Topical Dorzolamide 2%/Timolol 0.5% Ophthalmic Solution

Summary

Abstract

Topically administered dorzolamide 2%/timolol 0.5% (dorzolamide/timolol ophthalmic solution; Cosopt®) is a fixed combination of two ocular hypotensive drugs (the carbonic anhydrase inhibitor dorzolamide and the β-adrenoceptor antagonist timolol) that have an additive effect on lowering intraocular pressure (IOP) when administered together. This product is indicated for the treatment of elevated IOP in patients with open-angle glaucoma or ocular hypertension (OH) who are insufficiently responsive to topical β-adrenoceptor antagonist monotherapy. As such, it can be considered for use in individuals who, as a consequence of failing to achieve target IOP with β-adrenoceptor antagonist monotherapy, require the addition or substitution of another class of topical antiglaucoma medication. Clinical trials have demonstrated that dorzolamide/timolol (1 drop per eye twice daily) is an effective and generally well tolerated fixed combination for lowering IOP in patients with open angle glaucoma or OH, including individuals uncontrolled on β-adrenoceptor antagonist monotherapy. Compared with concomitant therapy with the individual components, the primary advantage of fixed combination dorzolamide/timolol is convenience.

Pharmacological Properties

Dorzolamide/timolol comprises dorzolamide, a highly selective inhibitor of carbonic anhydrase isoenzyme II, and timolol, a nonselective β-adrenergic antagonist. Both components decrease elevated IOP by inhibiting aqueous humour production; they each achieve this by a different mechanism of action and have an additive effect when administered together. Dorzolamide/timolol also improves some markers of ocular blood flow (an effect likely attributable to the dorzolamide component).

After topical administration, both components enter the systemic circulation. Systemically absorbed dorzolamide undergoes slow hepatic metabolism; both the single N-desethyl metabolite and the parent drug accumulate in erythrocytes, although the resulting inhibition of carbonic anhydrase isoenzyme I and II (by N-desethyldorzolamide and dorzolamide, respectively) is not sufficient to disrupt normal physiological function. Dorzolamide and its metabolite are eliminated primarily by the kidneys.

Timolol has a high systemic bioavailability via the ocular route and may cause typical systemic β-adrenoceptor antagonist effects. The mean peak plasma timolol concentration was 0.46 and 0.35 μg/L after the morning and afternoon dose, respectively, in six subjects who received topical timolol 0.5% twice daily.

Therapeutic Efficacy

Randomised clinical trials of 1.5–6 months’ duration have compared the IOP-lowering efficacy of dorzolamide 2%/timolol 0.5% 1 drop per eye twice daily with that of other topically administered ophthalmic therapies in patients with glaucoma (almost exclusively primary open angle glaucoma) or OH enrolled at one or more centres. All of these studies were preceded by a run-in period on timolol 0.5% twice daily or an ocular hypotensive medication washout period.

When evaluated in large, single- or double-masked, parallel-group comparisons, the IOP-lowering effect of dorzolamide/timolol was superior to that of monotherapy with each of the individual components (administered at their recommended dosing frequencies), equivalent to that of dorzolamide 2% two or three times daily plus timolol 0.5% twice daily given concomitantly, equivalent to that of monotherapy with latanoprost 0.005% once daily, and generally equivalent to that of brimonidine 0.2% twice daily plus timolol 0.5% twice daily given concomitantly. Whereas reductions in IOP significantly favoured monotherapy with bimatoprost 0.03% once daily (in patients inadequately controlled on β-adrenoceptor antagonist monotherapy) and fixed combination therapy with latanoprost 0.005%/timolol 0.5% once daily in large, double-masked, parallel-group comparisons, the IOP-lowering effect of dorzolamide/timolol was generally similar to that of these agents in small, single- or double-masked, cross-over comparisons. The IOP-lowering effect of dorzolamide/timolol was less than that of latanoprost 0.005% once daily plus brimonidine 0.2% twice daily given concomitantly in small, double-masked, parallel-group, comparisons.

Variable results were seen when dorzolamide/timolol was compared with monotherapy with travoprost 0.004% once daily or with fixed combination therapy with brimonidine 0.2%/timolol 0.5% (brimonidine/timolol) twice daily in small, single-blind, cross-over or parallel-group studies. Dorzolamide/timolol was either more or less effective than travoprost 0.004%, but similarly or less effective than brimonidine/timolol, in lowering IOP.

Reductions in IOP seen with the fixed combination were maintained for up to 1 year in a non-blind extension of one study.

Tolerability

Topically administered dorzolamide/timolol is generally well tolerated and has an adverse event profile reflecting that of the individual components. No additional tolerability issues specific to the fixed combination have been identified. The most common adverse events in patients with glaucoma or OH who received dorzolamide/timolol in large, randomised clinical trials were ocular and local reactions, including burning and/or stinging of the eyes (mostly of mild or moderate intensity and transient; likely due to the dorzolamide component) and dysgeusia.

In large comparative trials, the incidences of drug-related ocular burning and/ or stinging and dysgeusia with dorzolamide/timolol were mostly higher than those with latanoprost 0.005% and consistently higher than those with bimatoprost 0.03% or brimonidine 0.2% plus timolol 0.5% given concomitantly. Similarly, ocular burning, ocular stinging and unusual taste were reported more often by dorzolamide/timolol recipients than brimonidine/timolol recipients, based on preliminary reports of small comparative studies. More dorzolamide/timolol than latanoprost/timolol recipients experienced transient eye pain, although conjunctival hyperaemia was less common with dorzolamide/timolol than with bimatoprost 0.03%. The tolerability profile of dorzolamide/timolol was similar to that of brimonidine 0.2% plus latanoprost 0.005% given concomitantly in small comparative studies.

Systemic adverse events such as headache, nausea and urolithiasis (likely due to the dorzolamide component) and bradycardia/sinus bradycardia, cardiac failure, heart block, hypotension, and respiratory symptoms/failure (likely due to the timolol component) have been reported, albeit infrequently, with dorzolamide/ timolol during clinical trials or post-marketing experience.