Comparison of the safety and eYcacy of the fixed combination of dorzolamide/timolol and the concomitant administration of dorzolamide and timolol: a clinical equivalence study

Aims—To compare the tolerability and eYcacy of a fixed combination solution of dorzolamide/timolol (Cosopt), administered twice daily with the concomitant administration of its components, dorzolamide (Trusopt) twice daily and timolol (Timoptic) twice daily. Methods—After a 2 week timolol run in, patients with open angle glaucoma or ocular hypertension were randomised (1:1) to receive treatment with either the dorzolamide/timolol combination solution twice daily (combination) or the dorzolamide solution twice daily plus timolol maleate solution twice daily (concomitant) for 3 months. Results—299 patients were entered and 290 patients completed the study. Compared with the timolol baseline, additional IOP lowering of 16% was observed at trough (hour 0) and 22% at peak (hour 2) at month 3 in both the concomitant and combination groups. The IOP lowering eVects of the two treatment groups were clinically and statistically equivalent as demonstrated by the extremely small point diVerences (concomitant − combination) observed in this study−0.01 mm Hg at trough and 0.08 mm Hg at peak. The safety variables of the concomitant and combination groups were very similar. Both combination and concomitant therapy were well tolerated and few patients discontinued due to adverse eVects. Conclusions—The dorzolamide/timolol combination solution administered twice daily is equivalent in eYcacy and has a similar safety profile to the concomitant administration of the components administered twice daily. (Br J Ophthalmol 1998;82:1249–1253) The safety and eYcacy of timolol maleate (Timoptic) and dorzolamide hydrochloride (Trusopt) as monotherapy agents to lower intraocular pressure (IOP) has been demonstrated in previous clinical investigations. Timolol maleate remains the most widely prescribed treatment for elevated IOP in patients with open angle glaucoma or ocular hypertension. However, since open angle glaucoma is a chronic progressive disease, the majority of patients eventually require additional medication for control of IOP. In previous clinical studies, dorzolamide demonstrated a clinically significant additive eVect ranging from a 13–21% further reduction in IOP when added to ophthalmic â blockers. 3 This additive effect supported the development of a combination solution of dorzolamide and timolol (Cosopt), which is administered twice daily. Other agents additive to timolol (such as pilocarpine, adrenaline (epinephrine), and oral carbonic anhydrase inhibitors) have side eVects which may often result in discontinuation. However, the discontinuation rate due to side eVects has been low with dorzolamide and timolol. 5 In a crossover study, patients preferred therapy with dorzolamide and timolol to therapy with pilocarpine and timolol by more than 7:1. This combination product may also improve patient compliance with therapy since compliance decreases as the dosing frequency increases. Thus, a twice daily combination solution should lead to improved compliance compared with concomitant therapy with timolol and either dorzolamide, or other alternative agents which may have dosing regimens of up to four times daily. The safety and eYcacy of this combination solution has been evaluated in several large phase III studies in patients with ocular hypertension or open angle glaucoma. One study compared the 2.0% dorzolamide/0.5% timolol combination twice daily with the concomitant administration of 0.5% timolol twice daily and 2.0% dorzolamide three times daily (the US dosage regimen for “add on” therapy in patients with ocular hypertension or open angle glaucoma). That study showed that the IOP lowering eVect of the combination was equivalent (>95% confidence that the absolute diVerence between treatments in mean IOP change from baseline was <1.5 mm Hg) to that of the concomitant treatment at hours 0, 2, and 8 across the entire 3 month treatment period, although the point estimates at trough slightly favoured the concomitant treatment group (by <1 mm Hg). In a study comparing the 2.0% dorzolamide/0.5% timolol combination twice daily with monotherapy with either 2.0% dorzolamide three times daily or 0.5% timolol twice daily, the IOP lowering of the combination was 27% at trough and 33% at peak from the untreated baseline. These previous clinical studies compared the combination with the components administered as monotherapy or administered Br J Ophthalmol 1998;82:1249–1253 1249 Merck Research Laboratories, West Point, PA, USA