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

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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 (Clcr<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.

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Cosopt 2-0.5% Solution (MERCK SHARP &amp; DOHME): 10/$135.99 or 30/$392.95

Dorzolamide HCl 2% Solution (HI-TECH): 10/$61.99 or 30/$163.97

Dorzolamide-Timolol 2-0.5% Solution (HI-TECH): 10/$99.99 or 30/$279.97

Trusopt 2% Solution (MERCK SHARP &amp; DOHME): 10/$79.25 or 30/$215.09

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Merck & Company. Trusopt (dorzolamide hydrochloride) sterile ophthalmic solution 2% prescribing information. West Point, PA; 2001 Jan.

2. Serle JB. Pharmacological advances in the treatment of glaucoma. Drugs Aging. 1994; 5:156-70. [PubMed 7803944]

3. Biollaz J, Munafo A, Buclin T et al. Whole-blood pharmacokinetics and metabolic effects of the topical carbonic anhydrase inhibitor dorzolamide. Eur J Clin Pharmacol. 1995; 47:453-60.

4. Lippa EA, Carlson LE, Ehinger B et al. Dose response and duration of action of dorzolamide, a topical carbonic anhydrase inhibitor. Arch Ophthalmol. 1992; 110:495-99. [IDIS 294438] [PubMed 1562255]

5. Anon. A topical carbonic anhydrase inhibitor for glaucoma. Med Lett Drug Ther. 1995; 37:76-7.

6. Wilkerson M, Cyrlin M, Lippa EA et al. Four-week safety and efficacy study of dorzolamide, a novel, active topical carbonic anhydrase inhibitor. Arch Ophthalmol. 1993; 111:1343-50. [IDIS 320630] [PubMed 8216014]

7. Strahlman E, Tipping R, Vogel R and the International Dorzolamide Study Group. A double-masked, randomized 1-year study comparing dorzolamide (Trusopt), timolol, and betaxolol. Arch Ophthalmol. 1995; 113:1009-16. [IDIS 352153] [PubMed 7639651]

8. Yamazaki Y, Miyamoto S, Sawa M. Effect of MK-507 on aqueous humor dynamics in normal human eyes. Jpn J Ophthalmol. 1994; 38:92-6. [PubMed 7933704]

9. Sugrue MF, Harris A, Adamsons I. Dorzolamide hydrochloride a topically active, carbonic anhydrase inhibitor for the treatment of glaucoma. Drugs Today. 1997; 33:283-98.

10. Balfour JA, Wilde MI. Dorzolamide: a review of its pharmacology and therapeutic potential in the management of glaucoma and ocular hypertension. Drugs Aging. 1997; 10:384-403. [PubMed 9143858]

11. Heijl A, Strahlman E, Sverrisson T et al. A comparison of dorzolamide and timolol in patients with pseudoexfoliation and glaucoma or ocular hypertension. Ophthalmology. 1997; 104:137-42. [IDIS 381530] [PubMed 9022118]

12. Wang RF, Serle JB, Podos SM et al. MK-507 (L-671,152), a topically active carbonic anhydrase inhibitor, reduces aqueous humor production in monkeys. Arch Ophthalmol. 1991; 109:1297-99. [PubMed 1929960]

13. Strahlman ER, Vogel R, Tipping R et al et al. The use of dorzolamide and pilocarpine as adjunctive therapy to timolol in patients with elevated intraocular pressure. Ophthalmology. 1996; 103:1283-93. [IDIS 372463] [PubMed 8764800]

14. Laibovitz R, Boyle J, Snyder E et al. Dorzoloamide versus pilocarpine as adjunctive therapies to timolol: a comparison of patient preference and impact on daily life. Clin Ther. 1996; 18:821-32. [IDIS 376626] [PubMed 8930426]

15. Hartenbaum D. The efficacy of dorzolamide, a topical carbonic anhydrase inhibitor, in combination with timolol in the treatment of patients with open-angle glaucoma and ocular hypertension. Clin Ther. 1996; 18:460-5. [IDIS 370951] [PubMed 8829021]

16. Maus TL, Larsson LI, McLaren JW et al. Comparison of dorzolamide and acetazolamide as suppressors of aqueous humor flow in humans. Arch Ophthalmol. 1997; 115:45-9. [IDIS 379686] [PubMed 9006424]

17. Podos SM, Serle JB. Topically active carbonic anhydrase inhibitors for glaucoma. Arch Ophthalmol. 1991; 109:38-40. [IDIS 276557] [PubMed 1987945]

18. Derick RJ. Glaucoma therapy: carbonic anhydrase inhibitors. In: Havener WH. Havener’s ocular pharmacology. 6th ed. St. Louis: The CV Mosby Company; 1983:172-80.

19. Harris A, Arend O, Arend S et al. Effects of topical dorzolamide on retinal and retrobulbar hemodynamics. Acta Ophthalmol Scand. 1996; 74:569-72. [PubMed 9017044]

20. Maren TH, Conroy CW, Wynns GC et al. Ocular absorption, blood levels, and excretion of dorzolamide, a topically active carbonic anhydrase inhibitor. J Ocular Pharmacol Ther. 1997; 13:23-30.

21. Strahlman E, Tipping R, Vogel R et al. A six-week dose-response study of the ocular hypotensive effect of dorzolamide with a one-year extension. Am J Ophthalmol. 1996; 122:183-94. [IDIS 370635] [PubMed 8694086]

22. Hasegawa T, Hara K, Hata S. Binding of dorzolamide and its metabolite, n-deethylated dorzolamide, to human erythrocytes in vitro. Drug Metabol Dispos. 1994; 22:377-82.

23. Matuszewski BK, Constanzer ML, Woolf EJ et al. Determination of MK-507, a novel topically effective carbonic anhydrase inhibitor, and its de-ethylated metabolite in human whole blood, plasma, and urine by high-performance liquid chromatography. J Chromatogr. 1994; 653:77-85.

24. Kohlhaas M, Mammen A, Richard G. Change in corneal sensitivity after topical dorzolamide administration: a comparative study. Ophthalmologe. 1997; 94:424-7. [PubMed 9312318]

25. Ladas ID, Baltatzis S, Panagiotidis D et al. Topical 2.0% dorzolamide vs oral acetazolamide for prevention of intraocular pressure rise after neodymium: YAG laser posterior capsulotomy. Arch Ophthalmol. 1997; 115:1241-4. [IDIS 396001] [PubMed 9338667]

26. Fineman MS, Katz LJ, Wilson RP. Topical dorzolamide-induced hypotony and ciliochoroidal detachment in patients with previous filtration surgery. Arch Ophthalmol. 1996; 114:1031-2. [IDIS 371003] [PubMed 8694722]

27. Konowal A, Epstein RJ, Dennis RF et al. Irreversible corneal decompensation in patients treated with topical dorzolamide. Invest Ophthalmol Vis Sci. 1996; 37:S79.

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. Merck & Company. Cosopt (dorzolamide hydrochloride and timolol maleate) sterile ophthalmic solution prescribing information. West Point, PA; 2000 Aug.

33. Diamond JP. Systemic adverse effects of topical ophthalmic agents: implications for older patients. Drugs Aging. 1997; 11:352-60. [PubMed 9359022]

a. Merck & Company. Trusopt (dorzolamide hydrochloride) sterile ophthalmic solution 2% prescribing information. West Point, PA; 2001 Oct.

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