1/6/2014 PGAs • QHS dosing • Long duration of action Glaucoma Pharmacology A-Z • Flatten diurnal curve • Effective on trough and peak IOP Eric E. Schmidt, O.D. • No systemic side effects Omni Eye Specialists Wilmington, NC • Little tachyphylaxis [email protected] Selecting Therapy PGAs 2008 • Goals of primary therapy • Bimatoprost (Lumigan) – Achieve lowest IOP on monotherapy – High response rate—few to no nonresponders • Latanoprost (Xalatan) – Maintain consistent IOP lowering – Obtain patient compliance and adherence by meeting their goals and expectations • Travaprost, Travaprost Z (Travatan, Travatan Z) • Building-block approach to medical therapy – Establish the strongest foundation prior to resorting to adjunctive therapy Prostaglandin analogs Prostaglandin Side Effects • Lower IOP by enhancing uveoscleral • Conjunctival hyperemia: Severe outflow hyperemia • They also reduce episcleral venous – Lumigan 3.5% – Travatan 1.5% pressure – Xalatan <1% – Rescula 1% • PGAs work by causing up to a 26% • Is this a transient phenomenon? reduction in resistance to outflow • Is it an allergic conjunctivitis? • Breaks down collagen in the uveoscleral • Is it worth stopping the drop? meshwork • Create new channels for outflow 1 1/6/2014 Conjunctival hyperemia Prostaglandins • PGAs have an effect on EP receptors • Oh sure, we know they are good, but just which are vasodilators how good are they? – Average IOP drop of 34% • The stronger the drug binds to that – Improved compliance receptor the more pronounced the – Excellent safety profiles vasodilation effect will be. • In general, PGAs are the initial therapy of • Will switching from 1 PGA to another choice. decrease the hyperemia effect? Clinical Comparison Trials Prostaglandin Side Effects of the Once-Daily Lipids • Iris pigmentation • Evaluation of intra-class differences in – Is it reversible? – Is it pre-cancerous? efficacy and safety • Xalatan – 6.7% @ 6mths • Seven published, prospective, 16% @ 12mths randomized, investigator-masked, parallel- • Travatan – 3% @ 12 mths • Lumigan – 1.9% @ 12mths group studies • Rescula – 1 patient • Trials varied in duration, patient selection and characteristics, and methods of data • SO? analysis Other Prostaglandin side effects Bimatoprost and Travoprost • CME Parrish et Cantor et Noecker et • Uveitis al, al, al, 2003 † • Reactivation of HSK 2003 * 2005 • Hypertrichosis Sponsor Pfizer Allergan Allergan • Periorbital skin darkening Length 12 weeks 3 months 6 months Bimatopro n = 136 n = 16 n = 76 st • One must take into consideration the benefits of Travopros*Parrish et al also included studyn = arm 138 with bimatoprost (n n = =136 15). n = 81 †Study population comprised of African-American patients. low IOP with the risks of the side effects t (0.004%) Latanopro n = 136 st Parrish et al. Am J Ophthalmol . 2003; Noecker et al. Adv Ther . 2003; Cantor et al . B J Ophthalmol. 2006. 2 1/6/2014 Bimatoprost and Travoprost: Bimatoprost and Latanoprost+Timoptic- ® 12-Week Study XE : 6-Month Study Mean IOP at Week 12 Mean Diurnal IOP Over 6 Months 24 30 Latanoprost + Timoptic-XE ® (n = 28) 20 25 Bimatoprost (n = 28) 16 20 12 15 Travoprost (n = 138) 10 8 Bimatoprost (n = 136) Baseline mean diurnal IOP comparable between groups Mean IOP (mm Mean (mm IOP Hg) Mean IOP (mm Mean (mm IOP Hg) Bimatoprost 23.5 mm Hg 5 4 Baseline mean IOP comparable between groups Latanoprost / timolol gel 24.1 mm Hg Travoprost: 25.5, 23.8, 22.8, 22.0 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg) Bimatoprost: 25.7, 23.8, 22.8, 22.3 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg) 0 0 0 30 60 90 120 150 180 8 AM 12 PM 4 PM 8 PM Time of Day Day of Treatment Parrish et al. Am J Ophthalmol . 2003. Manni et al. Graefe’s Arch Clin Exp Ophthalmol . 2004. Bimatoprost and Travoprost: 6-Month Safety Results Prostaglandins • Both medications were well tolerated • All decrease IOP by increasing • Most common adverse event: ocular redness uveoscleral outflow – 16 patients (20.8%) in the bimatoprost group and 12 patients • All are effective at squashing the diurnal (14.8%) in the travoprost group ( P = .326) curve • Ocular itching reported for 7.4% of travoprost • They have either no effect or a positive patients and 2.3% of bimatoprost patients ( P = .278) effect on retinal perfusion • Treatment-related adverse events leading to patient • But does 1 work better than the others? discontinuations – 8 patients in the travoprost group exited early: 4 for lack of efficacy, 2 for ocular redness and lid erythema, 1 for ocular dryness and itching, and 1 for allergic symptoms – 2 patients in the bimatoprost group exitedCantor early: et al. Br1 J foOphthalmolr blurry. In press. Bimatoprost and Latanoprost: IOP reducing effect 6-Month Safety Results • Most common side effects: • According to package inserts: – Hyperemia (bimatoprost 44.4%; latanoprost – Latanoprost – 6.7mm 20.6%) – Unoprostone – 3-4mm • Similar rates of discontinuation due to AEs – Bimatoprost – 8.1mm – Bimatoprost: 4.5% overall; 2.3% for – Travaprost – 7.1mm hyperemia – Latanoprost: 3.7% overall; 0.0% for hyperemia • Uveitis: One patient in latanoprost group; no cystoid macular edema Noecker et al. Am J Ophthalmol . 2003. 3 1/6/2014 XLT Study – Parrish, Palmberg, et. al. Look at their failure rate: (AJO, May 2003, Vol. 135, No.5) • Multicenter study to compare IOP lowering • Percent of pxs who didn’t reach their efficacy of Bimatoprost vs Latanoprost vs target IOP Travaprost – Latanoprost – 14% • Also compared safety profiles of the 3 – Bimatoprost- 6% drugs – Travaprost – 8% • Conclusions: All 3 drugs were comparable in their ability to lower IOP at all time • SO? periods. – Latanoprost exhibited greater ocular tolerability Another way to look at efficacy: What If: • % of IOP reduction – • A patient failed on Xalatan? – Latanoprost – 27% – Unoprostone – 15% • If switched to Lumigan, 57% achieved – Bimatoprost – 33% target IOP – Travaprost – 28% • If switched to Travatan, 45.5% achieved target IOP • FYI: Timolol 24% • SO?- Are all prostaglandins really created eQual? What is their ability to lower IOP Bournias, et.al , Journal of Ocular <17mm? Pharmacology (2003) • Latanoprost – 49.5% of pxs • Replaced Xalatan w/ Lumigan • Bimatoprost – 64% • Results: • Travaprost – 56.3% – IOP <15mm dropped from 11% to 36% – IOP <18mm dropped from 33% to 66% – Mean IOP decrease of 3.4mm 4 1/6/2014 Final prostaglandin thoughts Beta-blocker side effects • They are additive to other G drugs but not • Respiratory- with each other – Fatigue, bronchospasm, SOB! • Travatan and Lumigan maintain target IOP • Cardiac – 36hrs after instillation and significant IOP – Lethargy, bradycardia, lower pulse rate drop up to 84 hrs after instillation • CNS depression- • Does one really work better than the – Impotence, confusion others on African –Americans? • But how common are they? • What about BID dosing? Beta-blockers Lama study (AJO 11/02) • 30 year history of successfully lowering IOP • Conclusions: – ...identifies no scientific studies supporting the • Reduces aQueous humor formation development of worsening claudication, depression, hypoglycemia,sexual dysfunction • Adrenergic agonists or impaired neuromuscular transmission – Recommends careful medical history and • Lowers IOP 22-28% checking pulse rate and rhythm • So? • Ocularly well tolerated Beta-blockers Beta-blocker side effects • Timolol maleate – Timoptic, Timoptic XE • Cardiac problems • Respiratory problems (1/2, 1/4 %) – Bradycardia – Bronchospasm – Hypotension – Status asthmaticus • Carteolol – Ocupress 1% (Intrinsic – Exercise intolerance sympathomimetic activity) – Heart block • Levobunolol – Betagan ½% • Timolol hemihydrate – Betimol ¼, ½% • Istalol ¼,1/2% - QD dosing indication • Betaxolol ¼% - cardioselective, safer? 5 1/6/2014 Beta-blocker side effects Adrenergic Agonists • CNS • Diabetic problems • Dual mechanism of action – Often overlooked – Decreased sense of 1. Reduce aQueous production – ACID caloric need due to 2. Enhance outflow mechanisms • Anxiety depressed adrenergic • Confusion surge • 22-28% IOP reduction • Impotence • Depression • Short duration of action – General decreased • TID dosage affect • Avoid in kids Beta-blocker side effects Mechanism of Action of Brimonidine-PURITE ® • 22% of pxs have contraindication to or • Complements lipids because it decreases significant side effect from beta-blocker aQueous production • Question, Query and Query some more! • Complements timolol because it increases • Be specific uveoscleral outflow • Remember the dose relationship so: – ¼% rather than ½% – QD rather than BID • They are real (may be anecdotal) Beta-blocker debate Brimonidine Formulation Comparison • Are they still useful? • As initial therapy? ALPHAGAN ® P ALPHAGAN ® • QD or BID? Concentration 0.1% 0.15% 0.2% • 0.25% or 0.5%? of Brimonidine • Gel or drop? pH 7.7 7.2 6.3-6.5 • Monocular therapy? ® • How bad are the side effects really? Preservative PURITE BAK • Do systemic beta-blockers affect the efficacy of the Viscosity agent Carboxymethylcellulose Polyvinyl alcohol drops? Potassium chloride, calcium chloride Electrolytes – • Tell me something good about beta-blockers! dihydrate, magnesium chloride hexahydrate 6 1/6/2014 Brimonidine-PURITE ® Effect of Brimonidine-PURITE ® 0.15% Development Strategy Formulation on Safety • Improved formulation • Ocular surface exposed to 25% less –Enhance tolerability drug with new formulation –Maintain efficacy –Less allergy, redness, irritation • Lower concentration also means –Alternative preservative to BAK fewer systemic effects as less drug –Vehicle based