Products Of Historical Interest

7.1.1 Pilocarpine-Epinephrine. Adrenergic and cholinergic combinations were reported as early as the 1960s.6'7 The first available combination of IOP-lowering agents was a mixture of pilocarpine and epinephrine. This product evolved during the period when these two classes represented available glaucoma medications, and with additive properties in combination.8'9 Many patients were receiving both in separate bottles, and combining them in a single bottle offered dosing convenience. Some patients may have been better off with concomitant therapy because the combination was approved for use four times daily, posing a significant overdosage of the epinephrine component.

7.1.2 Timolol-Pilocarpine and Timolol-Epinephrine. As the topical beta blocker timolol became first-line treatment, its combination with other topical agents such as epinephrine10 and pilocarpine11 was studied. These combinations arose due in large part to a paucity of available medications. The fixed timolol-pilocarpine12,13 and timolol-epinephrine10 combinations offered dosing convenience to glaucoma

Table 7.1 Fixed Combinations of Glaucoma Medications

Brand Name

Components

Manufacturer

Cosopt

Timolol 0.5% and dorzolamide 2.0%

Merck and Co., Inc.

Xalacom

Timolol 0.5% and latanoprost 0.005%

Pfizer, Inc.

DuoTrav, Extravan

Timolol 0.5% and travoprost 0.004%

Alcon Laboratories, Inc.

Ganfort

Timolol 0.5% and bimatoprost 0.03%

Allergan, Inc.

Combigan

Timolol 0.5% and brimonidine 0.2%

Allergan, Inc.

patients at the time. Like the pilocarpine-epinephrine combination, a dosing mismatch existed, with timolol requiring one to two drops per day and pilocarpine up to four drops daily to reach maximal efficacy. The timolol-pilocarpine combination was never approved for use in the United States.

7.1.3 Betaxolol-Pilocarpine. Although never released into the market, the fixed combination of betaxolol and pilocarpine14 was studied and approved by the FDA in April 1997.

7.2 MODERN FIXED COMBINATION APPROVED IN THE UNITED STATES: TIMOLOL-DORZOLAMIDE

Timolol maleate 0.5%-dorzolamide hydrochloride 2.0% fixed combination (Co-sopt; Merck and Co., Inc., Whitehouse Station, N.J.) was approved by the FDA in 1998. It is the only fixed combination drug available in the United States. At present, prostaglandins are first-line choice medications for most patients; however, in the mid-1990s, beta blockers were the drugs of choice for first-line IOP reduction. The choices besides beta blockers, prior to the approval of dorzolamide in 1994, included pilocarpine and dipivefrin. Because of its safety, efficacy, and convenience of dosing, dorzolamide quickly became a popular second-line choice until the introduction of latanoprost in 1996. Thus, as with the older combination products, the development of the timolol-dorzolamide fixed-combination product reflected common clinical usage at the time. The labeled indication reflects treatment practice at that time: The fixed combination is indicated for patients with primary open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta blockers.

Comparison studies confirmed that the timolol-dorzolamide fixed combination was more efficacious than either of its constituents in monotherapy.15,16 In the first study, 335 subjects underwent a washout period and were randomized into three groups (timolol, 112 subjects; dorzolamide, 109; fixed-combination timolol-dorzolamide, 114). At three months, the combination twice daily provided a 2-hour peak IOP reduction of 32.7% versus 19.8% and 22.6% for dorzolamide three times daily and timolol twice daily, respectively; and the morning trough IOP reduction of 27.4% for the combination twice daily versus 15.5% and 22.2% for the dorzola-mide three times daily and timolol twice daily (figure 7.1).16

Another study of 242 patients randomized to receive the fixed combination (121 subjects) or the concomitant administration of its components (121 subjects), after a 2-week timolol run-in, also demonstrated equivalence to concomitant therapy with components in separate bottles,17 with a nonsignificant difference of only 0.73 mm Hg favoring concomitant therapy at the 4 p.m. time point attributable to the three-times-daily dosing of dorzolamide in the concomitant group versus only twice daily in the fixed-combination group. In these studies, the fixed combination yielded peak and trough IOP reductions from untreated baseline of 9 mm Hg and 7.7mmHg, respectively.16 Following a 3-week timolol run-in, switching to the fixed combination of timolol and dorzolamide further reduced IOP at peak and trough by 15.8% to 17.3% and 10.6% and 11.3%, respectively.15

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