Modern Fixed Combinations Approved Outside The United States

In recent years, fixed combinations of commonly paired drugs have not received FDA approval due to insufficient additional demonstrated efficacy when compared to their components, despite such potential benefits as improved convenience and compliance and reduced cost to patients. Although the additive effects of pros-taglandins to beta blockers have been demonstrated in several studies,29-31 fewer data exist about the efficacy of adding beta blockers for subjects already on pros-taglandins.

7.3.1 Timolol-Latanoprost. The fixed combination timolol maleate 0.5%-latanoprost 0.005% (Xalacom; Pfizer, Inc., New York, N.Y.) was the first beta blocker-prostaglandin combination released in 2001 after gaining regulatory approval in many regions of the world. Latanoprost was the first approved prostaglandin (in 1996) and quickly became a first-line agent of choice in the United States and around the world. Because timolol remains a popular and effective choice for adjunctive therapy, development of a fixed combination of these two agents once again reflects common clinical use. This fixed combination is approved in several countries for the reduction of IOP in patients with open-angle glaucoma and ocular hypertension.

Several studies have compared the fixed combination to monotherapy with the component medications. Higginbotham et al.,32 in a 6-month, double-blind study, enrolled 418 patients that were randomized to receive either the fixed combination at 8 a.m. and placebo at 8 p.m. (138 subjects), timolol twice daily at 8 a.m. and 8 p.m. (140 subjects), or latanoprost at 8 a.m. and placebo at 8 p.m. (140 subjects), after a run-in treatment of timolol twice daily for 2 to 4 weeks. They demonstrated a 1mm Hg greater diurnal IOP reduction among patients receiving the fixed combination compared to latanoprost monotherapy; this difference, although small, did reach the level of statistical significance.32 Pfeiffer33 performed a similar study on 436 patients after a 2 to 4 week timolol run-in period. Subjects were randomized similarly into three groups: 140 subjects received the fixed combination at 8 a.m., 147 received latanoprost at 8 a.m., and 149 received timolol at 8 a.m. and 8 p.m. Patients receiving the fixed combination showed a 1.2 mm Hg greater difference in mean diurnal IOP reduction compared to latanoprost monotherapy.33 This result was also statistically significant.

The concomitant use of latanoprost and timolol did not demonstrate a statistically significant benefit over latanoprost monotherapy.34 After a 2 to 4 week run-in on timolol twice daily, 148 patients were randomized to receive either latanoprost alone once daily (50 subjects) or concomitant therapy with latanoprost once daily and timolol (49 subjects), or pilocarpine 2% three times daily and timolol (49 subjects). After 6 months of treatment, latanoprost lowered mean diurnal IOP 5.5mmHg, while the combination of latanoprost and timolol achieved a mean diurnal reduction of 6.1mm Hg. This 0.6mm Hg difference in mean diurnal IOP was not statistically significant compared to latanoprost monotherapy (figure 7.2).

In a second concomitant use study, Konstas et al.35 randomized 36 patients, after an 8-week timolol run-in, to receive either morning (8:00 a.m. and 8:15 a.m.) or evening (8:00 p.m. and 8:15 p.m.) dosing of latanoprost and timolol. The dosing regimen was continued for 7 weeks, after which the subjects were crossed over to the second dosing regimen for a minimum of 7 weeks. In-hospital diurnal IOP testing was performed every 4 hours for 24 hours. There were no statistical differences at individual time points or in mean diurnal IOP between the two dosing regimens.35

While it remains unclear whether the fixed combination of latanoprost and ti-molol offers clinically significant diurnal IOP reduction over latanoprost mono-therapy, both the Higginbotham et al. and Pfeiffer studies demonstrated larger

Figure 7-2. Latanoprost-timolol fixed combination versus components after timolol run-in. Adapted from Bucci MG. Intraocular pressure-lowering effects of latano-prost monotherapy versus latanoprost or pilocarpine in combination with timolol: a randomized, observer-masked multicenter study in patients with open-angle glaucoma. Italian Latanoprost Study Group. J Glaucoma. 1999;8(1):24-30. Adapted from reference 34.

Figure 7-2. Latanoprost-timolol fixed combination versus components after timolol run-in. Adapted from Bucci MG. Intraocular pressure-lowering effects of latano-prost monotherapy versus latanoprost or pilocarpine in combination with timolol: a randomized, observer-masked multicenter study in patients with open-angle glaucoma. Italian Latanoprost Study Group. J Glaucoma. 1999;8(1):24-30. Adapted from reference 34.

diurnal IOP reductions with the fixed combination compared to timolol monotherapy; Pfeiffer reported a 1.9mmHg advantage with the fixed combination,33 and in Higginbotham et al.'s study, the advantage was 2.9mmHg.32

Several other smaller studies have compared the fixed combination timolol-latanoprost with concomitant therapy with timolol and brimonidine36 and with the fixed combination timolol-dorzolamide.37,38 Comparisons of the timolol-dorzolamide fixed combination to the latanoprost-timolol fixed combination have produced mixed results, with one study showing no difference in mean diurnal IOP between the two combinations37 and another study finding a mean diurnal IOP approximately 1 mm Hg lower with the latanoprost-timolol combination.38

7.3.2 Timolol-Travoprost. The timolol 0.5%-travoprost 0.004% fixed combination (DuoTrav; Alcon Laboratories, Inc., Fort Worth, Tex.) was first approved in Australia in 2005 and is available in the European Union, Canada, Chili, Iceland, and Norway.

When compared to its individual components as monotherapy, the timolol-travoprost fixed combination produced greater IOP reductions than either of its components administered separately in a 3-month study of 263 subjects. The fixed combination produced a mean IOP reduction from baseline of 1.9 to 3.3mmHg greater than timolol that was statistically significant at 2-week, 6-week, and 3-month 8 a.m., 10 a.m., and 4 p.m. time points. Compared with travoprost, the fixed combination produced 0.9 to 2.4mm Hg greater IOP reduction. This was statistically significant at all time points at week 2 and at all except the 4 p.m. time point at week 6 and month 3 (vs. travoprost).39

Two double-masked studies comparing timolol-travoprost fixed combination to the concomitant use of its components were conducted. In the first, 316 patients with open angle glaucoma or ocular hypertension were randomized, after a therapeutic washout, to receive either the timolol-travoprost fixed combination dosed in the morning, or concomitant therapy with timolol dosed in the morning and tra-voprost dosed in the evening. Measurements of IOP were performed at 8 a.m., 10 a.m., and 4 p.m. Significant IOP reductions from baseline at 3 months were achieved by both the fixed combination (15.2 to 16.5mm Hg) and the concomitant use of timolol and travoprost (14.7 to 16.1mm Hg). Although reductions were similar at the 8 a.m. time point, the concomitant use of the components was slightly superior at the 10 a.m. and 4 p.m. time points by almost 1mm Hg.40 This may be due to different dosing times for the components versus the fixed combination. The second study was of similar design and randomized 403 subjects into three groups: the fixed combination administered in the morning, concomitant administration of timolol in the morning and travoprost in the evening, or timolol twice daily. The fixed combination produced statistically significant IOP reductions of 7.0 to 8.2mm Hg from baseline that lasted approximately 24 hours, with only slight increases in pressure between 4 p.m. and 8 a.m. The concomitant administration of the components produced slightly greater IOP reductions than the fixed combination at the 10 a.m. and 4 p.m. time points (mean differences from the fixed combination ranged from 0.4 to 1.1mmHg). Timolol twice daily was less effective than the two regimens containing timolol and travoprost in combination.41

7.3.3 Timolol-Bimatoprost. A bimatoprost 0.03%-timolol maleate 0.5% fixed combination (Ganfort; Allergan, Inc., Irvine, Calif.) has been recently approved in the European Union. Unpublished data (A. Hommer and colleagues) from a multicenter, double-blind, randomized study have been presented. In this trial, patients at 35 sites were randomized to one of three treatment arms. Each received the fixed combination dosed in the morning (178 subjects), or the concomitant use of timolol twice daily and bimatoprost once in the evening (177 subjects), or bimatoprost once in the evening (99 subjects). All subjects were naive to pharmacotherapy and returned 3 weeks after randomization for IOP measurements at 8 a.m., 10 a.m., and 4 p.m. The mean diurnal IOPs for the fixed-combination and concomitant-use groups were within 1.5mm Hg (95% confidence interval) at all three time points. This met the defined criterion for noninferiority. The fixed combination decreased mean diurnal IOP from baseline by 8.8mm Hg and was statistically significantly more effective than bimatoprost alone (0.8mm Hg difference).

7.3.4 Timolol-Brimonidine. The timolol 0.5%-brimonidine tartrate 0.2% fixed-combination product (Combigan; Allergan, Inc., Irvine, Calif.), first approved in 2006, is a recent addition to the fixed-combination group of glaucoma treatments. It is indicated for the reduction of IOP in patients with primary open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta blockers. The fixed combination of timolol and brimonidine is approved in Europe and several other countries worldwide.

The fixed combination provided significantly better IOP control compared to monotherapy with either brimonidine or timolol used alone. Craven et al.42 reported 3-month results from a study of patients with treated glaucoma or ocular hypertension who underwent a washout period and were randomized to receive the fixed brimonidine-timolol combination twice daily or the individual components (brimonidine three times daily, or timolol twice daily). A total of 999 patients completed 3 months of assigned therapy. The mean decrease in IOP from baseline ranged from 4.9 to 7.6mm Hg with the brimonidine-timolol combination. This was greater than reductions with the single components at all follow-up points at 8 a.m., 10 a.m., and 3 p.m. At the 5 p.m. measurements, when the brimonidine three-times-daily monotherapy group was at peak, and the fixed combination was approaching trough, there was no statistical difference between the brimonidine monotherapy and fixed combination groups. Sherwood et al.43 reported the 12-month results combined from two identical trials. A total of 1,159 patients were randomized, and 833 completed the study. The mean decrease in IOP from baseline for the fixed combination was 4.4 to 7.6mm Hg. Similar to previous observations, the fixed combination had greater IOP reductions than its individual components at the 8 a.m., 10 a.m., and 3 p.m. time points, but not the 5 p.m. time point, compared to brimonidine monotherapy (when dosed three times daily and at peak effect).

A study by Goni44 of 355 patients included in a double-masked 12-week trial compared the fixed combination to the concomitant use of its individual components. Mean IOP reduction from baseline was significant and ranged from 4.4 to 5.7mmHg in the combination group. The combination was as effective as concomitant therapy at all time points and visits.

Blood Pressure Health

Blood Pressure Health

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