dorzolamide hcl 2% eye drops generic trusopt

Uses

Ocular Hypertension and Glaucoma

Dorzolamide ophthalmic solution is used topically to reduce elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Dorzolamide hydrochloride and timolol maleate in a fixed-combination ophthalmic solution is used topically to reduce elevated IOP in patients with open-angle glaucoma or ocular hypertension who have not responded adequately (i.e., failed to achieve target IOP as determined after multiple measurements over time) to a topical β-adrenergic blocking agent. While the exact role of dorzolamide in the management of patients with elevated IOP remains to be determined, the drug is used as monotherapy when a topical β-adrenergic blocking agent or sympathomimetic agent, or latanoprost cannot be used because of intolerance or a contraindication. In addition, dorzolamide is useful as a first-line ''add-on'' agent when more than one drug is needed. The manufacturer states that topical dorzolamide has not been evaluated in patients with angle-closure glaucoma. Although dorzolamide has been used in a limited number of patients with glaucoma or ocular hypertension associated with pseudoexfoliation syndrome, further study is needed to evaluate the use of the drug in this condition.

Dorzolamide is effective in reducing IOP when used alone or in conjunction with other ocular hypotensive agents. Safety and efficacy of dorzolamide was evaluated in a multicenter, randomized, double-blind, active-controlled study that included several hundred patients with baseline IOP values of 23 mm Hg or higher. Patients were randomized to receive dorzolamide ophthalmic solution 2% three times daily, timolol ophthalmic solution 0.5% twice daily, or betaxolol ophthalmic solution 0.5% twice daily. In this study, dorzolamide was as effective as betaxolol in reducing IOP in patients with glaucoma or ocular hypertension; dorzolamide and betaxolol were less effective than timolol in reducing IOP. At 1 year, treatment with dorzolamide, timolol, or betaxolol produced a mean reduction in IOP of 4.3-6.2, 5.4-7.1, or 4-5.7 mm Hg from baseline, respectively. These IOP reductions correspond to a mean peak reduction of IOP of 23, 25, or 21% from baseline in patients receiving dorzolamide, timolol, or betaxolol, respectively, and a mean trough reduction of IOP of 17, 20, or 15%, respectively.

When dorzolamide is used in conjunction with a topical β-adrenergic blocking agent (e.g., betaxolol, timolol), the IOP-lowering effects of these agents may be additive. In one study in patients with open-angle glaucoma or ocular hypertension in whom IOP was not adequately controlled with timolol or betaxolol alone (i.e., IOP value remained at 22 mm Hg or higher, or monotherapy with timolol or betaxolol resulted in less than a 15% reduction of IOP from baseline), concomitant administration of dorzolamide 2% twice daily resulted in further decreases in IOP of about 15-25%. In patients with open-angle glaucoma or ocular hypertension receiving dorzolamide 2% three times daily in whom IOP was not adequately controlled (i.e., IOP value remained at 22 mm Hg or higher, or therapy with dorzolamide resulted in less than a 15% reduction of IOP from baseline), concomitant administration of timolol 0.5% twice daily resulted in further decreases in IOP of about 16-20%. While therapy with dorzolamide in fixed combination with timolol twice daily is associated with greater decreases in IOP than monotherapy with dorzolamide 2% three times daily or timolol 0.5% twice daily, therapy with dorzolamide 2% three times daily in combination with timolol 0.5% twice daily is associated with a slightly greater decrease in IOP (1 mm Hg) than the twice-daily regimen of dorzolamide in fixed combination with timolol. In patients with glaucoma or ocular hypertension receiving timolol 0.5% twice daily, concomitant administration of dorzolamide 2% two or three times daily produced similar IOP-lowering effects compared with concomitant administration of pilocarpine 2% four times daily; in addition, add-on therapy with dorzolamide was better tolerated than add-on therapy with pilocarpine.

Studies to date indicate that tolerance to dorzolamide does not occur and that the reduction in mean IOP is maintained over at least 12 months after initial stabilization.

Inhibition of Perioperative IOP Increases

Topical dorzolamide has been used prophylactically before neodymium yttrium aluminum garnet (Nd:YAG) lasar posterior capsulotomy. Results of a randomized controlled study indicate that administration of 1 drop (20 mcL) of dorzolamide 2% 1 hour prior to capsulotomy is more effective in preventing postoperative increases in IOP than placebo and as effective as oral acetazolamide 125 mg administered 1 hour prior to the procedure.

Dosage and Administration

Administration

Dorzolamide hydrochloride is applied topically to the eye as an ophthalmic solution. Care should be taken to avoid contamination of the solution container.(See Cautions: Precautions and Contraindications.)

Dorzolamide ophthalmic solution contains benzalkonium chloride, which may be absorbed by some contact lenses. Dorzolamide ophthalmic solution should not be administered while wearing soft contact lenses. Contact lenses may be reinserted 15 minutes after a dose of dorzolamide ophthalmic solution or a dose of the fixed-combination ophthalmic solution of dorzolamide hydrochloride and timolol maleate.

If the patient is receiving more than one ophthalmic drug, the drugs should be administered at least 10 minutes apart.

Dosage

Dosage and concentration of dorzolamide hydrochloride are expressed in terms of dorzolamide.

For the treatment of glaucoma or ocular hypertension, the usual dosage of dorzolamide is 1 drop of a 2% solution in the affected eye(s) 3 times daily.

If further reduction in IOP is required in patients receiving the usual dosage of dorzolamide, a topical β-adrenergic blocking agent (e.g., betaxolol, carteolol, levobunolol, metipranolol, timolol), a topical miotic (e.g., pilocarpine), topical latanoprost, topical dipivefrin, or topical epinephrine may be used in conjunction with dorzolamide. For the treatment of glaucoma or ocular hypertension, the usual dosage of dorzolamide hydrochloride in fixed combination with timolol maleate is 1 drop in the affected eye(s) twice daily. Because of the potential for additive systemic effects, combined use of topical dorzolamide and an oral carbonic anhydrase inhibitor (e.g., acetazolamide, dichlorphenamide, methazolamide) is not recommended by the manufacturer.

Dosage in Renal and Hepatic Impairment

Topical dorzolamide has not been evaluated in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/minute). Because dorzolamide and N-desethyldorzolamide are eliminated principally via renal excretion, the manufacturer states that topical ocular use of the drug in patients with severe renal impairment is not recommended. Topical dorzolamide has not been evaluated in patients with hepatic impairment, and the manufacturer states that the drug should be used with caution in such patients.

Cautions

Dorzolamide hydrochloride ophthalmic solution generally is well tolerated following topical application to the eye. Discontinuance of dorzolamide therapy was required in about 6% of patients in clinical studies, principally because of ocular reactions (e.g., conjunctivitis).

In clinical studies, the incidences of most adverse ocular effects in patients receiving dorzolamide generally were similar to those in patients receiving topical timolol or topical betaxolol. In studies evaluating the role of dorzolamide versus pilocarpine as add-on therapy in patients receiving timolol, add-on therapy with dorzolamide was better tolerated than pilocarpine.

Ocular and Other Local Effects

The most frequent adverse effects of topical dorzolamide are ocular burning, stinging, and discomfort following instillation of the solution; these adverse ocular effects have been reported in about 33% of patients receiving the drug in clinical studies. Superficial punctate keratitis has been reported in 10-15% of patients receiving topical ocular dorzolamide in clinical studies and manifestations of ocular allergic reactions (e.g., conjunctivitis, itching, lid reactions) have occurred in about 10% of patients receiving the drug. Blurred vision, redness, tearing, dryness, or photophobia has been reported in 1-5% of topical dorzolamide-treated patients. Iridocyclitis has occurred rarely. Transient myopia, eyelid crusting, palpebral reactions, and ocular pain have occurred. Irreversible corneal decompensation occurred in a few patients with borderline corneal endothelial function receiving topical ocular dorzolamide. Two patients who had undergone glaucoma filtration surgery developed hypotony following addition of topical dorzolamide to existing therapy for glaucoma.

Compared with baseline, topical ocular dorzolamide therapy has not been associated with substantial changes in visual acuity, refraction, or slit-lamp biomicroscopic examination. Results of a long-term (i.e., 1 year) comparative study indicate that effects on corneal endothelial cell counts and corneal thickness measurements were similar among patients receiving dorzolamide ophthalmic solution 2% three times daily and those receiving betaxolol ophthalmic solution 0.5% twice daily or timolol maleate ophthalmic solution 0.5% twice daily. There was a mean loss of approximately 4% in the endothelial cell counts for each group over the one-year period.

Systemic Effects

Although systemic absorption occurs following topical application of dorzolamide to the eye, topical ocular administration of the drug is not associated with clinically important inhibition of carbonic anhydrase (CA) in erythrocytes, and the risk of systemic effects attributable to CA inhibition following topical application to the eye in usual dosages is low. Adverse systemic effects including acidosis and electrolyte imbalance that occur in patients receiving oral carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, methazolamide) have not been reported in patients receiving topical dorzolamide to the eye.

While rash has occurred infrequently in patients receiving dorzolamide in clinical studies, signs and symptoms of systemic allergic reaction including angioedema, pruritus, bronchospasm, or urticaria have been reported with topical ocular therapy in postmarketing studies. Whether sulfonamide toxicity such as Stevens-Johnson syndrome could occur in patients receiving topical dorzolamide to the eye remains to be determined.

Dizziness, paresthesia, throat irritation, dyspnea, and contact dermatitis have been reported with topical application of dorzolamide to the eye.

About 25% of patients receiving dorzolamide report a bitter taste following topical ocular administration of the drug. Adverse effects reported infrequently in patients receiving topical ocular dorzolamide in clinical studies include headache, nausea, and asthenia/fatigue. Urolithiasis has occurred in at least one individual.

Precautions and Contraindications

Dorzolamide is absorbed systemically following topical application to the eye, and the usual precautions associated with systemic use of sulfonamides should be considered when using topical dorzolamide. Serious adverse events associated with sulfonamides include Stevens-Johnson syndrome, toxic epidermal necrosis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias; rarely, these reactions have resulted in death. While serious adverse events such as these have not been reported in patients receiving topical dorzolamide to the eye, sensitization may recur when a sulfonamide is readministered, regardless of the route of administration. Dorzolamide ophthalmic solution should be discontinued if signs or symptoms of hypersensitivity occur. Conjunctivitis or lid reactions that appear to be allergic-type reactions have occurred in patients receiving topical ocular dorzolamide. While these reactions resolve when the drug is discontinued, the patient should be reevaluated before restarting dorzolamide since a more serious allergic-type reaction may occur.

Because timolol is absorbed systemically following topical application of ophthalmic solutions containing dorzolamide in fixed combination with the β-blocker, the toxic potentials of systemically administered timolol, and the usual precautions of systemic timolol therapy should be observed with such topical preparations. Severe respiratory and cardiac reactions, including death resulting from bronchospasm in patients with asthma and, rarely, death associated with cardiac failure, have been reported in patients receiving systemic or topical (ocular) timolol.

Bacterial keratitis has been reported with the use of multiple-dose containers of topical ophthalmic preparations. These containers were contaminated inadvertently by patients who, in most cases, had concurrent corneal disease or disruption of the ocular epithelial surface. Patients should be informed that improper handling of ocular solutions can result in contamination of the solution by common bacteria known to cause ocular infections and that they should avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic solutions. Patients receiving dorzolamide ophthalmic solution should be advised to contact a clinician at the first sign of conjunctivitis, lid reactions, or any other ocular reaction and immediately seek advice regarding the continued use of the present multiple-dose container if an intercurrent ocular condition (e.g., trauma, ocular surgery or infection) occurs.

Choroidal detachment also has been reported with administration of aqueous suppressant therapy (e.g., timolol) following filtration procedures.

Dorzolamide ophthalmic solution has not been systematically evaluated in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/minute). Because dorzolamide and N-desethyldorzolamide are excreted by the kidney, the manufacturer recommends that the drug not be used in patients with severe renal impairment.

The manufacturer states that dorzolamide ophthalmic solution should be used with caution in patients with hepatic impairment since the drug has not been evaluated systematically in such patients.

Patients who wear contact lenses should be warned to remove their lenses prior to receiving a dose of dorzolamide ophthalmic solution since the solution contains benzalkonium chloride which may be absorbed by some lenses.(See Dosage and Administration: Administration.)

Dorzolamide ophthalmic solution is contraindicated in patients with known hypersensitivity to the drug, benzalkonium chloride, or any ingredient in the formulation. In addition, ophthalmic solutions containing dorzolamide in fixed combination with timolol are contraindicated in patients with bronchial asthma or a history of bronchial asthma and in patients with severe chronic obstructive pulmonary disease, sinus bradycardia, atrioventricular block greater than first degree, overt cardiac failure, cardiogenic shock, or known hypersensitivity to any ingredient in the formulation.

Pediatric Precautions

Safety and efficacy of dorzolamide ophthalmic solution in children younger than 16 years of age have not been established.

Geriatric Precautions

Safety and efficacy of dorzolamide alone or in fixed combination with timolol were similar in patients 65 years of age or older compared with younger patients, and special precautions do not appear necessary. However, the possibility of greater sensitivity of some older patients cannot be ruled out.

Mutagenicity and Carcinogenicity

Dorzolamide was not mutagenic in the in vitro microbial (Ames test), in vivo (mouse) cytogenetic assay, in vitro chromosome aberration assay, alkaline elution assay, or V-79 assay.

Long-term (i.e., 2 years) studies in rats have revealed some carcinogenic potential associated with high doses of dorzolamide. Urinary bladder papillomas were detected in male Sprague-Dawley rats given oral dorzolamide 20 mg/kg daily (250 times the recommended human daily ophthalmic dose) for 2 years. Papillomas were not detected in female rats given dorzolamide 20 mg/kg daily, or in male or female rats given oral doses of dorzolamide equivalent to about 12 times the recommended human daily ophthalmic dose. Treatment-related tumors were not detected in female or male mice given oral dorzolamide doses up to 75 mg/kg daily (approximately 900 times the recommended human daily ophthalmic dose) for 21 months. Changes in bladder urothelium were not detected in dogs given oral dorzolamide 2 mg/kg daily (25 times the recommended human daily ophthalmic dose) for 1 year or in monkeys receiving topical dorzolamide 0.4 mg/kg daily (about 5 times the recommended human daily ophthalmic dose) for 1 year. The increased incidence of urinary bladder papillomas in male rats receiving dorzolamide 20 mg/kg daily is a class-effect of carbonic anhydrase inhibitors in rats. Rats are especially prone to the development of papillomas in response to foreign bodies, crystalluria, and sodium salts.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rabbits using oral dorzolamide dosages of 2.5 mg/kg daily or more (31 or more times the recommended human daily ophthalmic dose) revealed malformations of the vertebral bodies. These malformations occurred at dosages that caused metabolic acidosis and decreased body weight gain in dams and decreased fetal weight. Reproductive studies in rabbits using oral dorzolamide dosages of 1 mg/kg daily (13 times the recommended human daily ophthalmic dose) did not reveal evidence of teratogenic effects or embryotoxicity. There are no adequate and controlled studies to date using dorzolamide hydrochloride ophthalmic solution in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

Reproduction studies in rats using dorzolamide dosages of 94 or 188 times the recommended human daily ophthalmic dose have not revealed evidence of impaired fertility.

Lactation

In lactating rats given oral dorzolamide 7.5 mg/kg daily (94 times the recommended human daily ophthalmic dose), decreases of 5-7 % in body weight gain in offspring and developmental delay (i.e., incisor eruption, vaginal canalization, eye opening) secondary to lower fetal body weight have been reported.

It is not known whether dorzolamide is distributed into human milk. Because of the potential for serious adverse reactions to dorzolamide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Oral Carbonic Anhydrase Inhibitors

Concomitant use of topical ocular dorzolamide and an oral carbonic anhydrase inhibitor (e.g., acetazolamide, dichlorphenamide, methazolamide) is not recommended by the manufacturer because of the potential for additive systemic effects. Although acid-base and electrolyte disturbances have not been reported in patients receiving dorzolamide, such disturbances have been reported in patients receiving oral carbonic anhydrase inhibitors and have, in some instances, resulted in drug interactions (e.g., toxicity associated with high-dose salicylate therapy). The potential for such drug interactions should be considered in patients receiving dorzolamide.

Ocular Hypotensive Agents

When dorzolamide is used in conjunction with a topical β-adrenergic blocking agent (e.g., betaxolol, carteolol, levobunolol, metipranolol, timolol), the IOP-lowering effects of these agents may be additive. This additive effect may be used to therapeutic advantage in the management of glaucoma or ocular hypertension. However, when more than one topical ophthalmic drug is used in a patient receiving dorzolamide ophthalmic solution, the drugs should be administered at least 10 minutes apart.

The possibility of an additive effect on systemic β-adrenergic blockade also should be considered in patients receiving topical ophthalmic solutions containing dorzolamide in fixed combination with timolol (Cosopt) and an oral β-adrenergic blocking agent concomitantly. The manufacturer does not recommend concomitant use of 2 topical β-adrenergic blocking agents. For further information about drug interactions with timolol ophthalmic solutions,

Pharmacokinetics

Absorption

The extent of ocular and systemic absorption of dorzolamide following topical application to the eye in humans has not been elucidated. Following topical application to the eye of dorzolamide 2% in rabbits, peak dorzolamide concentrations in cornea, iris/ciliary body, and aqueous humor were achieved within 1-2 hours and averaged 24 mcg/g, 27 mcg/g, and 7.8 mcg/mL, respectively.

A reduction in intraocular pressure (IOP) generally peaks within 2-3 hours after topical administration of dorzolamide to the eye, and persists for 8 hours or longer. In dose- ranging studies, administration of topical dorzolamide 3 times daily resulted in greater reduction in IOP than administration of the drug twice daily.

Some systemic absorption of dorzolamide occurs following topical application to the eye, although use of dorzolamide ophthalmic solution appears to be associated with a low potential for causing systemic effects. Topically administered dorzolamide that does not penetrate the eye may reach systemic circulation through blood vessels in the conjunctiva, and mucous membranes in the nose, pharynx, esophagus, and GI tract. Because systemically absorbed dorzolamide is preferentially distributed into erythrocytes, dorzolamide concentrations in blood and erythrocytes are substantially higher than concentrations in plasma. Following topical administration to the eye of a single dose of dorzolamide, whole blood concentrations of the drug peaked within 24-72 hours. In a limited number of healthy individuals receiving 1 drop (32 mcL) of dorzolamide 3% (0.96 mcg) in each eye 3 times daily, drug concentrations in whole blood on day 14 ranged from 1.7-2.7 mcg/mL. In patients with glaucoma or ocular hypertension and in healthy individuals receiving 1 drop of dorzolamide 2% in each eye 3 times daily, steady-state erythrocyte concentrations of the drug of 20-25 µM are reached within 8 days. In patients receiving long-term therapy with the recommended dosage of dorzolamide 2%, concentration of the drug in erythrocytes at 6 or 12 months was 21.1 or 20.5 µM, respectively, and concentration of N-desethyldorzolamide was 8.6 or 7.7 µM at these times. Following topical administration of dorzolamide 2% as a single dose of 3 drops into each eye (total dose of dorzolamide actually administered 0.74 mcg) or 1 drop (32 mcL) of a 3% solution (0.96 mcg) into each eye 4 times daily for 14 days in healthy individuals, the concentration of dorzolamide in plasma was below the level of detection (i.e., less than 5 ng/mL). In another study in individuals with glaucoma or ocular hypertension receiving 1 drop (30 mcL) of dorzolamide ophthalmic solution 2% (0.6 mg) in each eye 3 times daily for 6 months, the concentration of dorzolamide in plasma was 11 ng/mL; this plasma concentration was 1/700 of that in erythrocytes.

Administration of oral dorzolamide 2 mg twice daily is expected to result in systemic exposure equivalent to that associated with topical administration of 1 drop of dorzolamide 2% into each eye 3 times daily. Following administration of oral dorzolamide 2 mg twice daily in a limited number of healthy individuals, steady-state concentrations of the drug in erythrocytes were achieved within 8 weeks. In these individuals, inhibition of carbonic anhydrase, including CA-II, was below the level believed to be necessary for a pharmacologic effect on renal function and respiration.

Distribution

Distribution of dorzolamide into human ocular tissues and fluids has not been fully characterized. Following topical application to the eye in rabbits, dorzolamide is distributed throughout ocular tissue and fluids including cornea, aqueous humor, iris/ciliary body, and the retina. Dorzolamide binds to ocular pigment, which may result in a depot effect and extend the duration of action of the drug. In in vitro tests using pigment isolated from bovine iris/ciliary body, about 19% of dorzolamide was bound to the pigment.

Dorzolamide is about 33% bound to plasma proteins.

It is not known whether dorzolamide crosses the placenta or is distributed into human milk.

Elimination

Dorzolamide is metabolized in the liver by cytochrome P-450 isoenzymes to N-desethyldorzolamide. While both dorzolamide and N-desethyldorzolamide are excreted in urine, the drug is excreted principally (about 80%) unchanged.

Dorzolamide is eliminated from erythrocytes in a nonlinear manner. While the initial elimination half-life is rapid, the terminal elimination half-life of dorzolamide in erythrocytes is 120 days.