Brinzolamide (Page 2 of 3)

11 DESCRIPTION

Brinzolamide ophthalmic suspension USP, 1% contains a carbonic anhydrase inhibitor formulated for multidose topical ophthalmic use. Brinzolamide, USP 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:

formula
(click image for full-size original)

Brinzolamide, USP has a molecular weight of 383.5 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.

Brinzolamide ophthalmic suspension USP, 1% 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 Brinzolamide ophthalmic suspension USP, 1% contains: Active ingredient: brinzolamide USP, 10 mg. Preservative: Benzalkonium chloride 0.1 mg. Inactives: Carbomer homopolymer type B (974P), edetate disodium dihydrate, mannitol, sodium chloride, tyloxapol, and Water for Injection, with hydrochloric acid and/or sodium hydroxide to adjust pH.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Carbonic anhydrase (CA) 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 (CA-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 intraocular pressure (IOP).

Brinzolamide ophthalmic suspension 1% contains brinzolamide, an inhibitor of carbonic anhydrase II (CA-II). Following topical ocular administration, brinzolamide inhibits aqueous humor formation and reduces elevated intraocular pressure. Elevated intraocular pressure 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 CA-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 CA and accumulates in RBCs. This metabolite binds mainly to CA-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 Brinzolamide ophthalmic suspension 1% dosed to both eyes three times per day and simulates systemic drug and metabolite concentrations similar to those achieved with long-term topical dosing. RBC CA activity was measured to assess the degree of systemic CA inhibition. Brinzolamide saturation of RBC CA-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 to30 mcM. The inhibition of CA-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

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. 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. 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 recommended human ophthalmic dose).

14 CLINICAL STUDIES

In two, three-month clinical studies, brinzolamide ophthalmic suspension 1% dosed three times per day in patients with elevated intraocular pressure (IOP), produced significant reductions in IOPs (4 to 5 mmHg). These IOP reductions are equivalent to the reductions observed with dorzolamide hydrochloride ophthalmic solution, 2% dosed three times per day in the same studies.

In two clinical studies in patients with elevated intraocular pressure, brinzolamide ophthalmic suspension) 1% was associated with less stinging and burning upon instillation than dorzolamide hydrochloride ophthalmic solution, 2%.

16 HOW SUPPLIED/STORAGE AND HANDLING

Brinzolamide ophthalmic suspension USP, 1% is supplied in a translucent, low density polyethylene bottle with a translucent low density polyethylene nozzle and an orange high density polyethylene cap with a tamper evident ring retention mechanism as follows:

10 mL NDC 0591-2127-79

15 mL NDC 0591-2127-12

Storage and Handling

Store brinzolamide ophthalmic suspension 1% at 39° to 86°F (4° to 30°C). Shake well before use.

17 PATIENT COUNSELING INFORMATION

17.1 Sulfonamide 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.

17.2 Temporary Blurred Vision

Vision may be temporarily blurred following dosing with brinzolamide ophthalmic suspension 1%. Advise patients to exercise care in operating machinery or driving a motor vehicle.

17.3 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.

17.4 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 multidose container.

17.5 Concomitant Topical Ocular Therapy

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

17.6 Contact Lens Wear

The preservative in brinzolamide ophthalmic suspension 1%, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of brinzolamide ophthalmic suspension 1%, but may be reinserted 15 minutes after instillation.

Manufactured In India By:
Indoco Remedies Limited
Verna, Goa – 403722, India

Manufactured For:
Teva Pharmaceuticals USA, Inc.
Parsippany, NJ 07054

Iss. 9/2020

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