Dorzolamide Hydrochloride

DORZOLAMIDE HYDROCHLORIDE- dorzolamide hydrochloride solution
Prasco Laboratories

DESCRIPTION

Dorzolamide hydrochloride ophthalmic solution is a carbonic anhydrase inhibitor formulated for topical ophthalmic use.

Dorzolamide hydrochloride is described chemically as: (4S -trans)-4-(ethylamino)-5,6-dihydro-6-methyl-4H -thieno[2,3-b ]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride. Dorzolamide hydrochloride is optically active. The specific rotation is

25°
α (C=1, water) = ∼‑17°.
405

Its empirical formula is C10 H16 N2 O4 S3 •HCl and its structural formula is:

chemical structure

Dorzolamide hydrochloride has a molecular weight of 360.9 and a melting point of about 264°C. It is a white to off-white, crystalline powder, which is soluble in water and slightly soluble in methanol and ethanol.

Dorzolamide hydrochloride ophthalmic solution is supplied as a sterile, isotonic, buffered, slightly viscous, aqueous solution of dorzolamide hydrochloride. The pH of the solution is approximately 5.6, and the osmolarity is 260-330 mOsM. Each mL of dorzolamide hydrochloride ophthalmic solution 2% contains 20 mg dorzolamide (22.3 mg of dorzolamide hydrochloride). Inactive ingredients are hydroxyethyl cellulose, mannitol, sodium citrate dihydrate, sodium hydroxide (to adjust pH) and water for injection. Benzalkonium chloride 0.0075% is added as a preservative.

CLINICAL PHARMACOLOGY

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).

Dorzolamide hydrochloride is an inhibitor of human carbonic anhydrase II. Following topical ocular administration, dorzolamide hydrochloride ophthalmic solution reduces elevated intraocular pressure. Elevated intraocular pressure is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss.

Pharmacokinetics/Pharmacodynamics

When topically applied, dorzolamide reaches the systemic circulation. To assess the potential for systemic carbonic anhydrase inhibition following topical administration, drug and metabolite concentrations in RBCs and plasma and carbonic anhydrase inhibition in RBCs were measured. Dorzolamide accumulates in RBCs during chronic dosing as a result of binding to CA-II. The parent drug forms a single N-desethyl metabolite, which inhibits CA-II less potently than the parent drug but also inhibits CA-I. The metabolite also accumulates in RBCs where it binds primarily to CA-I. Plasma concentrations of dorzolamide and metabolite are generally below the assay limit of quantitation (15nM). Dorzolamide binds moderately to plasma proteins (approximately 33%). Dorzolamide is primarily excreted unchanged in the urine; the metabolite also is excreted in urine. After dosing is stopped, dorzolamide washes out of RBCs nonlinearly, resulting in a rapid decline of drug concentration initially, followed by a slower elimination phase with a half-life of about four months.

To simulate the systemic exposure after long-term topical ocular administration, dorzolamide was given orally to eight healthy subjects for up to 20 weeks. The oral dose of 2 mg b.i.d. closely approximates the amount of drug delivered by topical ocular administration of dorzolamide hydrochloride ophthalmic solution 2% t.i.d. Steady state was reached within 8 weeks. The inhibition of CA-II and total carbonic anhydrase activities was below the degree of inhibition anticipated to be necessary for a pharmacological effect on renal function and respiration in healthy individuals.

Clinical Studies

The efficacy of dorzolamide hydrochloride ophthalmic solution was demonstrated in clinical studies in the treatment of elevated intraocular pressure in patients with glaucoma or ocular hypertension (baseline IOP ≥ 23 mmHg). The IOP-lowering effect of dorzolamide hydrochloride ophthalmic solution was approximately 3 to 5 mmHg throughout the day and this was consistent in clinical studies of up to one year duration.

The efficacy of dorzolamide hydrochloride ophthalmic solution when dosed less frequently than three times a day (alone or in combination with other products) has not been established.

In a one year clinical study, the effect of dorzolamide hydrochloride ophthalmic solution 2% t.i.d. on the corneal endothelium was compared to that of betaxolol ophthalmic solution b.i.d. and timolol maleate ophthalmic solution 0.5% b.i.d. There were no statistically significant differences between groups in corneal endothelial cell counts or in corneal thickness measurements. There was a mean loss of approximately 4% in the endothelial cell counts for each group over the one year period.

INDICATIONS AND USAGE

Dorzolamide hydrochloride ophthalmic solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

CONTRAINDICATIONS

Dorzolamide hydrochloride ophthalmic solution is contraindicated in patients who are hypersensitive to any component of this product.

WARNINGS

Dorzolamide hydrochloride ophthalmic solution is a sulfonamide and, although administered topically, is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration with dorzolamide hydrochloride ophthalmic solution. Fatalities have occurred, although rarely, due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.

PRECAUTIONS

General

The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. Dorzolamide hydrochloride ophthalmic solution has not been studied in patients with acute angle-closure glaucoma.

Dorzolamide hydrochloride ophthalmic solution has not been studied in patients with severe renal impairment (CrCl < 30 mL/min). Because dorzolamide hydrochloride ophthalmic solution and its metabolite are excreted predominantly by the kidney, dorzolamide hydrochloride ophthalmic solution is not recommended in such patients.

Dorzolamide hydrochloride ophthalmic solution has not been studied in patients with hepatic impairment and should therefore be used with caution in such patients.

In clinical studies, local ocular adverse effects, primarily conjunctivitis and lid reactions, were reported with chronic administration of dorzolamide hydrochloride ophthalmic solution. Many of these reactions had the clinical appearance and course of an allergic-type reaction that resolved upon discontinuation of drug therapy. If such reactions are observed, dorzolamide hydrochloride ophthalmic solution should be discontinued and the patient evaluated before considering restarting the drug. (See ADVERSE REACTIONS.)

There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and dorzolamide hydrochloride ophthalmic solution. The concomitant administration of dorzolamide hydrochloride ophthalmic solution and oral carbonic anhydrase inhibitors is not recommended.

There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g., dorzolamide) after filtration procedures.

There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Precautions should be used when prescribing dorzolamide hydrochloride ophthalmic solution to this group of patients.

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