Fixed Combination Drugs

ALBERT S. KHOURI, TONY REALINI, and ROBERT D. FECHTNER

initial therapy for glaucoma typically consists of topical medications that lower intraocular pressure (IOP), and frequently more than one agent is required to achieve adequate control of IOP. For example, initial monotherapy failed to control IOP within the first 2 years of treatment in up to 50% of glaucoma patients in the United States.1 The recent Ocular Hypertension Treatment Study randomized patients to observation or treatment in which the therapeutic goal was a relatively modest 20% IOP reduction; in that study, 40% of patients randomized to treatment required more than one medication to achieve the therapeutic goal.2

The importance of making therapy convenient for glaucoma patients cannot be overemphasized. Consider the burdens of treatment from the patient's perspective: Early and even moderate glaucoma is often symptom-free, which tends to reduce adherence to medical regimens. Unlike chronic therapy for some medical ailments where a clear therapeutic benefit is evident to patients, no such benefit is evident to treated glaucoma patients. In fact, there often exist treatment disincentives: Medicines are costly and time-consuming to instill and may have side effects that are often perceived by the patient as being worse than the glaucoma prior to treatment.

These observations underscore the potential benefits of fixed-combination medications compared with using multiple medication bottles, thus reducing the burdens of therapy. Among the advantages of fixed combinations for patients are cost savings and a reduction in the total number of drops instilled per day. This also reduces the amount of preservative applied to the eye, which may improve tolerability and may favorably influence eventual surgical outcomes in patients who ultimately require filtering procedures.3,4 A frequent occurrence in patients using multiple medication bottles is the established washout effect resulting from rapid-sequence instillation of multiple drops. Although it is recommended that patients wait approximately 5 minutes between eye drops,5 the inconvenience of this recommendation may affect adherence.

Attempts to develop effective fixed combinations of glaucoma medications date back several decades. Few such combinations have emerged, due in part to limitations such as differences between the component optimal dosing frequency, indications and contraindications, additive side effects, and drug interactions of the components (table 7.1).

The evaluation of a potential fixed combination of topical IOP-lowering drugs should include, at a minimum, studies comparing the combination to the individual components and to the components administered as concomitant therapy. One would expect the fixed combination to provide greater IOP reduction than either of the components administered as monotherapy, and safety and efficacy comparable to concomitant dosing. A fixed combination may show slightly less efficacy at some time points if there are dosing differences (e.g., component administered three times daily versus twice-daily administration of a fixed combination), but if small enough, such a difference may be a worthwhile trade-off to gain the advantages of combination therapy.

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