VA Class:OP105

ATC Class:S01EC03

AHFS Class:

• Carbonic Anhydrase Inhibitors 52:40.12

Generic Name(s):

• Dorzolamide Hydrochloride

Chemical Name:

• (4 S ,6 S )-4-(Ethylamino)-5,6-dihydro-6-methyl-4 H -thieno[2,3- b ]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride

Molecular Formula:

• C₁₀H₁₆N₂O₄S₃•HCl

Dorzolamide is a carbonic anhydrase inhibitor.1,2,3,4,5,6,7,8,9,10

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.1,2,3,4,5,6,7,8,9,10 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.32

Elevated IOP in patients with glaucoma can be reduced by medical treatment, laser therapy, and/or incisional glaucoma surgery; treatment with a topical ocular hypotensive agent frequently is the initial intervention for primary open-angle glaucoma.130 Selection of an initial ocular hypotensive agent is influenced by the extent of the required reduction in IOP, coexisting medical conditions, and the characteristics of the individual drugs (e.g., dosing frequency, adverse effect profile, cost).130,132 With single-agent regimens, the reduction in IOP is approximately 25-33% with topical prostaglandin analogs; 20-25% with topical β-adrenergic blocking agents, α-adrenergic agonists, or miotic (parasympathomimetic) agents; 20-30% with oral carbonic anhydrase inhibitors; 18% with topical rho kinase inhibitors; and 15-20% with topical carbonic anhydrase inhibitors.130,131 In the absence of other considerations (e.g., contraindications, cost considerations, intolerance, adverse effects, patient refusal), a prostaglandin analog frequently is considered for initial therapy because of the relatively greater activity, once-daily administration, and low frequency of systemic adverse effects with this drug class; however, ocular adverse effects can occur.130,131,132,134

IOP should be reduced toward a target level that the clinician believes will slow disease progression and avoid visual field losses that would substantially reduce quality of life during the patient's lifetime.130,132 The target level is an estimate and should be individualized based on such factors as the extent of optic nerve damage and/or visual field loss, the baseline IOP at which damage occurred, rate of progression, life expectancy, and other considerations.130,132 Reducing the pretreatment IOP by 25% or more has been shown to slow progression of primary open-angle glaucoma.130,131 The target IOP should be adjusted up or down as needed over the course of the disease.130,131,132 If the target IOP is not achieved with single-agent therapy, alternative or additional ocular hypotensive agents may be selected depending on the patient's response to the initial drug.130 Combination therapy with drugs from different therapeutic classes often is required to achieve adequate control of IOP.131,133

Clinical Experience

Dorzolamide is effective in reducing IOP when used alone or in conjunction with other ocular hypotensive agents.1,2,3,4,5,6,7,8,9,10,11,12,32 In clinical studies of up to one year's duration in patients with glaucoma or ocular hypertension (baseline IOP of 23 mm Hg or higher), topical application of dorzolamide reduced IOP by approximately 3-5 mm Hg throughout the day.1 In one such study, dorzolamide 2% administered 3 times daily was as effective as betaxolol 0.5% administered twice daily in reducing IOP in patients with glaucoma or ocular hypertension; dorzolamide and betaxolol were less effective than timolol 0.5% administered twice daily in reducing IOP.5,7,9,10 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.5,7,9,10 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.5,7,9,10

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.7,9,10,13,14,15,32 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%.7,9 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%.10,15 In clinical studies of 3-15 months' duration, the IOP-lowering effect of the fixed-combination ophthalmic solution containing dorzolamide 2% and timolol 0.5% administered twice daily was 1-3 mm Hg greater than that of dorzolamide 2% administered 3 times daily or timolol 0.5% administered twice daily; the IOP-lowering effect of the fixed combination administered twice daily was slightly (approximately 1 mm Hg) less than that achieved with concurrent use of dorzolamide 2% administered 3 times daily and timolol 0.5% administered twice daily.32 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.14

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.7,30

Administration

Dorzolamide hydrochloride is applied topically to the eye as an ophthalmic solution.1,2,3,4,5,6,7,8,9,10,13,14,15 Dorzolamide hydrochloride also is commercially available in fixed combination with timolol maleate for topical application to the eye as an ophthalmic solution.32

Care should be taken to avoid contamination of the solution container.1,32 (See Cautions: Precautions and Contraindications.)

Dorzolamide ophthalmic solution and some formulations of dorzolamide and timolol ophthalmic solution contain benzalkonium chloride, which may be absorbed by soft contact lenses.1,32 Contact lenses should be removed prior to topical application of each dose of these preparations, but may be reinserted 15 minutes after the dose.1,32

Preservative-free dorzolamide and timolol ophthalmic solution in single-use containers should be administered topically to one or both eyes immediately after the container is opened; since sterility cannot be maintained after the individual unit is opened, any remaining contents should be discarded immediately after administration.34

If the patient is receiving more than one ophthalmic preparation, the preparations should be administered at least 5 minutes apart.1,32

Dosage

Dosage and concentration of dorzolamide hydrochloride are expressed in terms of dorzolamide.1

For the treatment of open-angle glaucoma or ocular hypertension in adults and pediatric patients, the usual dosage of dorzolamide is 1 drop of a 2% ophthalmic solution in the affected eye(s) 3 times daily.1,2,5,6,7,9,10

If the target intraocular pressure (IOP) is not achieved, alternative or additional ocular hypotensive agents may be required.130,131,133 (See Uses: Ocular Hypertension and Glaucoma.) When dorzolamide is used in fixed combination with timolol for the treatment of open-angle glaucoma or ocular hypertension in adults and pediatric patients 2 years of age or older, the usual dosage is 1 drop of an ophthalmic solution containing dorzolamide 2% and timolol 0.5% in the affected eye(s) twice daily.32 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.1

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).1,32 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.1,32

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.1,32

Dorzolamide hydrochloride ophthalmic solution generally is well tolerated following topical application to the eye.1,2,3,4,5,6,9,10 Discontinuance of dorzolamide therapy was required in about 6% of patients in clinical studies, principally because of ocular reactions (e.g., conjunctivitis).7,9,10

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.7,10 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.10,14

Ocular and Other Local Effects

The most frequent adverse effects of topical dorzolamide are ocular burning,1,2,3,6,7,9,10,13 stinging,1,2,3,5,6,7,9,10,13 and discomfort1,4,7,10 following instillation of the solution; these adverse ocular effects have been reported in about 33% of patients receiving the drug in clinical studies.1 Superficial punctate keratitis1,5,6,7 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.1,5,7,9,10,13 Blurred vision,1,3,5,7,9,10,13 redness,1 tearing,1,3,5,7,9,10,13 dryness,1,5 or photophobia1,5,13 has been reported in 1-5% of topical dorzolamide-treated patients.1 Iridocyclitis has occurred rarely.1,9 Transient myopia,1 eyelid crusting,1 palpebral reactions,32 ocular pain,1 and choroidal detachment following filtration surgery1 have occurred. Irreversible corneal decompensation occurred in a few patients with borderline corneal endothelial function receiving topical ocular dorzolamide.10,27 Two patients who had undergone glaucoma filtration surgery developed hypotony following addition of topical dorzolamide to existing therapy for glaucoma.10,26

Compared with baseline, topical ocular dorzolamide therapy has not been associated with substantial changes in visual acuity, refraction, or slit-lamp biomicroscopic examination.7,10 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 2% ophthalmic solution 3 times daily and those receiving betaxolol 0.5% ophthalmic solution twice daily or timolol 0.5% ophthalmic solution twice daily.1,9,29 There was a mean loss of approximately 4% in the endothelial cell counts for each group over the one-year period.1

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.1,10 Adverse systemic effects including acidosis and electrolyte imbalance that occur in patients receiving oral carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, methazolamide) were not reported in clinical trials in patients receiving topical dorzolamide to the eye.1,5,7,9,10

While rash1,9 has occurred infrequently in patients receiving dorzolamide in clinical studies, signs and symptoms of systemic allergic reaction (including angioedema,1 pruritus,1 bronchospasm,1 or urticaria1 ), Stevens-Johnson syndrome,1 and toxic epidermal necrolysis1 have been reported with topical ocular therapy in postmarketing studies.1

Dizziness,1,9 paresthesia,1,9 throat irritation,1 dyspnea,1 epistaxis,1 dry mouth,1 and contact dermatitis1 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.1,2,3,5,7,9,10 Adverse effects reported infrequently in patients receiving topical ocular dorzolamide in clinical studies include headache,1,9,10 nausea,1,9,10 and asthenia/fatigue.1,9 Urolithiasis has occurred in at least one individual.1,9

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.1 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.1 Sensitization may recur when a sulfonamide is readministered, regardless of the route of administration.1 Dorzolamide should be discontinued if signs or symptoms of hypersensitivity occur.1 Conjunctivitis or lid reactions that appear to be allergic-type reactions have occurred in patients receiving topical ocular dorzolamide.1 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.1,29

Bacterial keratitis has been reported with the use of multiple-dose containers of topical ophthalmic preparations.1 These containers were contaminated inadvertently by patients who, in most cases, had concurrent corneal disease or disruption of the ocular epithelial surface.1 Patients should be informed that improper handling of ophthalmic 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.1 Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic solutions.1 Patients receiving single-use preparations of dorzolamide and timolol ophthalmic solution should be advised that the solution contains no preservative and should be administered topically to one or both eyes immediately after opening the container; since sterility cannot be maintained after the individual unit is opened, any remaining contents should be discarded immediately after administration.34 Patients receiving dorzolamide also should be advised to immediately contact their clinician for advice regarding continued use of the preparation if they experience an intercurrent ocular condition (e.g., trauma, infection) or ocular reaction (particularly conjunctivitis and lid reactions) or require ocular surgery.1,32,34

Carbonic anhydrase activity has been observed in the cytoplasm and around the plasma membranes of the corneal endothelium.1 Topical dorzolamide should be used with caution in patients with low endothelial cell counts, since these patients are at increased risk for development of corneal edema.1

Dorzolamide ophthalmic solution has not been systematically evaluated in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/minute).1 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.1

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.1

Management of acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents.1

Dorzolamide ophthalmic solution and preserved dorzolamide and timolol ophthalmic solutions contain benzalkonium chloride, which may be absorbed by soft contact lenses.1,32 Patients who wear contact lenses should be warned to remove their lenses prior to administration of each dose of these preparations.1,32 (See Dosage and Administration: Administration.)

When dorzolamide is used in fixed combination with timolol, the cautions, precautions, contraindications, and drug interactions associated with timolol should be considered in addition to those associated with dorzolamide.32 (See Timolol 52:40.08.)

Dorzolamide is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1,32

Pediatric Precautions

Safety and efficacy of dorzolamide ophthalmic solution in pediatric patients have been established in a 3-month, double-blind, active-controlled clinical trial.1

Safety and efficacy of the fixed-combination dorzolamide and timolol ophthalmic solution have been established (when the drugs were administered individually) in pediatric patients 2 years of age or older; use of these drugs in this age group is supported by evidence from adequate and well-controlled studies in children and adults.32 Safety and efficacy have not been established in pediatric patients younger than 2 years of age.32

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.1,30,32,33

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.1

Long-term (i.e., 2 years) studies in rats have revealed some carcinogenic potential associated with high doses of dorzolamide.1 Urinary bladder papillomas were detected in male Sprague-Dawley rats given oral dorzolamide for 2 years at dosages that resulted in estimated peak plasma concentrations that were 138 times higher than the lower limit of detection in human plasma following ocular administration.1 Papillomas were not detected in male or female rats given oral dorzolamide at dosages that resulted in estimated peak plasma concentrations that were 7 times higher than the lower limit of detection in human plasma following ocular administration.1 Treatment-related tumors were not detected in female or male mice given oral dorzolamide for 21 months at dosages that resulted in estimated peak plasma concentrations that were up to 582 times higher than the lower limit of detection in human plasma following ocular administration.1 Changes in bladder urothelium were not detected in dogs given oral dorzolamide for 1 year at dosages that resulted in estimated peak plasma concentrations that were 137 times higher than the lower limit of detection in human plasma following ocular administration or in monkeys receiving topical dorzolamide for 1 year at dosages approximately equivalent to the recommended human ophthalmic dosage.1 The increased incidence of urinary bladder papillomas in male rats receiving high dosages of dorzolamide is a class effect of carbonic anhydrase inhibitors in rats.1 Rats are especially prone to the development of papillomas in response to foreign bodies, crystalluria, and sodium salts.1

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rabbits using oral dorzolamide at dosages that resulted in estimated peak plasma concentrations that were 37 times higher than the lower limit of detection in human plasma following ocular administration revealed malformations of the vertebral bodies.1 These malformations occurred at dosages that caused metabolic acidosis and decreased body weight gain in dams and decreased fetal weight.1 Reproductive studies in rabbits using oral dorzolamide at dosages that resulted in estimated peak plasma concentrations that were 15 times higher than the lower limit of detection in human plasma following ocular administration did not reveal evidence of teratogenic effects or embryotoxicity.1

There are no adequate and controlled studies to date using dorzolamide in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1

Fertility

Reproduction studies in rats using dorzolamide at dosages that resulted in estimated peak plasma concentrations that were 52 or 104 times higher (in female or male rats, respectively) than the lower limit of detection in human plasma following ocular administration have not revealed evidence of impaired fertility.1

Lactation

In lactating rats given oral dorzolamide at dosages that resulted in estimated peak plasma concentrations that were 52 times higher than the lower limit of detection in human plasma following ocular administration, 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.1

It is not known whether dorzolamide is distributed into human milk.1 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.1

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.1

Salicylates

Acid-base and electrolyte disturbances produced by oral carbonic anhydrase inhibitors have been associated with toxicity in some patients receiving high-dose salicylates.1 (See Drug Interactions in the Carbonic Anhydrase Inhibitors General Statement 52:10 and Drug Interactions: Acidifying and Alkalinizing Agents, in the Salicylates General Statement 28:08.04.24.) Although acid-base and electrolyte disturbances were not reported in clinical trials in patients receiving dorzolamide ophthalmic solution, the possibility of toxicity in patients receiving concomitant therapy with topical ophthalmic dorzolamide and high-dose salicylates should be considered.1

Acute Toxicity

In general, overdosage of dorzolamide would be expected to produce signs and symptoms associated with carbonic anhydrase inhibition including electrolyte imbalance, systemic acidosis, and CNS effects.1

Serum electrolytes, including serum potassium, and blood pH values should be monitored in patients experiencing dorzolamide overdosage.1

Pharmacology

Dorzolamide has pharmacologic actions similar to those of other carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, methazolamide).1,2,3,4,5,6,7,8,9,10 Carbonic anhydrase inhibitors reduce the formation of hydrogen and carbonate ions from carbon dioxide and water by noncompetitive, reversible inhibition of carbonic anhydrase, a zinc metalloenzyme, thereby reducing the availability of these ions for active transport into secretions.1,9,10,18,22

While carbonic anhydrase is widely distributed throughout the body, including the kidney, pancreas, CNS, lung, and eye, the enzyme is located principally in erythrocytes.1,9,10,17,22 Carbonic anhydrase exists in several isoforms; the isoenzymes present in erythrocytes include carbonic anhydrase I (CA-I) and II (CA-II) and isoenzymes present in the eye include CA-I, CA-II, and carbonic anhydrase IV (CA-IV).9 CA-I and CA-II are present in the corneal endothelium and lens; CA-II is the most active isoform of the enzyme, and is the only form present in the secretory cells of the ciliary process, where its main function is to regulate secretion of aqueous humor.1,9,10,17,22 CA-II also is present in the retina.9,10 In contrast to CA-I and CA-II, CA-IV is membrane bound; a definitive role for CA-IV in the production of aqueous humor remains to be established.9,10,29,30 Because the quantity of carbonic anhydrase (i.e., CA-I and CA-II) present in erythrocytes exceeds that present in the ciliary process by 100-fold, metabolic activity catalyzed by these isoenzymes in the ciliary process may be more susceptible to inhibition than activity in blood.18

Dorzolamide is a highly specific inhibitor of CA-II,1,3,4,9,10,15 although the drug also inhibits CA-IV.3,4,9,10,15 The dorzolamide metabolite, N -desethyldorzolamide, inhibits CA-I, CA-II, and CA-IV.9 On a molar basis, dorzolamide is a more potent inhibitor of CA-II isolated from erythrocytes than is acetazolamide, methazolamide, or N -desethyldorzolamide.9 The IC₅₀ of dorzolamide (concentration of the drug required to inhibit 50% of the isoenzyme) for CA-II is 0.18 n M .9 In addition, dorzolamide is more potent than acetazolamide, methazolamide, or N -desethyldorzolamide at blocking CA-IV isolated from lung.9

Although the precise mechanisms of action of dorzolamide have not been fully determined, results of X-ray crystallography studies indicate that the ethylamino group of dorzolamide changes the position of histidine 64 in the active site of CA-II so that the isoenzyme cannot bind water.9

Ocular Effects

Dorzolamide is an ocular hypotensive agent.1,2,3,4,5,6,7,8,9,10 Following topical application to the eye, dorzolamide reduces both elevated and normal intraocular pressure (IOP) in patients with or without glaucoma.1,4,6,9,10 In patients with elevated IOP, topical dorzolamide can produce mean IOP reductions of about 17-23%.4,5,7 While dorzolamide has pharmacologic activity similar to the carbonic anhydrase inhibitors that are administered orally (e.g., acetazolamide, dichlorphenamide, methazolamide), animal studies indicate that topical dorzolamide exerts its ocular hypotensive effect by locally mediated inhibition of carbonic anhydrase.9,10,12,28,29 The IOP response to dorzolamide does not appear to be affected by age, gender, baseline IOP, diagnosis, or previous treatment with β-adrenergic receptor blocking agents (e.g., timolol).6,29 Dorzolamide reduces IOP without affecting pupil size or accommodation.9,29,30

The exact mechanism by which carbonic anhydrase inhibitors, including dorzolamide, reduce IOP has not been fully elucidated.9,10,12 Fluorophotometric studies suggest that reduced aqueous humor formation is the principal effect.1,9,10,12,17 In a study in nonhuman primates, aqueous humor flow rate decreased from a baseline rate of 1.27 µL/minute to 0.9 µL/minute following topical administration of 1 drop (50 µL) of dorzolamide 2%.10,12 Inhibition of CA-II in the ciliary process by dorzolamide decreases the rate of aqueous humor secretion and IOP by slowing bicarbonate formation and reducing sodium and fluid transport.1,9,10,18 Dorzolamide does not appear to affect outflow of aqueous humor.9,10,12 While dorzolamide may increase retinal blood velocity, the clinical importance of changes in retinal blood flow or velocity in patients with glaucoma remains to be determined.9,10,19,29 Topical administration of the drug is not associated with substantial local anesthetic activity, ocular irritation, or lenticular toxicity.9,24

While results of in vitro studies indicate that dorzolamide is more potent than acetazolamide or methazolamide in inhibiting CA-II,9 oral acetazolamide may be a more effective ocular hypotensive agent than topical dorzolamide.16,29 In one study, oral acetazolamide (250 mg 4 times daily for 6 doses) suppressed aqueous humor flow in individuals with normal ocular tension to a greater extent than topical dorzolamide (1 drop of a 2% solution 3 times daily for 5 doses).16 However, the half-life of oral acetazolamide is substantially longer than that of topical dorzolamide, and further study is needed to assess the relative potency of their agents.16,29

Systemic Effects

While systemic absorption of dorzolamide occurs following topical administration to the eye, use of dorzolamide ophthalmic solution to date has not been associated with adverse effects resulting from systemic carbonic anhydrase inhibition.1,3,6,9

Following long-term administration of topical dorzolamide, the drug accumulated in erythrocytes as a result of CA-II binding.1,9 In addition, the N -desethyl metabolite accumulates in erythrocytes as a result of binding to CA-I.9 Following administration of 1 drop of dorzolamide 2% into each eye 3 times daily for 1 or 12 months, CA-II activity in erythrocytes averaged 20 or 12% of baseline, respectively.6,9,21 Because greater than 99% inhibition of this enzyme is necessary to induce a physiologic effect, topical dorzolamide does not exhibit physiologic effects consistent with systemic carbonic anhydrase inhibition.1,9,21

Pharmacokinetics

Absorption

The extent of ocular and systemic absorption of dorzolamide following topical application to the eye in humans has not been elucidated.1,9,10 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.9,10

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.4,6,8,10 In dose- ranging studies, administration of topical dorzolamide 3 times daily resulted in greater reduction in IOP than administration of the drug twice daily.6,10

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.1,3,6,9,10,21 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.9 Because systemically absorbed dorzolamide is preferentially distributed into erythrocytes, dorzolamide concentrations in blood and erythrocytes are substantially higher than concentrations in plasma.1,3,9,10,20 Following topical administration to the eye of a single dose of dorzolamide, whole blood concentrations of the drug peaked within 24-72 hours.3,10 In a limited number of healthy individuals receiving 1 drop (32 µL) 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.22 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 µ M are reached within 8 days.10,20,21 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 µ M , respectively, and concentration of N -desethyldorzolamide was 8.6 or 7.7 µ M at these times.21 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 µL) 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).3,9,10 In another study in individuals with glaucoma or ocular hypertension receiving 1 drop (30 µL) 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.10,20

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.1 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.1 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.1

Distribution

Distribution of dorzolamide into human ocular tissues and fluids has not been fully characterized.1,9,10 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.9,10 Dorzolamide binds to ocular pigment.9 In in vitro tests using pigment isolated from bovine iris/ciliary body, about 19% of dorzolamide was bound to the pigment.9

Dorzolamide is about 33% bound to plasma proteins.1,10

It is not known whether dorzolamide crosses the placenta or is distributed into human milk.1

Elimination

Dorzolamide is metabolized in the liver by cytochrome P-450 isoenzymes to N -desethyldorzolamide.1,9,10 While both dorzolamide and N -desethyldorzolamide are excreted in urine, the drug is excreted principally (about 80%) unchanged.1,10,20

Dorzolamide is eliminated from erythrocytes in a nonlinear manner.1 While the initial elimination half-life is rapid, the terminal elimination half-life of dorzolamide in erythrocytes is 120 days.1,3,10

Chemistry and Stability

Chemistry

Dorzolamide is a carbonic anhydrase inhibitor.1,2,3,4,5,6,7,8,9,10 Similar to other carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, methazolamide), dorzolamide is a nonbacteriostatic sulfonamide derivative.1,2,3,4,5,6,7,8,9,10

Dorzolamide is a thienothiopyran-2-sulfonamide derivative and differs structurally from orally administered carbonic anhydrase inhibitors (e.g., acetazolamide, dichlorphenamide, methazolamide), which contain an unsubstituted sulfamyl group.2,5,10 Various thienothiopyran-2-sulfonamide derivatives, including dorzolamide, have been investigated for use as topical ocular hypotensive agents; these derivatives have improved water solubility, chemical stability, and ocular penetration compared with carbonic anhydrase inhibitors that are commercially available for oral administration (e.g., acetazolamide, dichlorphenamide, methazolamide).2,5,10,18 Dorzolamide is pharmacologically related to orally administered carbonic anhydrase inhibitors.2,5,10

Dorzolamide is commercially available for ophthalmic use as the hydrochloride salt.1 Dosage and concentration of the drug are expressed in terms of the base; each mL of dorzolamide 2% contains 20 mg of dorzolamide, which is equivalent to 22.3 mg of dorzolamide hydrochloride.1

Dorzolamide hydrochloride occurs as a white to off-white crystalline powder.1 The drug is soluble in water and slightly soluble in alcohol.1

For ophthalmic use, dorzolamide hydrochloride, alone or in fixed combination with timolol maleate, is commercially available as an ophthalmic solution.1,32,34 Dorzolamide ophthalmic solution is a slightly viscous, isotonic solution of the drug in water for injection; benzalkonium chloride is added as a preservative.1 The fixed-combination ophthalmic solution of dorzolamide hydrochloride and timolol maleate is a clear, colorless to nearly colorless, slightly viscous, isotonic solution; preservative-free and preserved (with benzalkonium chloride) formulations are available.32,34 The pH of the ophthalmic solutions is approximately 5.6-5.65.1,32,34

Stability

Dorzolamide hydrochloride ophthalmic solution should be stored at 15-30°C and protected from light.1

The preserved fixed-combination ophthalmic solution of dorzolamide hydrochloride and timolol maleate should be stored at 20-25°C and protected from light.32 The 0.2-mL single-use containers of preservative-free dorzolamide hydrochloride and timolol maleate ophthalmic solution should be stored at 20-25°C in the original foil pouch for protection from light; any unused containers should be discarded 15 days after the pouch is first opened.34 The preservative-free solution should not be frozen.34

1. Merck & Company. Trusopt^® (dorzolamide hydrochloride 2%) ophthalmic solution prescribing information. Whitehouse Station; NJ; 2014 Feb.

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28. Sugrue MF, Mallorga P, Schwam H et al. Preclinical studies on L-671,152, a topically effective ocular hypotensive carbonic anhydrase inhibitor. Br J Pharmacol . 1989; 98(Suppl):820P. [PubMed 2611526]

29. Reviewers' comments (personal observations).

30. Merck, West Point, PA; Personal communication.

31. Kohlhaas H, Mammen A, Richard G. Change in corneal sensitivity after topical dorzolamide administration: a comparative study. Ophthalmology . 1997; 94:424-7.

32. Akorn. Cosopt^® (dorzolamide hydrochloride 2% and timolol maleate 0.5%) ophthalmic solution prescribing information. Lake Forest, IL; 2018 Jan.

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34. Akorn. Cosopt^® PF (dorzolamide hydrochloride 2% and timolol maleate 0.5%) ophthalmic solution prescribing information. Lake Forest, IL; 2017 Jun.

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