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Current Medical Research & Opinion Vol. 26, No. 11, 2010, 2575–2578

0300-7995 Article 5600/517718

doi:10.1185/03007995.2010.517718 All rights reserved: reproduction in whole or part not permitted

CommentaryBrinzolamide 1%/timolol 0.5%: safety andefficacy of a new fixed-combinationIOP-lowering product for glaucoma

Ingrida JanulevicieneKaunas University of Medicine, Kaunas, Lithuania

Address for correspondence:Ingrida Januleviciene, MD, PhD, Eye Clinic of Kaunas

University of Medicine, Eiveniu Street 2,

Kaunas 50009, Lithuania.

Tel.: þ 370 686 55792; Fax: þ 370 37 326146;

ingrida.januleviciene@kmuk.lt

KeywordsBrinzolamide – Dorzolamide – Drug combinations –

Glaucoma – Intraocular pressure – Timolol

Accepted: 27 August 2010; published online: 24 September 2010

Citation: Curr Med Res Opin 2010; 26:2575–78

Abstract

Objective:

To provide a commentary on recent studies with the new IOP-lowering fixed-combination product

brinzolamide 1%/timolol 0.5%.

Methods:

Medline was searched for brinzolamide/timolol fixed-combination clinical literature (up to May 18, 2010)

and the current comprehensive brinzolamide/timolol literature was reviewed.

Results:

Compared with another carbonic anhydrase inhibitor-containing product, dorzolamide 2%/timolol 0.5%,

brinzolamide/timolol has similar IOP-lowering efficacy. Brinzolamide/timolol also produces superior comfort

ratings as assessed by patients who have tried both drugs – this may be explained by the more physiologic

pH of brinzolamide/timolol. A recent study reported that brinzolamide/timolol was preferred over

dorzolamide/timolol at a ratio of nearly 4:1 among those expressing a preference.

Conclusion:

These results demonstrate that brinzolamide/timolol is equally effective and more comfortable than

dorzolamide/timolol, a fact that may positively impact patient adherence, leading to an increased

likelihood of reaching target IOP goals.

The goal of glaucoma treatment is to maintain the patient’s visual function.Currently, the only approach proven to be effective at preserving visual functionis lowering the intraocular pressure (IOP). Single ocular hypotensive agenttherapy is sometimes an inadequate option for prevention or control of thisdisease. Two or more agents are frequently required to achieve a modest 20%reduction in IOP. Although different classes of ocular hypotensive drugs arecommonly used concurrently to maximize IOP reduction, other therapieshave been developed that combine agents from two drug classes in a fixedcombination. Fixed-combination products have the combined efficacy of thetwo individual ocular hypotensive drugs, while adding several advantages overindividually dosed concurrent monotherapies. First, these products eliminatethe washout effect that occurs when the administration of one drug closelyfollows the administration of another. Second, fixed-combination therapiesreduce the lifetime exposure of the eye to preservatives. Finally, the convenienceof a fixed-combination product is two-fold – first, it provides both drugs in a

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single container, and second, it simplifies dosing from twodistinct schedules (e.g., once in the morning for one med-ication, three times daily for another) to only one (e.g.,twice daily). These conveniences are advantageousbecause they could possibly have a favorable effect onpatient adherence.

All of the widely available fixed-combination productsconsist of the �-blocker timolol 0.5% combined withanother IOP-lowering agent, such as a prostaglandinanalog, an a-agonist, or a carbonic anhydrase inhibitor(CAI). One of the earliest fixed-combination productswas the CAI-containing dorzolamide 2%/timolol 0.5%.While dorzolamide/timolol has been shown to provide effi-cacy similar to that of the concomitant administration ofthe individually dosed agents1, it does have some tolerabil-ity issues, including ocular burning and stinging in up to30% of patients2, which might negatively impact patients’adherence.

New fixed-combination products have been developedto provide patients with the efficacy expected of a fixed-combination product, while reducing the tolerability issuesobserved with dorzolamide/timolol. One of the mostrecently available products is brimonidine 0.2%/timolol0.5%, which combines an a2-adrenergic agonist witha �-adrenergic antagonist (�-blocker), respectively.Although these two drugs both inhibit adenylate cyclase,albeit via different receptor pathways3, the fixed-combina-tion product produces sustained improvements in IOPsuperior to either of its components alone4. However,one-quarter of patients using this product experienceadverse events related to conjunctival allergy and inflam-mation (i.e., hyperemia, pruritus, edema)4.

Brinzolamide 1%/timolol 0.5%, another CAI-containing combination, has recently been developed byAlcon Laboratories, Inc. as a potential improvement overdorzolamide/timolol. Brinzolamide/timolol produces aneye irritation incidence between 1% and 10% comparedto up to 30% ocular burning and/or stinging with dorzola-mide/timolol2,5. The following discussion examines thefour clinical trials of brinzolamide/timolol (search terms:brinzolamide[ti], timolol[ti], fixed combination; selectioncriteria: must have been clinical trials that reported onbrinzolamide/timolol fixed combination) that have beenpublished in Medline to date (May 18, 2010): the Kabackcontribution of elements trial6, the Manni non-inferioritytrial7, the Vold comfort study8, and the Mundorf patientpreference study9.

Kaback and colleagues tested brinzolamide/timolol ina randomized, double-masked, multicenter trial of 523patients with open-angle glaucoma or ocular hyperten-sion to compare its efficacy to that of each monotherapy(brinzolamide alone or timolol alone)6. Brinzolamide/timolol produced IOP reductions from baseline(8.0� 3.7 to 8.7� 3.9 mmHg) that were greater thanreductions from either brinzolamide (5.1� 3.9 to

5.6� 3.4 mmHg) or timolol (5.7� 3.6 to 6.9�3.6 mmHg) alone. These IOP reductions by brinzola-mide/timolol were not only significantly greater thaneither monotherapy, at all time points and visits, butthey were also clinically relevant, ranging from 1.5 to3.0 mmHg improvements over monotherapy. To directlycompare the newer fixed-combination brinzolamide/timolol to dorzolamide/timolol, Manni and colleaguesconducted a multicenter, randomized, non-inferioritytrial of 437 patients with open-angle glaucoma orocular hypertension who required a change in therapydue to elevated IOP while receiving IOP-lowering med-ication7. They discovered that the IOP-lowering efficacyof brinzolamide/timolol was non-inferior to dorzolamide/timolol at every time point and visit across a 1-yearperiod, with brinzolamide/timolol demonstrating numeri-cally superior IOP values at 9 of the 12 time points.

It has been suggested that carbonic anhydrase inhibitors(CAIs) might improve ocular blood flow in patients withglaucoma. In a study conducted by Siesky and colleagues ofocular blood flow in patients with primary open-angleglaucoma taking IOP-lowering medications, both brinzo-lamide and dorzolamide increased oxygen saturation in theretina and decreased the number of zero-flow pixels (indi-cating no blood flow) in the retina compared to timololalone (by 6.76� 1.7 for brinzolamide and by 0.452� 1.7for dorzolamide); brinzolamide produced 6.41 fewerzero-flow pixels than dorzolamide, which was a statisticallysignificant difference (p¼ 0.024)10. Because vascularconsiderations are important to the pathophysiology andtreatment of glaucoma, oxygen saturation and ocular bloodflow may be important measures of efficacy for ocularhypotensive drugs. While no studies are currentlypublished comparing the ocular blood flow of fixed com-binations of brinzolamide/timolol and dorzolamide/timolol, one study has compared these agents used concur-rently11. Although the authors concluded that patientstreated with dorzolamide and timolol had more favorableocular blood flow measures than those treated with brin-zolamide and timolol, an editorial revealed that the study’sflaws, which included small end-point sample size and lackof statistical power, required that the results be interpretedwith caution12. In contrast to these results, the results fromthe Siesky study suggest that brinzolamide has more favor-able ocular blood flow characteristics than dorzolamide.A large, randomized, appropriately powered study isneeded to conclusively determine which fixed-combina-tion product has the more favorable blood flow character-istics and to assess the relationship between blood flow andefficacy.

Systemic safety of brinzolamide/timolol has beendemonstrated in several randomized studies. In two ofthe randomized, controlled studies, the only systemicadverse event related to brinzolamide/timolol was dysgeu-sia, a distortion of taste, at an incidence of 3.2% in the

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Manni non-inferiority study7 and 0.8% in the Mundorfpatient preference study9. The Kaback contribution ofelements study, in which the combination therapy wascompared to each monotherapy, reported a low incidenceof treatment-related systemic side-effects (six events in apopulation of 174 patients) that included dysgeusia(n¼ 2), blood pressure decrease (n¼ 2), pharyngolaryn-geal pain (n¼ 1), and exacerbation of chronic obstructivepulmonary disease (COPD; n¼ 1)6. The COPD was theonly serious adverse event reported in patients receivingbrinzolamide/timolol. Furthermore, as noted by Hollo ina brinzolamide/timolol review13, each of these systemicevents had already been known to be associated witheither brinzolamide monotherapy or timolol monotherapy,indicating that the combination therapy produces noadditional systemic safety issues.

With respect to ocular adverse events, the brinzola-mide/timolol group from the Manni non-inferiority studyhad a significantly lower incidence of ocular irritation(burning) than the dorzolamide/timolol group (2.7 vs.10.6%, p¼ 0.0009)7. The brinzolamide/timolol groupalso had a lower incidence of ocular pain (stinging) anda higher incidence of blurred vision, but neither of theseparameters reached statistical significance. Overall, thesedata suggest that brinzolamide/timolol is more tolerablethan dorzolamide/timolol. To directly compare the com-fort of these two products, Vold and colleagues conducteda randomized study in which patients with open-angleglaucoma or ocular hypertension completed ocular dis-comfort assessments after 1 week on either brinzolamide/timolol or dorzolamide/timolol8. Mean ocular discomfortscores (from a scale of 0 [none] to 4 [very severe]) weresignificantly lower in the brinzolamide/timolol group (0.77vs. 1.53, p¼ 0.0003). Furthermore, three times as manypatients taking brinzolamide/timolol reported having noocular discomfort after 1 week of treatment (49 vs. 15%,p¼ 0.0004). Therefore, it appears that brinzolamide/timo-lol is, in fact, more comfortable than dorzolamide/timolol.This result corresponds with the lower rates ofdiscomfort for dorzolamide/timolol reported in theManni non-inferiority study7. The reason for the superiorcomfort of brinzolamide/timolol is likely due to differencesin pH; dorzolamide/timolol has an acidic pH of 5.652,whereas brinzolamide/timolol has a pH of 7.28, muchcloser to physiologic pH.

Because of the similar efficacy and increased comfort ofbrinzolamide/timolol relative to dorzolamide/timolol, itwould be predicted that patients might prefer the formerfixed-combination product. A randomized, multicenter,crossover, patient preference study conducted byMundorf and colleagues confirmed this hypothesis9.After instillation of both fixed-combination products,127 patients with open-angle glaucoma or ocular hyper-tension rated ocular discomfort of both products and chosewhich medication they preferred. Mean ocular discomfort

scores were twice as high in the dorzolamide/timolol group(2.9 vs. 1.4, p50.0001), confirming once again theincreased comfort of brinzolamide/timolol. Also consistentwith the Manni non-inferiority study results7 was theobservation that more patients receiving dorzolamide/timolol experienced ocular pain and discomfort, whilemore patients receiving brinzolamide/timolol experiencedtransient blurred vision. Of the 106 patients who expresseda preference for one medication, nearly four times as manypatients preferred brinzolamide/timolol (79.2 vs. 20.8%,p50.0001). Again, the reason for this heavily weightedpreference toward brinzolamide/timolol may be linked toits comfort and tolerability. This suggests that the blurredvision caused by brinzolamide/timolol was less trouble-some to patients than the ocular pain and discomfort ofdorzolamide/timolol.

Moreover, it is reasonable to suggest that not only doescomfort impact patient preference, but it may also havea favorable effect on patient adherence. Thisrelationship has been proposed in numerous glaucomapublications14–18.

Summary

Evidence in the literature demonstrates that the two CAI/�-blocker fixed-combination products, brinzolamide/timo-lol and dorzolamide/timolol, have similar IOP-loweringefficacies. The major difference between these two pro-ducts appears to be comfort, with patients rating brinzola-mide/timolol significantly more comfortable, likely dueto its reduced incidence of burning and stinging. Thisincreased comfort probably explains the preference ofmost patients in a recent study for brinzolamide/timololand may lead to better adherence, thus increasing thechance that patients will reach their target IOPs andmitigate disease progression.

TransparencyDeclaration of fundingPublication support was provided by Alcon Laboratories, Inc.

Declaration of financial/other relationshipsThe author has no proprietary interest in the products discussedin this manuscript, nor has any financial support been received.Peer reviewers may receive honoraria from CMRO for theirreview work. The peer reviewers have disclosed no relevantfinancial relationships.

AcknowledgmentsJennifer Klem, PhD, provided medical writing assistance, whichwas funded by Alcon Laboratories, Inc.

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