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  • 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 Ophthalmic Susp: 1%

    DOSAGE & INDICATIONS

    For the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
    Ophthalmic dosage
    Adults

    Instill 1 drop in the affected eye(s) 3 times daily. May be used concomitantly with other topical ophthalmic agents to lower intraocular pressure.

    MAXIMUM DOSAGE

    Adults

    3 drops/day ophthalmic solution in each affected eye.

    Elderly

    3 drops/day ophthalmic solution in each affected eye.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

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

    ADMINISTRATION

    Ophthalmic Administration

    Brinzolamide is administered topically to the eye. Shake well prior to using.
    If more than one ophthalmic drug is to be administered, the two drugs should be administered at least 10 minutes apart. Contact lenses should be removed prior to instilling brinzolamide; they can be reinserted after 15 minutes.

    STORAGE

    Azopt:
    - Store between 39 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    No overall differences in efficacy or safety of brinzolamide have been observed between elderly and younger adult patients.

    Sulfonamide hypersensitivity

    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.

    Renal disease, renal impairment

    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.

    Hepatic disease

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

    Closed-angle glaucoma

    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.

    Pregnancy

    Brinzolamide is classified in FDA pregnancy category C. There are no adequate and well-controlled studies in pregnant women. According to the manufacturer, brinzolamide should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

    Breast-feeding

    According to the manufacturer, a decision should be made whether to discontinue nursing or to discontinue brinzolamide. It is not known whether this drug is excreted in human milk. It may be prudent to consider an alternative glaucoma therapy in a woman who is breast-feeding, such as dorzolamide and acetazolamide (see individual monographs). 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 ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children

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

    Contact lenses

    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

    Severe

    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

    Moderate

    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

    Mild

    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

    Pregnancy

    Brinzolamide is classified in FDA pregnancy category C. There are no adequate and well-controlled studies in pregnant women. According to the manufacturer, brinzolamide should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.

    According to the manufacturer, a decision should be made whether to discontinue nursing or to discontinue brinzolamide. It is not known whether this drug is excreted in human milk. It may be prudent to consider an alternative glaucoma therapy in a woman who is breast-feeding, such as dorzolamide and acetazolamide (see individual monographs). 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 ingested drug, healthcare 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).

    Oral Route

    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 because of the extensive distribution of brinzolamide to erythrocytes. Brinzolamide saturation of erythrocyte CA-II was achieved within 4 weeks (erythrocyte concentrations of approximately 20 micromol).

    Other Route(s)

    Ophthalmic Route
    Following topical ocular administration, brinzolamide is absorbed into the systemic circulation. 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 because of the extensive distribution of brinzolamide to erythrocytes. Brinzolamide saturation of erythrocyte CA-II was achieved within 4 weeks (erythrocyte concentrations of approximately 20 micromol).