Study Finds Increased Dosage of Timolol-Dorzolamide Fixed Combination Safe, Effective in Open-Angle Glaucoma

Increasing dosage of timolol-dorzolamide fixed combination from twice a day to 3 times a day may significantly reduce intraocular pressure (IOP) in patients with newly diagnosed primary open-angle glaucoma (POAG), according to study findings published in the Journal of Drug Assessment.

As the most frequently prescribed fixed-combination therapy in the treatment of glaucoma, timolol-dorzolamide (0.5% and 2.0%, respectively), sold as Consopt, has been shown to reduce IOP more than monotherapy of each agent alone, with safety and efficacy similar to that of concomitant use of timolol and dorzolamide.

Currently, dosage of timolol-dorzolamide is recommended at twice daily, but researchers note that findings of the Early Manifest Glaucoma Trial as well as concerns regarding the diurnal IOP-controlling effects of fixed-combination medications have led some ophthalmologists to increase dosage to 3 times daily.

“Although increasing the dosage of timolol from twice to 3 times a day resulted in more IOP reduction in one study, concern remains regarding the systemic adverse events, especially cardiovascular, of more frequent exposure to non-selective beta-blocker activity of timolol,” noted the study authors.

Seeking to compare the efficacy and cardiovascular safety of administration 2 times vs 3 times a day of timolol-dorzolamide fixed-combination therapy, researchers conducted a prospective, interventional case series study of patients with newly diagnosed POAG (N = 31; mean [SD] 24-hour IOP at baseline, 23.1 [3.15] mm Hg; 95% CI, 20.0-29).

Participants began treatment of timolol-dorzolamide eye drops at the twice a day dosage for 1 month and were then switched to 3 times a day for an additional month. Comprehensive ophthalmic examination, diurnal IOP, blood pressure (BP), and 24-hour heart rate measurements were conducted at baseline, month 1, and month 2, with the primary outcome measure being IOP and secondary measures including changes in heart rate and BP.

After one month, IOP in patients with POAG was found to be significantly decreased by twice-daily administration of timolol-dorzolamide (mean [SD] 24-hour IOP at month 1, 16.5 [2.21] mm Hg; 95% CI, 14-20; P < .0001), with a 28.5% average IOP reduction.

In examining the dosage switch at month 2, administration of timolol-dorzolamide 3 times a day led to significantly lower IOP reduction than that found in month 1 (mean [SD] 24-hour IOP at month 2, 13.9 [2.23] mm Hg; mean [SD] difference from month 1 to month 2, 2.7 [1.35] mm Hg; P < .0001). Compared with baseline, average IOP reduction was 39.8% after month 2 (P < .0001).

Furthermore, mean 24-hour systolic BP and mean 24-hour heart rate in patients with POAG were indicated to be significantly reduced after twice-daily administration of timolol-dorzolamide from baseline to month 1 (P < .0001), with both metrics remaining unchanged after changing to 3 times a day administration at month 2 compared with month 1 (P < .62).

“Although we did not observe any change in BP by increasing the dose of timolol, aggravated nocturnal hypotension remains a concern for administering timolol-dorzolamide 3 times a day,” said researchers. “Moreover, we only followed our patients for 2 months, and it is possible that a longer follow-up and more exposure to timolol could result in inadvertent cardiac and respiratory adverse events.”

Reference

Pakravan M, Beni AN, Yazdani S, Esfandiari H, Mirshojaee S. Efficacy and safety of timolol-dorzolamide fixed-combination three times a day versus two times a day in newly diagnosed open-angle glaucoma. J Drug Assess. 2021;10(1):91-96. doi:10.1080/21556660.2021.1967642