Azopt (Page 2 of 2)

8.5 Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

10 OVERDOSAGE

Although no human data are available, electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur following oral administration of an overdose. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored.

11 DESCRIPTION

AZOPT contains a 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 C12 H21 N3 O5 S3 , and its structural formula is:

Brinzolamide structural formula
(click image for full-size original)

Brinzolamide has a molecular weight of 383.5 g/mol and a melting point of about 131°C. It is a white powder, which is insoluble in water, very soluble in methanol and soluble in ethanol.

AZOPT is supplied as a sterile, aqueous suspension of brinzolamide which has been formulated to be readily suspended and slow settling, following shaking. It has a 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.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism 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 a 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 a 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 a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.

12.3 Pharmacokinetics

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 a 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 I 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 1 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 3 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 4 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 6 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 a pharmacological effect on renal function or respiration in healthy subjects.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Brinzolamide caused urinary bladder tumors in female mice at oral doses of 10 mg/kg/day and in male rats at oral doses of 8 mg/kg/day in 2-year studies. Brinzolamide was not carcinogenic in male mice or female rats dosed orally for up to 2 years. The carcinogenicity appears secondary to kidney and urinary bladder toxicity. These levels of exposure cannot be achieved with topical ophthalmic dosing in humans.

Mutagenesis

The 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 Fertility

In 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).

14 CLINICAL STUDIES

In two, 3-month clinical studies, AZOPT dosed 3 times per day in patients with elevated IOP, produced significant reductions in IOPs (4 mmHg to 5 mmHg). These IOP reductions are equivalent to the reductions observed with TRUSOPT* (dorzolamide hydrochloride ophthalmic solution) 2% dosed 3 times per day in the same studies.

In 2 clinical studies in patients with elevated IOP, AZOPT was associated with less stinging and burning upon instillation than TRUSOPT* 2%.

16 HOW SUPPLIED/STORAGE AND HANDLING

AZOPT (brinzolamide ophthalmic suspension) 1% is supplied in plastic dispensers with a controlled dispensing-tip as follows:

10 mL NDC 0078-0722-10

15 mL NDC 0078-0722-15

Storage and Handling

Store AZOPT at 4°C to 30°C (39°F to 86°F). Shake well before use. After opening, AZOPT can be used until the expiration date on the bottle.

17 PATIENT COUNSELING INFORMATION

Sulfonamide Hypersensitivity Reactions

Advise 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 immediately [see Warnings and Precautions (5.1)].

Temporary Blurred Vision

Vision may be temporarily blurred following dosing with AZOPT. Advise patients to exercise care in operating machinery or driving a motor vehicle.

Avoiding Contamination of the Product

Instruct 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 Conditions

Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued use of the present multi-dose container.

Concomitant Topical Ocular Therapy

If more than one topical ophthalmic drug is being used, the drugs should be administered at least ten minutes apart.

Contact 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.

*TRUSOPT is a registered trademark of Merck & Co., Inc.

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

© Novartis

T2023-37

PRINCIPAL DISPLAY PANEL

NDC 0078-0722-10

Azopt®

(brinzolamide
ophthalmic
suspension) 1%

10 mL

NOVARTIS

PRINCIPAL DISPLAY PANEL
									NDC 0078-0772-10
									Azopt®
									(brinzolamide ophthalmic suspension) 1%
									10 mL
									NOVARTIS
(click image for full-size original)
AZOPT
brinzolamide suspension/ drops
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0078-0722
Route of Administration OPHTHALMIC DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
BRINZOLAMIDE (BRINZOLAMIDE) BRINZOLAMIDE 10 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
MANNITOL
TYLOXAPOL
EDETATE DISODIUM
SODIUM CHLORIDE
HYDROCHLORIC ACID
SODIUM HYDROXIDE
WATER
BENZALKONIUM CHLORIDE
CARBOMER HOMOPOLYMER TYPE C
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0078-0722-10 1 BOTTLE in 1 CARTON contains a BOTTLE
1 10 mL in 1 BOTTLE This package is contained within the CARTON (0078-0722-10)
2 NDC:0078-0722-15 1 BOTTLE in 1 CARTON contains a BOTTLE
2 15 mL in 1 BOTTLE This package is contained within the CARTON (0078-0722-15)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA020816 04/30/1998
Labeler — Novartis Pharmaceuticals Corporation (002147023)

Revised: 06/2023 Novartis Pharmaceuticals Corporation

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