Dorzolamide Hydrochloride

Class: Carbonic Anhydrase Inhibitors
ATC Class: S01EC03
Chemical Name: (4S,6S)-4-(Ethylamino)-5,6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7,7-dioxide monohydrochloride
Molecular Formula: C₁₀H₁₆N₂O₄S₃•HCl
CAS Number: 130693-82-2
Brands: Cosopt Ocumeter Plus, Trusopt

Introduction

Carbonic anhydrase inhibitor;^{1 2 3 4 5 6 7 8 9 10} nonbacteriostatic sulfonamide derivative.^{1 2 3 4 5 6 7 8 9}

Uses for Dorzolamide Hydrochloride

Ocular Hypertension and Glaucoma

Reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.^{1 2 3 4 5 6 7 8 9 10}

Fixed-combination preparation containing dorzolamide and timolol (Cosopt) 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 Fixed-combination preparation associated with slightly smaller decrease in IOP than combination therapy with dorzolamide (administered 3 times daily) and timolol (administered twice daily).³²

A first-line “add-on” agent when more than one drug is needed.⁵ Add-on therapy with dorzolamide to existing timolol therapy is as effective and better tolerated than add-on therapy with pilocarpine.¹⁴

Safety and efficacy not established for the treatment of acute angle-closure glaucoma.¹

Inhibition of Perioperative IOP Increases

Used prophylactically before neodymium yttrium aluminum garnet (Nd:YAG) laser posterior capsulotomy†.²⁵

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.²⁵

Dorzolamide Hydrochloride Dosage and Administration

Administration

Ophthalmic Administration

Apply topically to the affected eye(s) as an ophthalmic solution.^{1 2 3 4 5 6 7 8 9 10 13 14 15}

Avoid contamination of the solution container.¹

Remove soft contact lenses prior to administration of each dose (since benzalkonium chloride preservative may be absorbed by the lenses); may reinsert lenses 15 minutes after administration.^{1 32}

If more than one topical ophthalmic drug is used, administer the drugs at least 10 minutes apart.^{1 32}

Dosage

Available as dorzolamide hydrochloride; dosage expressed in terms of dorzolamide.^{1 32}

Adults

Ocular Hypertension and Glaucoma

Ophthalmic

Dorzolamide 2% solution: 1 drop in the affected eye(s) 3 times daily.^{1 2 5 6 7 9 10}

Fixed-combination with timolol: 1 drop in the affected eye(s) twice daily.³²

Cautions for Dorzolamide Hydrochloride

Contraindications

• Known hypersensitivity to dorzolamide or any ingredient in the formulations (e.g., benzalkonium chloride).^{1 32}

• Fixed-combination preparation with timolol also 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, or cardiogenic shock.³²

Warnings/Precautions

Warnings

Timolol Component

When using fixed-combination preparation containing timolol maleate, consider the warnings, cautions, precautions, and contraindications associated with timolol.³²

Sensitivity Reactions

Sulfonamide Sensitivity Reactions

Serious adverse events (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, other blood dyscrasias) associated with sulfonamide therapy possible.^{1 32}

Usual precautions associated with systemic use of sulfonamides apply.^{1 32} Discontinue dorzolamide if serious reactions or signs or symptoms of hypersensitivity occur.^{1 32}

Major Toxicities

Ocular Effects

Conjunctivitis or lid reactions reported with long-term therapy;^{1 32} may resolve upon discontinuance of therapy.^{1 32} If these reactions occur, discontinue therapy and evaluate patient before restarting dorzolamide (since a more serious allergic-type reaction may occur).^{1 29 32}

Choroidal detachment reported with administration of aqueous suppressant therapy (e.g., dorzolamide, timolol) following filtration procedures.^{1 32 a}

Specific Populations

Pregnancy

Category C.^{1 32}

Lactation

Not known whether distributed into human milk following topical application to eye.^{1 32} Discontinue nursing or the drug.^{1 32}

Pediatric Use

Safety and efficacy not established.^{1 9}

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults,^{1 30 32 33} but increased sensitivity cannot be ruled out.^{30 33}

Hepatic Impairment

Not studied in patients with hepatic impairment; use with caution.^{1 32}

Renal Impairment

Not studied in patients with severe renal impairment (Cl_cr<30 mL/minute).^{1 32} Not recommended in such patients, since dorzolamide and its metabolite are excreted mainly by the kidneys.¹

Common Adverse Effects

Ocular burning or stinging, taste disturbances (bitter, sour, or unusual taste), superficial punctate keratitis, conjunctival hyperemia, blurred vision, ocular itching.^{1 32}

Interactions for Dorzolamide Hydrochloride

When using fixed-combination preparation containing timolol maleate, consider the drug interactions associated with timolol.³²

Dorzolamide is metabolized by CYP isoenzymes.^{1 9 10}

Specific Drugs

Drug	Interaction	Comments
Carbonic anhydrase inhibitors, oral	Additive systemic effects1 32	Concomitant use not recommended1
β-adrenergic blocking agents	Additive systemic β-adrenergic blockade when used with fixed-combination preparation32	Concomitant use with fixed-combination preparation not recommended32
Ocular hypotensive agents	Additive IOP-lowering effects1 5 7 9 10 13 14 15	Use to therapeutic advantage.1 5 7 9 10 13 14 15 If more than one topical ophthalmic drug is used, administer the drugs at least 10 minutes apart1 32
Salicylates	Rare reports of toxicity associated with acid-base disturbances in patients receiving oral carbonic anhydrase inhibitors with high-dose salicylates1 32	Consider possibility of similar interaction with ophthalmic dorzolamide1 32

Dorzolamide Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Peak concentrations in cornea, iris/ciliary body, and aqueous humor achieved within 1–2 hours following ocular instillation in rabbits.^{9 10}

Some systemic absorption may occur; low potential for causing systemic effects.^{1 3 6 9 10 21}

Onset

Reduction in IOP generally peaks within 2–3 hours after topical administration.^{4 6 8 10}

Duration

Reduction in IOP persists for 8 hours or longer.^{4 6 8 10}

Distribution

Extent

Distributed into cornea, aqueous humor, iris/ciliary body, and retina following ocular instillation in rabbits.^{9 10}

Approximately 19% bound to ocular pigment (isolated from bovine iris/ciliary body).⁹

Systemically absorbed dorzolamide is preferentially distributed into erythrocytes.^{1 3 9 10 20}

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

Plasma Protein Binding

Approximately 33%.^{1 10 32}

Elimination

Metabolism

Metabolized in liver by cytochrome P-450 isoenzymes to N-desethyldorzolamide (active).^{1 9 10}

Elimination Route

Excreted in urine, principally (about 80%) as unchanged drug.^{1 10 20}

Half-life

Nonlinear elimination from erythrocytes.^{1 32} Initial elimination half-life is rapid; terminal elimination half-life is 120 days.^{1 3 10}

Stability

Storage

Ophthalmic

Solution

Dorzolamide 2% solution: 15–30°C.¹ Protect from light.¹

Fixed-combination preparation: 15–25°C.³² Protect from light.³²

Actions

• Potent ocular hypotensive agent;^{1 2 3 4 5 6 7 8 9 10} can produce mean IOP reductions of about 17–23% in patients with elevated IOP.^{1 4 5 7}

• Highly specific inhibitor of CA-II, the main carbonic anhydrase isoenzyme involved in aqueous humor secretion.^{1 3 4 9 10 15}

  Inhibition of carbonic anhydrase in the ciliary process of the eye decreases the rate of aqueous humor secretion and IOP by slowing bicarbonate formation and reducing sodium and fluid transport.^{1 9 10 18}

• Tolerance does not occur; reduction in mean IOP maintained over at least 12 months after initial stabilization.^{7 30}

• Accumulates in erythrocytes after long-term topical administration as a result of CA-II binding; however, sufficient CA-II activity remains so that adverse effects resulting from systemic carbonic anhydrase inhibition are not observed.^{1 9 21}

Advice to Patients

• Risk of adverse effects, including sensitivity reactions; discontinue therapy and consult clinician if serious or unusual ocular or systemic reactions (e.g., conjunctivitis, lid reactions) or signs of sensitivity occur.^{1 32}

• Importance of learning and adhering to proper administration techniques to avoid contamination of the solution with common bacteria that can cause ocular infections (e.g., bacterial keratitis).^{1 32} Serious damage to the eye and subsequent loss of vision may result from using contaminated ophthalmic solutions.^{1 8}

• Importance of informing clinicians if an intercurrent ocular condition (e.g., trauma, infection) develops or ocular surgery is planned.^{1 32}

• Importance of administering different topical ophthalmic preparations at least 10 minutes apart.^{1 32}

• Importance of removing soft contact lenses prior to administering the drug and of delaying reinsertion of the lenses for at least 15 minutes after administration.^{1 32}

• Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.^{1 32}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 32}

• Importance of informing patient of other important precautionary information.^{1 32} (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Dorzolamide Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Ophthalmic	Solution	2% (of dorzolamide)	Trusopt Ocumeter Plus (with benzalkonium chloride)	Merck

Dorzolamide Hydrochloride Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Ophthalmic	Solution	2% (of dorzolamide) with Timolol Maleate 0.5% (of timolol)	Cosopt Ocumeter Plus (with benzalkonium chloride)	Merck