Should fixed combinations be given as first-line glaucoma therapy? YES

Key Points

In the wake of the successful launch, ten years ago, of Merck's fixed combination therapy for glaucoma, Cosopt (dorzolamide/timolol), the popularity of these drugs has escalated; so too has research and development in this area. We Europeans are fortunate to have several fixed combination products available to us, thus affording us the luxury of choice.

I currently use the dorzolamide/timolol fixed combination alone or in combination with a prostaglandin analogue in many of my glaucoma patients who require adjunctive therapy. I have also increased the use of three other fixed combinations: latanoprost/timolol (Xalacom; Pfizer); travoprost/timolol (DuoTrav; Alcon); and bimatoprost/timolol (Ganfort; Allergan). Overall, I prescribe fixed combinations to more than 50% of my patients.

Greater efficacy a clear benefit

The dorzolamide/timolol fixed combination is probably the only fixed combination to date that has been evaluated as initial therapy in glaucoma patients with high baseline pressures. It demonstrated a significant IOP-lowering effect, and was therefore found to be a viable option for treating these patients.

Admittedly, if a fixed combination is administered in the first instance, the effect that the individual components exert on the patient cannot be confirmed, although administering fixed combinations as first-line treatment allows us to understand quickly whether our patients are non-responders or insufficient responders to this adjunctive therapy. As such, we can determine whether the patient requires additional therapy, laser or even surgery, faster. In addition to this, in busy practices and health systems that are under a lot of pressure, fixed combination therapy allows us to reserve patient appointments for those that need them the most.

Reduced burden, increased adherence

Fixed combinations reduce the burden of daily glaucoma therapy and provide a clear therapeutic benefit to our patients. By providing a less complex regime, particularly when compared with unfixed therapy, they enhance adherence and real-world IOP control. They are also associated with better tolerability and have an improved safety profile.

It is a known fact that inadequate drug adherence greatly diminishes drug efficacy, often leading to disease worsening or under-treatment, and an increased rate of complications. Unsurprisingly, several studies have observed that patients taking glaucoma medications more than twice daily demonstrate worse adherence. The lower dosing schedule is therefore a clear advantage of fixed combinations in glaucoma therapy.

How do they stack up against unfixed therapies?

When compared with unfixed combination therapies, I have noticed that fixed combinations provide better adherence, better tolerance, and fewer adverse events in real life practice. This may be due to the reduced exposure to the active ingredient, or to less exposure to the preservative benzalkonium chloride (BAK), a known ocular surface irritant. In fact, more than 30% of my patients on combined therapy develop signs of ocular surface disease (OSD) and require chronic therapy with non-preserved tears. Importantly, OSD is significantly less common with fixed combination therapies, especially the prostaglandin-timolol fixed combinations that only require Q.D. dosing. I also believe that conjunctival inflammation associated with long-term exposure to BAK may constitute an important risk factor for the future failure of filtering surgery. Consequently, our patients clearly benefit from fixed combination therapy because it limits their exposure to BAK by half or even two-thirds. In Greece, we are currently awaiting the launch of the preservative-free dorzolamide/timolol fixed combination (preservative-free Cosopt; Merck), which is now available in several European countries. I believe this formulation will significantly reduce the rates of OSD in our patients.