Brinzolamide (Ophthalmic)
VA CLASSIFICATION
Primary: OP112
Commonly used brand name(s): Azopt.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antiglaucoma agent (ophthalmic)—
Indications
Accepted
Glaucoma, open-angle (treatment) or
Hypertension, ocular (treatment)—Brinzolamide is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma {01}.
Acceptance not established
Ophthalmic brinzolamide has not been studied in patients with acute angle-closure glaucoma {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Chemical group—
Sulfonamide {01}.
Molecular weight—
383.5 {01}
pH
Brinzolamide ophthalmic suspension: 7.5 {01}.
Solubility
Insoluble in water, very soluble in methanol, and soluble in ethanol {01}.
Mechanism of action/Effect:
Brinzolamide is a sulfonamide and a carbonic anhydrase inhibitor. Carbonic anhydrase is an enzyme found in many tissues of the body, including the eye. Carbonic anhydrase catalyzes the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid. In humans, carbonic anhydrase exists as a number of isoenzymes, the most active of which is carbonic anhydrase II. Carbonic anhydrase II is found primarily in red blood cells, but it also appears in other tissues. {01}
Antiglaucoma agent—Brinzolamide inhibits human carbonic anhydrase II. 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 a reduction in intraocular pressure, and thereby a reduction in the risk of optic nerve damage and glaucomatous visual field loss. In clinical studies of up to 3 months in duration in patients with glaucoma or ocular hypertension, brinzolamide had an intraocular pressure (IOP)–lowering effect of approximately 4 or 5 mm of mercury (mm Hg). {01}
Other actions/effects:
When brinzolamide was administered orally in doses of 1 mg twice a day for up to 32 weeks to healthy volunteers, inhibition of carbonic anhydrase II activity at steady state was approximately 70 to 75%, which was less than the degree of inhibition considered to be necessary for a pharmacological effect on renal function and respiration in healthy persons. (The oral dose of 1 mg twice daily approximates the amount of medication delivered systemically by ophthalmic administration of 1% brinzolamide to both eyes three times per day, and simulates systemic drug and metabolite concentrations similar to those achieved with long-term ophthalmic dosing.) {01}
Absorption:
Brinzolamide is systemically absorbed when applied to the eye. In a study designed to simulate systemic absorption during long-term ophthalmic administration, healthy subjects were given 1 mg of oral brinzolamide twice a day for up to 32 weeks. (The oral dose of 1 mg twice daily closely approximates the amount of medication delivered systemically by ophthalmic administration of 1% brinzolamide in both eyes three times a day). Saturation of red blood cell carbonic anhydrase II by brinzolamide (concentrations of approximately 20 micromolar) was reached within 4 weeks, and steady-state accumulation of the metabolite N-desethyl brinzolamide in red blood cells (6 to 30 micromolar) was reached within 20 to 28 weeks. {01}
Distribution:
During chronic dosing, brinzolamide accumulates in red blood cells by binding to carbonic anhydrase II. The N-desethyl metabolite also accumulates in red blood cells by binding primarily to carbonic anhydrase I in the presence of brinzolamide. Plasma concentrations of brinzolamide and the N-desethyl metabolite are generally below the minimum assay limit of 10 nanograms per mL. {01}
Protein binding:
Moderate (approximately 60%) {01}.
Biotransformation:
To an N-desethyl metabolite that binds mainly to carbonic anhydrase I in the presence of brinzolamide {01}.
Half-life:
Following ophthalmic administration—In whole blood, approximately 111 days {01}.
Elimination:
Renal, primarily as unchanged drug. Metabolites N-desethyl brinzolamide and, in lower concentrations, the N-desmethoxypropyl and O-desmethyl metabolites also appear in the urine. {01}
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to sulfonamides may also be sensitive to brinzolamide {01}.
Carcinogenicity
Studies have not been done {01}.
Mutagenicity
No evidence of mutagenicity was found in the in vivo mouse micronucleus assay, the in vivo sister chromatid exchange assay, or the Ames Escherichia coli test. The in vitro mouse lymphoma forward mutation assay was negative in the absence of microsomal activation, but positive in the presence of activation. {01}
Pregnancy/Reproduction
Fertility—
Studies in male and female rats at doses of up to 18 mg per kg of body weight (mg/kg) per day (375 times the recommended human ophthalmic dose) found no adverse effects on fertility {01}.
Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.
Radiolabeled brinzolamide has been found to cross the placenta and appear in the fetal tissues and blood in pregnant rats. Studies in rabbits at oral brinzolamide doses of 1, 3, and 6 mg/kg per day (20, 62, and 125 times the recommended human ophthalmic dose, respectively) found maternal toxicity at the 6 mg/kg per day dose and a significant increase in the number of fetal variations (such as accessory skull bones) that was only slightly higher than the historic value at 1 and 6 mg/kg. Studies in female rats at oral doses of 18 mg/kg per day (375 times the recommended human ophthalmic dose) during gestation found statistically decreased body weights of fetuses that 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 6 and 18 mg/kg were not statistically significant. No treatment-related malformations have been seen. {01}
It is recommended that risk-benefit be considered before using ophthalmic brinzolamide during pregnancy {01}.
FDA Pregnancy Category C {01}.
Breast-feeding
It is not known whether ophthalmic brinzolamide passes into human breast milk. A study in lactating rats at an oral dose of 15 mg/kg per day (312 times the recommended human ophthalmic dose) found decreases in body weight gain in offspring during lactation. When radiolabeled oral brinzolamide was administered to lactating rats, radioactivity was found in milk at concentrations below those in the blood and plasma. {01}
It is recommended that risk-benefit be considered before patients breast-feed during treatment with ophthalmic brinzolamide {01}.
Pediatrics
Safety and efficacy have not been established {01}.
Geriatrics
No information is available on the relationship of age to the effects of brinzolamide in geriatric patients.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
» Carbonic anhydrase inhibitors, oral (potential additive systemic effect; concurrent use is not recommended {01})
Salicylates, high doses (acid-base and electrolyte alterations have not been reported with the use of ophthalmic brinzolamide; however, in patients treated with oral carbonic anhydrase inhibitors, rare cases of adverse effects have occurred with concurrent high-dose salicylate therapy {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
Hepatic function impairment (although studies with brinzolamide have not been done in patients with hepatic function impairment, caution is advised when brinzolamide is administered to these patients {01})
» Renal function impairment, severe (creatinine clearance less than 30 mL per minute){01} (although studies with brinzolamide have not been done in patients with renal function impairment, brinzolamide is eliminated renally, and the risk of side effects may be increased because of decreased elimination; use is not recommended {01})
» Sensitivity to brinzolamide{01}
Side/Adverse Effects
Note: Because it is absorbed systemically, there is a possibility that ophthalmic brinzolamide could cause serious side effects associated with other sulfonamides, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias {01}.
Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. The effect of continued administration of ophthalmic brinzolamide on the corneal endothelium has not been fully evaluated. {01}
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent
Blepharitis{01} (redness or soreness of eyelid)
dermatitis{01} (skin rash)
feeling of something in the eye{01}
headache{01}
hyperemia{01} (redness of the eye)
keratitis{01} (eye redness, irritation, or pain)
ocular discharge{01} (discharge from the eye)
ocular pain{01} (eye pain)
Incidence rare
Allergic reaction, ocular{01} (itching, redness, swelling, or other sign of eye or eyelid irritation)
alopecia{01} (hair loss)
chest pain{01}
conjunctivitis{01} (redness of inner lining of eyelid)
diplopia{01} (seeing double)
dizziness{01}
dyspnea{01} (shortness of breath)
hypertonia{01} (excessive muscle tone)
keratoconjunctivitis{01} (eye redness, irritation, or pain)
keratopathy{01} (eye redness, irritation, or pain)
kidney pain{01}
pharyngitis{01} (sore throat)
urticaria{01} (hives)
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Bitter, sour, or other unusual taste{01}
blurred vision, transient, after application{01}
Incidence less frequent
Burning, stinging, or discomfort when medicine is applied{01}
dry eye{01}
rhinitis{01} (runny nose)
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
No human data are available. However, electrolyte imbalance, acidosis, and possible nervous system effects may occur with oral overdose. {01}
Treatment of overdose
Monitoring of serum electrolyte concentrations (especially potassium) and blood pH is recommended {01}.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Brinzolamide (Ophthalmic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to brinzolamide or other sulfonamides
Pregnancy—Crosses the placenta in animals; maternal and fetal toxicity occurs in animals administered large doses of medication
Breast-feeding—Risk-benefit should be considered
Other medicines, especially oral carbonic anhydrase inhibitors
Other medical problems, especially renal function impairment
Proper use of this medication
Shaking medication before each use
Proper administration technique; preventing contamination of medication in bottle
» Importance of using medication only as directed
Waiting 10 minutes between use of two different ophthalmic preparations to prevent “washing out” of the first one
» Proper dosing
Missed dose: Using as soon as possible; not using if almost time for next dose; not doubling doses
» Proper storage
Precautions while using this medication
Regular visits to physician to check progress during therapy
» Checking with physician if signs of ocular allergic reaction occur
Removing soft contact lenses before instillation of suspension; may be reinserted 15 minutes after instillation
» Checking with physician about possible need for a fresh bottle of medication to use in case of surgery, injury, or infection
» Temporary blurring of vision may occur following administration; caution in driving or operating machinery
Side/adverse effects
Signs of potential side effects, especially blepharitis, dermatitis, feeling of something in the eye, headache, hyperemia, keratitis, ocular discharge, ocular pain, ocular allergic reaction, alopecia, chest pain, conjunctivitis, diplopia, dizziness, dyspnea, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, pharyngitis, or urticaria
General Dosing Information
Because of the preservative benzalkonium chloride, the manufacturer recommends that patients remove soft contact lenses before instillation of brinzolamide. Lenses may be reinserted 15 minutes after instillation {01}.
Brinzolamide may be used concurrently with other medications instilled in the eye to lower intraocular pressure. However, the medications should be administered at least 10 minutes apart. {01}
It is recommended that brinzolamide be discontinued if signs of hypersensitivity or other serious reactions occur {01}.
Ophthalmic Dosage Forms
BRINZOLAMIDE OPHTHALMIC SUSPENSION
Usual adult dose
Antiglaucoma agent (ophthalmic)
Topical, to the conjunctiva, 1 drop in the affected eye(s) three times a day {01}.
Usual pediatric dose
Antiglaucoma agent (ophthalmic)
Safety and efficacy have not been established {01}.
Strength(s) usually available
U.S.—
1% (Rx) [Azopt (benzalkonium chloride 0.01%) (mannitol) (carbomer 974P) (tyloxapol) (edetate disodium) (sodium chloride) (hydrochloric acid and/or sodium hydroxide)]
Packaging and storage:
Store between 4 and 30 °C (39 and 86 °F) {01}.
Auxiliary labeling:
• For the eye.
• Shake well before using {01}.
Developed: 08/06/1998
References
- Azopt package insert (Alcon—US), Rev 4/98, Rec 5/14/98.
- Manufacturer's response to new Introductory Version monograph Volume 1 and 2, dated 8/5/98.
