Clinical Studies On Additivity

Because PG analogs have a different mechanism of action than other ocular hypo-tensive drugs, the IOP reduction from PGs can be expected to be additive to that of other glaucoma medications. Multiple clinical studies have demonstrated that the

effect of PGs is additive to the effect of other ocular hypotensive agents, including timolol, pilocarpine, topical and oral carbonic anhydrase inhibitors (CAIs), alpha-2 agonists, and dipivefrin91-98 and when used in patients on otherwise maximally tolerated medical therapy.8,99 Also, patients on a nonselective beta blocker with pilocarpine or dorzolamide achieved significantly lower IOP when latanoprost was added to the regimen.99

2.8.1 Beta Blockers. Beta-adrenergic antagonists reduce IOP by inhibiting the production of aqueous humor, whereas PGs work by increasing uveoscleral outflow. Thus, it is expected that the effects of beta blockers and PGs on IOP reduction would be additive, and this has been confirmed in clinical studies. In several trials in which latanoprost once daily was added to timolol twice daily, additional IOP reductions of 24% to 37% were achieved.91 The additive effect is less with twice-daily dosing of latanoprost or when timolol is added to latanoprost. Interestingly, when patients are switched from timolol to latanoprost monotherapy, they experience almost as much IOP reduction (21% to 25%) as when latanoprost is added to timolol therapy. The additive effect of pilocarpine and timolol is not as great as with latanoprost and timolol.91 Studies with the other PG analogs also demonstrate an additive effect when used in combination with beta blockers.94-96 Fixed combinations of PGs and timolol are discussed in section 2.8.5.

PG analogs and beta blockers are often used together, typically with morning dosing of a beta blocker and evening dosing of a PG analog.

2.8.2 Carbonic Anhydrase Inhibitors. The additivity of PG analogs to oral and topical CAIs has been demonstrated in clinical studies.83,91,99,100 Oral CAIs combined with PG analogs can give a dramatic decrease in IOP. For example, latanoprost 0.005% once daily gives an additional 15% decrease in IOP when added to an acetazolamide regimen of 250 mg twice daily.100 Latanoprost gives an additional 24% reduction in IOP when added to dorzolamide three times a day,83 and dorzolamide gives an additional 15% to 20% reduction in IOP when added to latanoprost.82,101 It has also been demonstrated that latanoprost further reduces IOP when added to a fixed combination of timolol and dorzolamide.102 The other PG analogs also have an additive effect when used with CAIs.103,104

2.8.3 Cholinergic Agonists. Cholinergic agonists, such as pilocarpine, act by increasing trabecular outflow facility. This increase is accomplished through contraction of the ciliary muscle, which pulls on the scleral spur and opens channels in the trabecular meshwork. The contraction of the ciliary muscle also contracts the spaces between the muscle bundles and causes a reduction in uveoscleral outflow. Therefore, theoretically, pilocarpine could reduce the increase in uveoscleral outflow caused by PGs. Although this effect has been observed with pilocarpine and PGF2a in monkeys, human studies show no blockage of the PG effect with concurrent pilocarpine treatment.15,105 Clinical studies have demonstrated that latanoprost produces an additional reduction in IOP when added to pilocarpine or physostigmine.15,91 When added to a regimen of pilocarpine 2%, latanoprost reduces IOP an additional 14% to 18% compared to pilocarpine alone; conversely, pilocarpine reduces IOP an additional 7% when added to latanoprost alone.15'105 A study with 13 patients in which pilocarpine up to 6% four times daily was added to bimatoprost once daily showed no significant additive or antagonistic effect from the added pilocarpine.92 In general, the PG analogs produce a substantial additional IOP reduction when added to regimens with pilocarpine; however, less additional effect can be expected when adding pilocarpine to a PG regimen.15'92'105

2.8.4 Adrenergic Agonists. Epinephrine increases trabecular outflow facility and uveo-scleral outflow. There is evidence that PGs are involved in the ocular hypotensive effects of epinephrine' which may stimulate the production of endogenous PGs.106 In any case' clinical studies have demonstrated that latanoprost is indeed additive to dipivefrin, an epinephrine prodrug.91'99 Studies in which latanoprost has been added to dipivefrin show an additional reduction in IOP of 19% to 28%. When dipivefrin is added to latanoprost the additional IOP reduction is less (15% to 16%) but still significant.91 Dipivefrin and latanoprost are both analogs of mediators that are naturally present in the eye (epinephrine and PGF2a). They may work by modulating normal physiologic mechanisms. The combination of these two medications is very effective in lowering IOP, producing total IOP reduction of up to 47% from initial baseline.91

Brimonidine has a significant additional effect when added to PG ana-logs.101,104,107,108 In one study, brimonidine added to latanoprost seems to have an effect similar to that of adding topical dorzolamide to latanoprost.108 Also, concomitant therapy with brimonidine and latanoprost has been reported to have a similar effect on IOP compared with latanoprost-timolol fixed combination.109 However, another study reported a lesser effect from brimonidine than either timolol or brinzolamide when added to a regimen of once-daily travoprost.104 Studies with bimatoprost have also shown an additive effect with brimonidine.93

2.8.4 Fixed Combinations With PG Analogs. Because of the potent additive effect that PG analogs have when combined with other ocular hypotensive agents and the common clinical usage of PG analogs with beta blockers, much attention has been given to the development of fixed combinations of PGs with other medications, especially timolol (table 2.2).

A fixed-combination of latanoprost 0.005% and timolol 0.5% (Xalacom) is available in some countries but is not yet approved in the United States. There is substantial evidence that the fixed-combination product is more effective than either timolol or

Table 2.2 Prostaglandin Fixed-Combination Products Either Commercially Available or Under Investigation

PG analog

Combination Drug

Brand Name

Manufacturer

Latanoprost 0.005%

Timolol 0.5%

Xalacom

Pfizer

Bimatoprost 0.03%

Timolol 0.5%

Ganfort

Allergan

Travoprost 0.004%

Timolol 0.5%

DuoTrav, Extravan

Alcon

latanoprost alone.91'97'98'110-113 Fixed combinations of latanoprost and timolol reduce IOP an additional 15% to 25% below a timolol-treatment baseline or a lata-noprost-treatment baseline.91'97'98'110-113 The reduction in IOP achieved with the fixed-combination product dosed once daily either in the morning or in the evening is not substantially less than that achieved with concomitant treatment of once-daily latanoprost with twice-daily timolol.97'113'114 Other studies have shown that the la-tanoprost-timolol combination is at least as effective as twice-daily dorzolamide-timolol (Cosopt).115'116

Fixed-combination travoprost-timolol and bimatoprost-timolol products are under investigation. Fixed combinations of travoprost 0.004% and timolol 0.5% used once daily in the morning have been reported to be as effective as concomitant therapy with the individual drugs and significantly more effective than timolol alone.94-96

Fixed-combination products have the advantage of being more convenient and potentially less expensive for patients' and therefore have the potential advantage of improving patient compliance. They also reduce preservative exposure by decreasing the number of daily drops. Beta blockers and PG analogs are especially well suited for a fixed-combination product. Since nonselective beta blockers or PG analogs both are effective when given once daily' a fixed combination of these products given once daily does not compromise circadian efficacy based on the duration of action of each component. Other fixed combinations may be less effective since other glaucoma medications require more frequent administration to maintain efficacy' and a combination product with a PG analog given once daily would sacrifice circadian efficacy.

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