metabolite mainly binds to CA-I. Plasma concentrations of both brinzolamide and the metabolite are low and generally below the level of assay detection (< 10 ng/ml). Brinzolamide is eliminated primarily 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.
 
Because of the extensive distribution of brinzolamide to erythrocytes, an oral pharmacokinetic study was undertaken using doses that approximated the systemic exposure that would occur after ocular administration of brinzolamide at usual ocular doses. Brinzolamide saturation of erythrocyte CA-II was achieved within 4 weeks (erythrocyte concentrations of approximately 20 micromol). N-Desethyl brinzolamide accumulated in erythrocytes to steady-state within 20—28 weeks reaching concentrations ranging from 6—30 micromol. Systemic CA-II was inhibited 70—75%; this level of inhibition is below the level necessary to exert a pharmacological effect on either renal function or respiration in healthy subjects (product literature).