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 Ophthalmic Solution contains dorzolamide hydrochloride, 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 stimulate 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 IOPlowering 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

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.

Information for patients

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. Patients should be advised that if serious or unusual reactions including severe skin reactions or signs of hypersensitivity occur, they should discontinue the use of the product (see WARNINGS).

Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis and lid reactions, they should discontinue use and seek their physician’s advice.

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures.

Patients should also be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, 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.

Patients also should be advised 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.

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

Patients should be advised that Dorzolamide Hydrochloride Ophthalmic Solution contains benzalkonium chloride which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following Dorzolamide Hydrochloride Ophthalmic Solution administration.

Drug Interactions

Although acid-base and electrolyte disturbances were not reported in the clinical trials with Dorzolamide Hydrochloride Ophthalmic Solution, these disturbances have been reported with oral carbonic anhydrase inhibitors and have, in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy). Therefore, the potential for such drug interactions should be considered in patients receiving Dorzolamide Hydrochloride Ophthalmic Solution.

Carcinogenesis, mutagenesis, impairment of fertility

In a two-year study of dorzolamide hydrochloride administered orally to male and female Sprague-Dawley rats, urinary bladder papillomas were seen in male rats in the highest dosage group of 20 mg/kg/day (250 times the recommended human ophthalmic dose). Papillomas were not seen in rats given oral doses equivalent to approximately 12 times the recommended human ophthalmic dose. No treatment-related tumors were seen in a 21-month study in female and male mice given oral doses up to 75 mg/kg/day (~900 times the recommended human ophthalmic dose).

The increased incidence of urinary bladder papillomas seen in the high-dose male rats is a class-effect of carbonic anhydrase inhibitors in rats. Rats are particularly prone to developing papillomas in response to foreign bodies, compounds causing crystalluria, and diverse sodium salts.

No changes in bladder urothelium were seen in dogs given oral dorzolamide hydrochloride for one year at 2 mg/kg/day (25 times the recommended human ophthalmic dose) or monkeys dosed topically to the eye at 0.4 mg/kg/day (~5 times the recommended human ophthalmic dose) for one year.

The following tests for mutagenic potential were negative: (1) in vivo (mouse) cytogenetic assay; (2) in vitro chromosomal aberration assay; (3) alkaline elution assay; (4) V-79 assay; and (5) Ames test.

In reproduction studies of dorzolamide hydrochloride in rats, there were no adverse effects on the reproductive capacity of males or females at doses up to 188 or 94 times, respectively, the recommended human ophthalmic dose.

Pregnancy

Nursing mothers

In a study of dorzolamide hydrochloride in lactating rats, decreases in body weight gain of 5 to 7% in offspring at an Dorzolamide Hydrochloride Ophthalmic Solution Sterile Ophthalmic Solution 2% oral dose of 7.5 mg/kg/day (94 times the recommended human ophthalmic dose) were seen during lactation. A slight delay in postnatal development (incisor eruption, vaginal canalization and eye openings), secondary to lower fetal body weight, was noted.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Dorzolamide Hydrochloride Ophthalmic Solution, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

Safety and IOP-lowering effects of Dorzolamide Hydrochloride Ophthalmic Solution have been demonstrated in pediatric patients in a 3-month, multicenter, double-masked, active-treatment-controlled trial.

Geriatric use

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

ADVERSE REACTIONS

Controlled clinical trials:

The most frequent adverse events associated with Dorzolamide Hydrochloride Ophthalmic Solution were ocular burning, stinging, or discomfort immediately following ocular administration (approximately onethird of patients). Approximately one-quarter of patients noted a bitter taste following administration. Superficial punctate keratitis occurred in 10-15% of patients and signs and symptoms of ocular allergic reaction in approximately 10%. Events occurring in approximately 1-5% of patients were conjunctivitis and lid reactions (see PRECAUTIONS, General), blurred vision, eye redness, tearing, dryness, and photophobia. Other ocular events and systemic events were reported infrequently, including headache, nausea, asthenia/fatigue; and, rarely, skin rashes, urolithiasis, and iridocyclitis.

In a 3-month, double-masked, active-treatment-controlled, multicenter study in pediatric patients, the adverse experience profile of Dorzolamide Hydrochloride Ophthalmic Solution was comparable to that seen in adult patients.

Clinical practice:

The following adverse events have occurred either at low incidence (<1%) during clinical trials or have been reported during the use of Dorzolamide Hydrochloride Ophthalmic Solution in clinical practice where these events were reported voluntarily from a population of unknown size and frequency of occurrence cannot be determined precisely. They have been chosen for inclusion based on factors such as seriousness, frequency of reporting, possible causal connection to Dorzolamide Hydrochloride Ophthalmic Solution, or a combination of these factors: signs and symptoms of systemic allergic reactions including angioedema, bronchospasm, pruritus, and urticaria; Stevens-Johnson syndrome and toxic epidermal necrolysis; dizziness, paresthesia; ocular pain, transient myopia, choroidal detachment following filtration surgery, eyelid crusting; dyspnea; contact dermatitis, epistaxis, dry mouth and throat irritation.

OVERDOSAGE

Storage

Store Dorzolamide Hydrochloride Ophthalmic Solution at 20°-25°C (68°-77°F). Protect from light.

Rx only

Manufactured by:

Hi-Tech Pharmacal Co., Inc.

Amityville, NY 11701

Rev. 232:02 12/10

MG #21226

INSTRUCTIONS FOR USE