Treatment Issues, Problems & Repairs

Using combination drugs in glaucoma management

Eve J. Higginbotham

Department of Ophthalmology, University of Maryland School of Medicine, Baltimore, MD, USA

Introduction

One of the biggest issues that clinicians and patients face is compliance to a prescribed therapeutic plan. The reality is that the patients will often miss their medications and they will not necessarily discuss their difficulties regarding following a medical regimen with their physicians. Epstein noted that some patients did not wish to hurt the physician’s feelings and thus would fail to mention that a drop was missed.1 In a study by Kass and coworkers, patients claimed to have taken 97.1% of their prescribed drops, however, a concealed electronic monitor in their bottles indicated a much lower rate of compliance, i.e., only 76%.2 Given the difficulties associated with maintaining a consistent regimen, the prospect of combining two medications in one bottle becomes an important consideration as a solution to this chronic problem. This manuscript will highlight issues related to compliance, review the efficacy of at least one fixed combination in use currently, timolol and dorzolamide, and will then discuss a future combination, timolol and latanoprost.

The challenge of adhering to a prescribed therapeutic plan

Compliance has been assessed among patients with either hypertension, glaucoma, seizure disorders, or other chronic diseases. Only 50-60% of patients take their medications appropriately, and 5-10% of patients are generally considered poorly compliant. The remaining patients fall somewhere in between these two groups, and thus would not be considered perfectly compliant.3 Using an electronic monitor concealed in eye drop bottles, Kass and coworkers assessed the compliance to treatment with timolol b.i.d. and pilocarpine q.i.d. When patients used both these drugs, compliance with pilocarpine was less than adherence to an appropriate timolol dosage: 77.7 ± 18.7% versus 84.3 ± 14.0%, respectively.1,4 A previous study

Address for correspondence: Eve J. Higginbotham, MD, Department of Ophthalmology, University of Maryland School of Medicine, 419 W. Redwood Street, Suite 580, Baltimore, MD 21201, USA. e-mail: fcwejh6786@aol.com

Glaucoma in the New Millennium, pp. 213–222

Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001

edited by Jonathan Nussdorf

© 2003 Kugler Publications, The Hague, The Netherlands

by this same group noted that patients only administered 75% of the prescribed doses of pilocarpine and 25% of patients did not use their medication for an entire day per month. Thus, it is likely that the side-effects of pilocarpine compared to timolol contributed to the lower rate of compliance with the former drug. Although the frequency of timolol is only b.i.d. or q.d. in many instances, given the cardiopulmonary side-effects, the physician should be as concerned if this drug is administered more than twice daily. Kass and coworkers also noted that 12.7% of patients in their study administered timolol three or more times a day for at least seven days per month.2

Patients with a chronic disease face ongoing challenges with their treatment. It has been estimated that the patients will default as often as 82% of the time, and as little as 20%.5 It is interesting to note the findings of one study that assessed the compliance of patients who were diagnosed with epilepsy. Given the social, medical, and psychological issues related to untreated epilepsy, the motivation of these patients to adhere to a medical regimen would be assumed to be very high. However, using standard pill bottles that had been equipped with microprocessors in their caps that would record every bottle opening, researchers assessed the compliance rates of patients who used medication as frequently as four times daily and as infrequently as once daily. These researchers noted that the frequency of the medication was important. When the medication was prescribed once daily the compliance rate was 87%, twice daily was slightly less than 81%, however, medication prescribed four times daily was as low as 39%. It is also interesting to note that counting pills was not a reliable way to determine compliance, and in fact this method failed to identify 87% of patients who were considered non-compliers based on serum levels of the drugs. Thus, frequency of the medication is an important consideration, and if weighing the bottles is considered a way of measuring compliance in ophthalmic practice, there may be an underestimation of the problem.

However, even in those instances when the therapy may be as simple as once or twice daily timolol, adherence to a regimen is unpredictable. In a South African study,6 compliance to therapy with timolol was assessed. The investigators questioned patients, as well as assessing how frequently their prescriptions were being filled for the medication. It was noted that 24% of patients admitted to missing eyedrops either occasionally or frequently. Among those patients who were not compliant, it was noted that patients were without treatment for as many as 85 days a year.

Unlike other disciplines in medicine, spacing of eye medications is as important as taking the medication. The diffusion of the drug into the eye is proportional to the concentration of the drug in the precorneal tear film. Given that there is a finite volume in the cul-de-sac that measures 7 l, when a drop that measures 25-50 l is instilled into the eye, there is a significant amount of dilution that takes place. If we consider the tearing that can occur once the drug has been instilled, then the amount of drug that ultimately enters the anterior chamber is significantly less than expected. When a second drug is added to the first, the spacing of the medications becomes very important. In studies conducted in rabbits, Chrai and coworkers7 assessed the impact of instilling a second drug within a specific interval. There was a 46% loss of concentration in the second drug when no time was allowed between the two drugs. On the other hand, when a period of five minutes was allowed between the drugs, there was only a 1.2% loss of concentration in the

second drug. Of course, when both drugs were administered together in the same drop, there was no loss of concentration in either drug. Thus, it is important to review the appropriate timing of the instillation of drugs with patients, as well as the appropriate frequency.

So why are patients poorly compliant? Certainly there are a plethora of reasons, many of which are specific to any given patient. This question has been explored in the ophthalmic literature. Patel and Spaeth8 interviewed 100 patients regarding their medical regimen for glaucoma. Most of the 59 patients admitted that they had not used their medications appropriately. Some of the reasons for noncompliance included frequency of instillation, forgetfulness, cost, and inconvenience. Interestingly, side-effects and age were not significant factors that contributed to this noncompliance.

Given the importance that intraocular pressure (IOP) has been shown to contribute to the progression of glaucomatous disease,9 adherence to medical therapy is an important issue. A clinician can certainly provide a detailed explanation of the disease process and can clearly record the regimen for the patient. However, it is ultimately the patient who must adhere to that program on a daily basis. Combination medications are not the only ‘answer’ to this age-old problem, however, such medications add a dimension of convenience to the regimen.

The efficacy and safety of a fixed combination of timolol and dorzolamide

In the USA, previous experience with a combination antiglaucoma medication has generally not been positive. Pilocarpine combined with epinephrine was available years ago in two concentrations of pilocarpine, 2% and 4%. Patients were expected to use this medication four times a day. Such a frequent instillation of this medication forced the patient to overdose with epinephrine, a drug that typically causes hyperemia, can often lead to an allergic response, and can increase systemic blood pressure. Furthermore, patients remained unhappy with the side-effects of pilocarpine, a drug which, of its own accord, contributes to conjunctival hyperemia. Thus, in this case, the convenience of a combination drug was outweighed by the side-effects of the components.

The fixed combination of timolol 0.5% and dorzolamide 2% offers an alternative for patients that combines two drugs that are generally well tolerated, and does not increase the frequency of instillation of either component beyond the recommended levels. Both these drugs lower IOP by suppressing aqueous production. The magnitude of the suppression is as great as 51%, as measured by fluorophotometry in normal human volunteers.10 There have been several stud- ies11-13 that have demonstrated the superiority of this fixed combination to either of the monotherapy components. In one study, Boyle and coworkers10 assessed the efficacy and safety of the dorzolamide-timolol combination compared to each of the components in 335 patients who were either on no prior medication or who had previously been cleansed of their intraocular medication. The IOP was measured at morning trough and at peak, two hours post-dose on day 1, week 2, and months 1, 2, and 3. These investigators noted at a mean reduction in IOP from baseline that measured 27.4% (-7.7 mmHg) for the combination (administered twice daily) at morning trough and 32.7% (-9.0 mmHg) at peak at month 3. The corresponding measurements for the monotherapy components were as follows: trough

for dorzolamide administered t.i.d., 15.5% (-4.6 mmHg) and peak, -19.8% (-5.4 mmHg); trough for timolol administered b.i.d., 22.2% (-6.4 mmHg) and peak, 22.6% (-6.3 mmHg). Complaints with regard to blurred vision, stinging, and burning were more common in the combination and dorzolamide groups compared to the timolol group.

A more recent paper illustrated the benefits that combination therapy may have in actual practice compared to concomitant use of the components. Choudhri et al.14 assessed IOP reduction in a series of 74 consecutive glaucoma patients who were switched from an unfixed combination of timolol 0.5% and dorzolamide 2% to a fixed combination in one eye. The fellow eye remained on the unfixed combination. After four weeks of therapy, these investigators noted that there was a statistically significant difference (p = 0.01) in the mean IOP change of 2.1 mmHg compared to baseline in eyes on the fixed combination versus fellow eyes that changed only 0.8 mmHg. There may be two explanations for this finding. As the authors noted, one explanation relates to patient compliance. The convenience of keeping up with one bottle of medication versus two bottles is worth highlighting. However, another explanation may relate to the higher precorneal tear film concentration of the medication that may actually contribute to a higher concentration of the drugs in the aqueous. This observation has been previously confirmed in animal studies conducted by Chrai and coworkers.6 Thus, it is important to consider the therapeutic advantages of combination drugs.

Case study

The benefits of having a combination drug that is generally well tolerated and effective can best be illustrated by the following case study:

A 61-year-old Caucasian male presented with a long-standing history of primary open-angle glaucoma. He was status post-argon laser trabeculoplasty in both eyes. His medications included timolol b.i.d. and brimonidine tartrate t.i.d. He attested to excellent compliance but had missed several appointments according to the referring physician. His visual acuity measured 20/25 OU and his visual fields are illustrated in Figure 1. His nerve fiber analysis confirmed the asymmetry of his glaucomatous disease (Fig. 2), which was also illustrated in his optic nerve photographs (Fig. 3). His IOP measured 18 mmHg OU. An IOP goal of less than 18 mmHg was set for OD and of less than 14 mmHg OS. Considering the magnitude of his loss in the left eye, surgery was recommended, however, the patient was very hesitant. Upon further questioning, it was noted that the patient may have missed some doses of one his medications, and often does not wait the recommended five minutes between the instillation of his medications. After this discussion, the patient agreed to try another drug and, thus, both timolol b.i.d. and brimonidine tartrate were discontinued. Cosopt was initiated. On return, the patient’s IOP measured 12, 14 mmHg OU. The patient attested to better compliance with one bottle used twice daily versus the multiple drops that he was previously using. The patient continues to be closely monitored.

This case illustrates a few points. It is important to encourage the patient to discuss his or her concerns honestly, regarding the management of any chronic disease. In this case, the patient had difficulty keeping up with multiple drops, thus, by simplifying his regimen, his compliance improved. Furthermore, by elimi-

Fig. 1a.

Fig. 1b.

nating the need to take two different medications in separate bottles, spacing of the drops became less of an issue. Thus, there was no need for concern that the effect of one of the drops was being washed out. Obviously, it would have been ideal to have initiated the medication in one eye as a monocular trial, however, we can still test the efficacy of this regimen by asking the patient to hold the medication for

two weeks in his better eye. However, since surgery had just recently been discussed, it may be more prudent to initiate such an action after the patient returns for two or three more appointments.

The efficacy and safety of a fixed combination of timolol and latanoprost

At the time when this manuscript was in preparation, the fixed combination consisting of timolol 0.5% and latanoprost 0.005% had not yet been approved. However, considering the importance that the unfixed combination of these component drugs has played in the armamentarium of the clinician, it is important to review the available results that have been conducted on the fixed combination.

Of the three large clinical trials that have been conducted, one focused on two different concentrations of latanoprost, and two others compared the efficacy of the fixed combination to the monotherapy components. Diestelhorst and Almegard15 evaluated the efficacy of two combinations of latanoprost and timolol. One hundred and thirty-nine patients with either open-angle glaucoma or ocular hypertension were randomized to either a fixed combination of timolol 0.5% and latanoprost 0.001%, timolol 0.5% and latanoprost 0.005%, or the individual monotherapy components of either latanoprost 0.005% or timolol 0.5%. IOP reduction measured by group was as follows: 3.7, 6.1, 4.9, and 2.1 mmHg, respectively. Thus, these data confirmed the superiority of the fixed combination of latanoprost 0.005% and timolol 0.5%.

As previously mentioned, there have been two trials that compared the efficacy of the fixed combination with the monotherapy components. One was conducted in Germany16 and the other in the USA.17 Both these trials involved patients with either ocular hypertension or primary open-angle glaucoma, as well as a twoto four-week run-in period on timolol b.i.d. In the German study, patients were initially randomized to either the fixed combination of latanoprost 0.005% and timolol 0.5% or the monotherapy components, latanoprost 0.005% administered once daily in the morning or timolol 0.5% instilled twice daily. This double-masked, randomized period lasted for six months and then the patients were invited to continue on the fixed combination for a further six months. The investigators noted that the difference in mean change from baseline in diurnal IOP during the randomized phase was –1.2 mmHg when the fixed combination was compared to latanoprost. The difference in mean change from baseline in IOP during the same time period when the fixed combination was compared to timolol b.i.d. was –1.9 mmHg. The diurnal IOP reduction in the fixed combination group was maintained up to 52 weeks.

In the study conducted in the USA,17 latanoprost 0.005% was administered in the evening rather than in the morning. The remainder of the protocol was very similar to the German study. Of course, the demographic characteristics differed from the German population. Mean diurnal IOP at baseline was 23.1 ± 3.8 mmHg in the fixed combination group, 23.7 ± 4.1 in the timolol group, and 22.9 ± 4.1 mmHg in the latanoprost group. At the end of the randomized phase of the study at week 26, the mean diurnal IOP was as follows in the respective groups: fixed combination group 19.9 ± 3.4 mmHg, timolol 23.4 ± 5.4 mmHg, and latanoprost, 20.8 ± 4.6 mmHg. When comparisons were made between the fixed combination and either of the monotherapy groups, statistical differences were noted. The mean

Fig. 2.

diurnal IOP at weeks 26 and 52 for the group that remained on fixed combination for the entire year measured 19.4 ± 3.0 and 18.9 ± 3.2 mmHg, respectively. Thus, both studies indicate the superior efficacy of the fixed combination to either of the components. It is expected that, when this combination becomes available, it will be an important adjunct to our armamentarium.

a

b

Fig. 3.

Summary

Combination drugs are convenient for our patients and are thus important adjuncts to consider in the medical management of patients with glaucoma. The combination of two drugs in the same bottle reduces dosing errors. Additional advantages not highlighted in this manuscript include reduced exposure to preservatives, and potentially reduced costs18 for our patients. The fixed combination of timolol and dorzolamide has provided the clinician with an important, generally well-tolerated alternative which was previously unavailable. On the horizon, the

addition of other combinations such as latanoprost and timolol holds promise. In any case, the use of these medical options must be judged on an individual basis, with careful consideration to the systemic status of the patients as well as to the severity of the glaucomatous disease.

References

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