Eye drops for glaucoma – past, present and future Jonathan G Crowston MBBS, FRCOphth, FRANZCO, PhD MD, Centre for Eye Research Australia

No financial interests in any of the commercial products mention. Consultant/ Scientific Advisory Boards: Alcon Allergan Annexon AusBio Pfizer MSD Polyactiva Seagull Technologies Santaris

Castor seeds (4000 – 2000 BC) Georgi Markos

The Ebers Papyrus Kohl, Antimony 1553 BC

Glaucoma drops 1950 Alexander and Connor

Glaucoma Therapeutic Timeline Neuroprotection Gene transfer Immunotherapy SiRNA’s Betagan Betoptic Timoptic Pilocarpine Propine But what has the clinician historically had available to address these concerns? Up until the 1970s, relatively little. And what was available was generally of only moderate efficacy by today’s standards, presented unacceptable side effects—if not toxicity—in a large percentage of patients, and required less convenient QID dosing. The introduction of topical dipivefrin in the early 1970s was a significant step forward. Its twice-daily dosing was more convenient, and it proved more effective and better tolerated than the epinephrine from which it was derived. Another significant advance was the ophthalmic beta-blockers, introduced in the late 1970s. Nonselective beta-blockers combined effective IOP management with convenient twice-daily dosing—though they still posed cardiopulmonary side effects in some patients. Selective beta-blockers proved safer, but were so at the expense of efficacy. The 1990s was a decade of great change for glaucoma treatment. Topical carbonic anhydrase inhibitors were introduced that were safer and more effective than their systemic predecessors. Prostaglandins were introduced one of which proved highly effective at managing IOP in many—though not all—patients. And some established products released extended-action formulations that improved convenience. Finally, the 1990s was the decade in which one second-generation 2 agonist was proven exceptionally safe, highly effective at suppressing intraocular pressure, and perhaps most significantly, showed strong evidence of neuroprotection. Since the 1870s, glaucoma therapy has made significant strides in IOP management, ocular and systemic safety, patient convenience, and now—in addressing the fundamental mechanism of visual loss from glaucoma—optic neuropathy. 1870s ‘80s ‘90s 1900s ‘10s ‘20s ‘30s ‘40s ‘50s ‘60s ‘70s ‘80s ‘90s 2000 2010 2020 Alphagan Azopt Betoptic-S Cosopt Iopidine Trusopt Xalatan Travatan Lumigan Diamox Epinephrine Combigan Xalacom DuoTrav GanFort

An uncomfortable truth! Persistence with topical glaucoma medication 50% discontinued all drops by 6 months 37% of pts refilled at 3 years Only 10% had no gaps in refill rate Nordstrom and Friedman AJO 2005

Fixed combinations Xalacom – Xalatan + Tim DuoTrav – Travatan + Tim Ganfort – Lumigan + Tim Cosopt – Trusopt + Tim Combigan – Alphagan + Tim Azarga – Azopt + Tim Simbrinza – Alphagan and Azopt

RVEEH/ CERA Melbourne prospective case-control study POAG vs controls (mean age 66yrs , 33% single med) Significant increase in signs and symptoms in POAG vs controls POAG n=300 Controls n=100 Symptoms 31% 24% Signs 71% 33% Validated 7pt questionnaire (Shihpai) TBUT <5sSchirmer <5mmMGD testFluoresceine stain (CCLRU) S. Ghosh et al. CLEO 2012

Predictors of OSD signs in glaucoma No. of MEDICATIONS OR 2.31 (1.49-3.57) DURATION of THERAPY  OR 1.08 (1.03-1.14) S. Ghosh CLEO 2012

Benzalkonium Chloride (BAK) Generic (Trade Name) Preservative Brimonidine (Alphagan1) 0.005% BAK Brimonidine with Purite (Alphagan P1) 0.005% SOC Brinzolamide (Azopt 1) 0.01% BAK Levobunolol (Betagan1) Betaxolol (Betoptic S Suspension1) Dorzolamide/Timolol (Cosopt1) 0.0075% BAK Bimatoprost (Lumigan2) Timolol (Timoptol1) Timolol (Timoptol-XE1) 0.012% BDD Travoprost (Travatan3) 0.015% BAK Dorzolamide (Trusopt1) Latanoprost (Xalatan1) 0.02% BAK For most glaucoma agents that we use there are 2 constituents. The active drug and the preservative to keep bottles free of microbes Alkyldimethylbenzylammonium chloride BAK: Benzalkonium chloride; BDD: Benzododecinium bromide ; SOC: Stabilized Oxychloro Complex

BAK other uses

Preservative-free drops Lumigan, Ganfort (PF) Saflutan (PF) BAK free

Glaucoma Australia www.glaucoma.org.au

The washout effect % Loss of 1st Drug Besides a decrease in the percentage of patients who are compliant, other potential problems can develop with patients on multiple medications. Although we ask patients to wait a minimum of 5 minutes between dosing different medications, how many actually do this? This slide demonstrates the issue of “washout effect”. If patients only wait 30 seconds between dosing medications, up to 45% of the first medication can be washed out by the second. If the patient waits two minutes, 17% of the first medication is washed out. Patients should wait at least 5 minutes, to eliminate the potential to washout the first medication. 1 1. Chrai SS, Makoid MC, Eriksen SP, Robinson JR. Drop size and initial dosing frequency problems of topically applied ophthalmic drugs. J Pharm Sci. 1974;63(3):333-338. Chrai SS, Makoid MC, J Pharm Sci. 1974; 63(3): 333-338.

Double Dot technique Don’t Open eyes Technique and Digital Occlusion Tear duct Ivan Goldberg

Eye drop aids

Glaucoma drug delivery

Future eye drops Nerve protection

Thank you Maggie McNeil Val Scaf