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Efficacy, safety and tolerability of combination therapy with timolol and dorzolamide in glaucoma and ocular hypertension

Combination pharmacotherapy has simplified and improved glaucoma medication regimens. This update focuses on the previous and recent studies on efficacy and tolerability profile of dorzolamide–timolol in adult ocular hypertension and open angle glaucoma patients. Dorzolamide–timolol has been shown to be efficacious and well tolerated in clinical trials and the adverse effects reflect those of the individual components.


Introduction
Glaucoma is a worldwide epidemiological challenge affecting approximately 4% of the global population. [1][2][3][4][5][6][7] Research shows that by 2010, an estimated 60.5 million people globally will be living with either angle closure glaucoma (ACG) or primary open angle glaucoma (POAG). 8 Elevated intraocular pressure is the most important modifiable risk factor for glaucoma and hence lowering of IOP is the goal of glaucoma therapy. 9,10 Pharmacotherapy remains the chief management modality for the patients of glaucoma and ocular hypertension. 9 Topical antiglaucoma medications act either by decreasing aqueous production (beta adrenergic antagonists, carbonic anhydrase inhibitors [CAI]) or increasing aqueous outflow (prostaglandin derivatives, cholinergic agonists) or both (alpha-2 adrenergic agonists). 9 Treatment is started with monotherapy but in cases where monotherapy fails to attain the target IOP, other drugs are added. 9,10 Factors that influence the choice of an agent are efficacy, safety profile, ease of administration and cost. 11,12 Fixed drug combinations can help to avoid complex dosing schedules of multi drug glaucoma therapy and thus improve compliance. 12,13 Several fixed combinations of commonly used IOP-lowering medications have been developed and are available in various markets worldwide. Most fixed combinations contain timolol, as it can be dosed either once or twice daily and can be combined with prostaglandin analogs, adrenergic agonists, and CAIs. 13 Cosopt ® (Merck & Co., Inc.,Whitehouse Station, NJ, USA), a commonly available combination drug that consists of dorzolamide hydrochloride 2% and timolol maleate 0.5% was first commercially introduced in 1998. Each milliliter of Cosopt consists of 22.26 mg dorzolamide hydrochloride and 6.83 mg timolol maleate with 0.0075% benzalkanoium chloride as preservative. 14

Mode of action, pharmacodynamic and pharmacokinetic profile
The pharmacodynamic properties of timolol and dorzolamide have been extensively reviewed elsewhere. [15][16][17] As there is no direct pharmacodynamic interaction between the two drugs, a brief overview of the pharmacodynamic and pharmacokinetic profile of each drug is presented here.
Timolol is a non-selective β-blocker (β1 and β2) which has little or no local anesthetic, membrane stabilizing or sympathomimetic properties. 16 Timolol lowers IOP by inhibiting aqueous humor production [18][19][20] and it has been suggested that timolol down-regulates adenylate cyclase by inhibiting β2-adrenoceptor sites at the ciliary process. 21 Dorzolamide is a highly selective inhibitor of CA-II, an isoenzyme present on the ciliary process in the eye. 15 Inhibition of CA-II slows local bicarbonate production, decreases sodium and fluid transport and, consequently, decreases aqueous humor production and lowers IOP. 17 Because their mechanisms of action differ, they have an additive effect when administered together. 22 Approximately 80% of the volume of topically administered eye drops is absorbed systemically within 15 to 30 seconds of instillation. 23 Chronic administration of dorzolamide leads to its accumulation in erythrocytes. Hepatic metabolism of dorzolamide produces N-desthyl metabolite which also binds to red blood cells but inhibits carbonic anhydrase I more than carbonic anhydrase II. 24 Approximately 24% to 32% of systemically absorbed dorzolamide is bound to plasma proteins. 25 Urine is the major route of excretion for both parent and metabolite drug. 26 There is a rapid decline of dorzolamide from red blood cells, on discontinuation of the medication. This is followed by a gradual decline due to an elimination phase half-life of approximately 4 months. 27 However, in patients with glaucoma treated with dorzolamide 2% 3 times daily, plasma concentrations after 12 months were similar to those after 6 months (≈20 µmol/L). 28 Because of its renal elimination, dorzolamide eyedrops are not recommended in patients with severe renal impairment. Topical dorzolamide has not been studied in patients with hepatic dysfunction, but should be used with caution as the drug undergoes hepatic metabolism.
Not much has been published on the pharmacokinetic characteristics of fixed combination of dorzolamide and timolol, accordingly the characteristics of individual components are being discussed.
Topical dorzolamide is absorbed through nasopharyngeal mucosa into systemic circulation. 15 Biollaz et al have shown that plasma concentration of dorzolamide remained below level of detection after instillation of single or multiple doses of dorzolamide 2 or 3% in healthy volunteers. 29 Dorzolamide undergoes slow metabolism by cytochrome P450 (CYP) 2B1/2, CYP2E1 and CYP3A2. 30 CAIs have been reported to improve ocular blood flow profile by causing ocular vasodilation through metabolic acidosis via elevated carbon dioxide levels. 31 Topically administered dorzolamide-timolol has been shown to improve some markers of ocular blood flow in small studies (n = 15-30) in patients with POAG. [32][33][34][35] Retinal arteriovenous time passage time from superior temporal artery to the corresponding vein was significantly shorter following 1 month of double masked treatment with dorzolamide-timolol twice daily (1.76 s) than with timolol 0.5% twice daily (2.13 s) (P = 0.01). 35 The fixed combination did not alter choroidal perfusion or retrobulbar hemodynamics relative to timolol 0.5% baseline in this randomized crossover comparison (n = 15). 35 However, this finding contrasts with that of a crossover comparison of latanoprost 0.005% in which 1 month of non-blind treatment with dorzolamide-timolol significantly (P = 0.003) increased pulsatile ocular blood flow by 2.05 ÂµL/s relative to the timolol 0.5% baseline. 32 Dorzolamide-timolol also significantly improved retrobulbar hemodynamic parameters relative to baseline in another randomized cross over comparative study with latanoprost. 34 The fixed combination increased end diastolic velocity and decreased the resistance index in both the ophthalmic artery and short posterior ciliary artery. Improvements in ocular blood flow markers following treatment with dorzolamide 2%/timolol 0.5% generally exceeded those observed with latanoprost 0.005% once daily in 2 cross over randomized studies. 32,34 A recent study has shown dorzolamide 2%/timolol 0.5% fixed combination increased blood flow significantly at the neuroretinal rim showing a combination of hypotensive and hemodynamic effects. 36 Twenty-eight patients with earlymoderate glaucomatous damage treated with beta-blockers (6 months) with IOP values ranging from 18 to 22 mmHg at trough participated in this trial. After a 4-week washout period, patients were randomized in two groups: group I started with dorzolamide 2% monotherapy and group II with timolol 0.5% monotherapy for 4 weeks. After this period, both groups switched to dorzolamide 2%/timolol 0.5% fixed combination for 4 weeks. IOP, ocular diastolic perfusion pressure (ODPP), heart rate, and Scanning Laser Doppler Flowmetry measurements at the peripapillary retina and neuroretinal rim were taken at T0 (enrolment), T1 (wash out), T2 (monotherapy), and T3 (dorzolamide-timolol). Between T1 and T3, IOP decreased significantly in group I (-21.40%) Combination therapy with timolol and dorzolamide in glaucoma and ocular hypertension Dovepress submit your manuscript | www.dovepress.com Dovepress (P  0.001) and in group II (-21.25%) (P  0.001). At the same time intervals, blood flow increased significantly at rim level for group I (+30.03%) (P  0.05) and also when all patients were considered (rim +17.99%) (P  0.05). Between T1 and T3, there was a significant increase of ODPP in group I (+7.24%) (P  0.01) and in group II (+6.08%) (P  0.05) and when all patients were considered (+8.43%) (P  0.01). 36 The improvement in ocular blood flow parameters with the fixed combination appears to reflect the activity of the dorzolamide 2% component. When included as a comparator, timolol 0.5% had no significant effect on ocular blood flow markers in these studies. 31,37,38 However these improved ocular blood flow parameters were not accompanied by any enhancement in visual function. 35,37 Dosage and administration Dorzolamide 2%/timolol 0.5% is indicated for the treatment of raised IOP in patients with ocular hypertension, open-angle glaucoma, pseudoexfoliative glaucoma or other secondary open-angle glaucomas when concomitant therapy is appropriate. It may be used alongwith prostaglandin analogs when IOP control is not possible with a single medication. It can also be used when prostaglandin analogs cannot be used such as, if patient has a history of herpetic keratitis or is concerned about side effects like iris heterochromia and periocular pigmentation.
Dorzolamide/timolol should be used with caution in those with hepatic insufficiency and is not recommended in patients with severe renal impairment (creatinine clearance 1.8 L/h [30 mL/min]). It is contraindicated in Europe in patients with hyperchloremic acidosis. Dorzolamide/ timolol is contraindicated in patients with a history of bronchial asthma, severe obstructive pulmonary disease, cardiac failure, sinus bradycardia, atrioventricular block or cardiogenic shock. Finally, the formulation should not be used in patients with known hypersensitivity to either of the components (eg, sensitivity to sulfonamides).
In most studies the primary efficacy endpoint was the mean change in IOP from time-matched baseline values, the mean change in diurnal IOP from baseline or the between group difference in the mean reduction in daytime diurnal IOP from baseline.

Versus concomitant or monotherapy
The efficacy of dorzolamide 2%/timolol 0.5% compared with mono or concomitant therapy with the same drugs has been evaluated in 4 major clinical studies involving a total of 1129 patients with glaucoma 39,40,53,54 (Table 1). All studies were multicenter, randomized, parallel and double-blind with active controls. Many patients enrolled in these trials were previously using one or the other antiglaucoma medications. 39,40,54 To establish a comparable baseline, patients underwent a 2-53,54 or 3-week 40 run-in period on timolol 0.5% twice daily, or a washout period of 3 to 21 days depending on the medication. 39 Where dorzolamide 2%/timolol 0.5% was compared with timolol 0.5% or dorzolamide 2% monotherapy, the hypothesis tested was that there was 95% confidence that mean IOP in the combined therapy group differed from that in the monotherapy groups by 6% 40 or 8%. 39 Only 1 trial reported p values for treatment comparisons. 40 The controlled study period was 90 days in all trials, with a 9-month open-label extension in 1 trial. 54 The age at entry was 21 to 85 years in 3 trials 40,53,54 and 21 years in 1 trial. 39 The IOP at baseline in the worst eye was required to be 22 mmHg in 3 of the studies 40,53,54 and 24 mmHg in 1 study. 39 In all studies change in IOP was the primary end-point and was measured at trough (0 hours) and peak (2 hours Dovepress initiation of therapy. In 1 study, an additional measurement was made at 8 hours. 53 The concentrations of the individual drugs in both the combined and monotherapy formulations were dorzolamide 2% and timolol 0.5%. In all studies the primary efficacy analyses were based on the last observation carried forward approach, although secondary analyses were performed using other methods in 3 studies. 39,40,53 The studies that compared combined and concomitant therapy were designed to determine equivalence and this was assessed by calculating the 90% 54 or 95% 53 confidence interval for the hypothesis that the mean IOP of each of the 2 treatment groups differed by 1.5 mmHg.

Versus prostaglandin analogs
Versus latanoprost 0.005% Dorzolamide 2%/timolol 0.5% was comparable to latanoprost 0.005% once daily in two double masked comparisons that followed a washout period 41 ( Table 2). The mean reduction of daytime diurnal IOP between the groups from baseline at 3 months was within ±1. Additional post hoc analyses of pooled data from these trials showed dorzolamide 2%/timolol 0.5% and latanoprost 0.005% were similar with respect to percentages of patients achieving target levels of IOP reduction. 69 Versus bimatoprost 0.03% Dorzolamide 2%/timolol 0.5% twice daily lowered IOP less consistently than did bimatoprost 0.03% once daily in a doublemasked, parallel-group comparison following a run-in period on timolol 0.5% twice daily. 49 Mean reductions in IOP from baseline at morning trough and peak were greater with bimatoprost 0.03% at all time points, with the exception of the morning peak time point at 3 months. 49 Dorzolamide 2%/timolol 0.5%  Combination therapy with timolol and dorzolamide in glaucoma and ocular hypertension Dovepress submit your manuscript | www.dovepress.com Dovepress provided a less stable reduction in IOP over the whole day, as evidenced significantly lower mean IOP values in bimatoprost 0.03% recipients at the 0-, 8-and 12-hour post-dose time points at 3 months (P  0.038). 49 The percentage of recipients reaching target IOPs of 17 to 20 mmHg was similar between the dorzolamide 2%/timolol 0.5% and bimatoprost 0.03% treatment groups based on measurements at 0-, 2-and 12-hour post-dose time points at 3 months; however, a significantly (P  0.008) greater percentage of bimatoprost 0.03% recipients reached the lower target pressures 13 mmHg (0% vs 8%), 14 mmHg (2% vs 17%), 15 mmHg (9% vs 24%) and 16 mmHg (14% vs 31%). 49 A relevant concern with this study is whether the selection of patients who are inadequately controlled on timolol 0.5% twice daily provides a valid basis on which to judge the relative merits of a timolol-containing therapy versus bimatoprost 0.03%. 49 Moreover, the study authors did not conduct a reverse therapeutic trial and hence did not know the number of trial participants who were non-responders to timolol. 49 Contrasting with the results of this trial, reductions in day time diurnal IOP (0800-1600 hours) and IOP at 2 of the 3 measured timepoints (morning peak and 8 hours post-dose) were not significantly different with dorzolamide 2%/timolol 0.5% twice daily vs. bimatoprost 0.03% once daily in a small (n = 35), double-masked, cross-over, 3-center, 8-week study that followed an initial washout period. 50 Versus travoprost 0.004% The IOP-lowering effect of dorzolamide 2%/timolol 0.5% twice daily was greater than that of travoprost 0.004% once daily in one 48 of two small (n = 50 45 and 56 48 ), single-blind, parallel-group, single-center studies that followed a washout period. After 6 months of treatment, the reduction in mean diurnal IOP (average of measurements made at 0800, 1000 and 1600 hours) from baseline with dorzolamide 2%/timolol 0.5% was superior to that with travoprost 0.004% (11.5 vs 9.3 mmHg; P  0.05). 48 The IOP-lowering effect of dorzolamide 2%/timolol 0.5% was also greater than that of another comparator, latanoprost 0.005% once daily (reduction in mean diurnal IOP from baseline, 8.2 mmHg; P  0.05 vs dorzolamide/timolol); the IOP-lowering effect of the two prostaglandin analogs was similar. Of note, this study exclusively enrolled patients with pseudoexfoliation glaucoma. Dorzolamide 2%/timolol 0.5% was, however, less effective than travoprost 0.004% 47,51 in the other single dose blind, parallel-group, single-center comparison, 51 and less effective than both travoprost 0.004% and latanoprost 0.005% Dovepress in a small (n = 38), single-blind, cross-over, single-center comparison that followed a run-in period on timolol 0.5% twice daily. 47 In the parallel-group comparison, 51 the reductions in mean diurnal IOP (average of measurements made at 0800, 1200, 1600 and 2000 hours) from baseline were significantly less with dorzolamide 2%/timolol 0.5% than with travoprost 0.004% after both 3 (23.1% vs 32.7%; P  0.01) and 6 (21.7% vs 30.7%; P  0.01) weeks of treatment. Similarly, in the cross-over comparison, 47 the decrease in mean diurnal IOP (average of measurements made at 8 am, 10 am and 4 pm) from baseline following 3 months of treatment with dorzolamide 2%/timolol 0.5% (14.3%; P  0.0001 vs baseline) was significantly less than that with travoprost 0.004% (18.4%; P  0.0001 vs baseline and dorzolamide 2%/timolol 0.5%) and latanoprost 0.005% (22.1%; P  0.0001 vs baseline and dorzolamide 2%/timolol 0.5%). 47 Again, the IOP-lowering effect of the two prostaglandin analogs was similar.
Versus unoprostone 0.15% and timolol 0.5% Day et al conducted a prospective multicenter, randomized, double-masked, crossover comparison study and found a similar efficacy and safety between dorzolamide 2%/timolol 0.5% and concomitant use of unoprostone 0.15%and timolol maleate 0.5% (n = 32). 52 After a 4-week run in period on timolol 0.5% twice daily, the patients received one treatment for 6 weeks and then crossed over to the opposite treatment. The authors found comparable IOP reduction for all the time points, for the diurnal curve or in the extended reduction from baseline 52 (Table 3).
Versus timolol 0.5% and pilocarpine 2% Dorzolamide 2%/timolol 0.5% was as effective as timolol 0.5% plus pilocarpine 2% in patients with glaucoma or ocular hypertension and was the preferred formulation. The dorzolamide/timolol has been compared with concomitant pilocarpine and timolol therapy in 2 trials (published as a single report). 60 Two randomized trials with identical drug week trial to compare the efficacy and safety of dorzolamide 2%/timolol 0.5% with fixed combination pilocarpine timolol, each given twice daily, in patients with POAG or ocular hypertensive patients. They found that both combinations were equally efficacious in IOP reduction 61 (Table 3).

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Teus et al have shown statistically significant difference in the amount of conjunctival hyperemia in travoprost 0.004%/timolol 0.5% group compared to dorzolamide 2%/ timolol 0.5%, but it does not present any untoward safety issues. 67 Long-term tolerability data are limited, although fixed combination was generally well tolerated for up to 1 year in a non-blind extension of one study. 54

Conclusions
Eff icacy and safety studies published till date show that dorzolamide with timolol is more eff icacious than the individual components, and as effective as the components used concomitantly in controlled settings. Dorzolamide-timolol also has efficacy comparable to latanoprost 0.004%, pilocarpine 2%/timolol 0.5%, brinzolamide 0.1%/timolol 0.5% and unoprostone 0.15%/timolol 0.5% KLC. Dorzolamide-timolol is slightly more efficacious than latanoprost 0.005%/timolol 0.05% and brimonidine 0.2%/timolol 0.5%. In conclusion, dorzolamide-timolol combination has a good efficacy, safety and tolerability profile and hence an increased patient compliance.

Disclosures
The authors declare no conflicts of interest.