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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
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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.
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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.
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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
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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?
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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
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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 on artificial tear technology enters nasolacrimal duct
Katz. J Glaucoma . 2002.
Preservative Composition of Glaucoma Agents Brimonidine side effects Products that contain a gentle preservative, such as ® PURITE , may pose less risk to the ocular surface . • 10 20% • Do these worsen with ® ® ALPHAGAN P Allergan, Inc. 50 ppm PURITE – Hyperemia ALPHAGAN ® Allergan, Inc. .005% BAK time? – Allergic conjunctivitis BETAGAN ® Allergan, Inc. .005% BAK – Ocular pruritis LUMIGAN ® Allergan, Inc. .005% BAK Cosopt ® Merck & Co., Inc. .0075% BAK • 5 9% • How do you know if Trusopt ® Merck & Co., Inc. .0075% BAK – burning sensation, the drops are the Azopt ® Alcon .01% BAK – conjunctival folliculosis, culprit? Betoptic ® S Alcon .01% BAK – ocular allergic reaction, ® Timoptic Merck & Co., Inc. .01% BAK – oral dryness, Timoptic - XE ® Merck & Co., Inc. .012% BDD – visual disturbance Rescula ® Novartis .015% BAK Travatan Alcon .015% BAK Xalata n® Pharmacia .02% BAK
BAK: benzalkonium chloride; BDD: benzododecinium bromide
Benzalkonium Chloride (BAK) Alphagan systemic side effects
• Most commonly used preservative in • Dry mouth (~20%) glaucoma products • Fatigue (1 2%) • BAK can accumulate and remain in ocular • Drowsiness tissue • Decreased BP –Has been shown to cause cytotoxic effects on the ocular surface in numerous studies (DeSaint, 2000; Gasset et al, 1974; Noecker, • This drug can cross blood brain barrier, 2004) esp in older and younger pxs
DeSaint et al. Curr Eye Res . 2000; Gasset et al. Am J Ophthalmol . 1974; Noecker et al. Cornea. 2004.
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Brimonidine questions CAI Side Effects
• What is the correct dosage? • ***Stinging*** • Which of the 3 products should be • **Dryness** prescribed? • HA • Can it be used as stand alone therapy? • Bad taste • Effect on diurnal curve? • Sulfa drug so: – Aplastic anemia? – Renal stones? • What about Cosopt?
Carbonic anhydrase inhibitors Oral CAI side effects
• Lower IOP by reducing aqueous production • Paresthesia • Depression • Reduce IOP by 16 22% • Kidney stones • Metallic taste • Sulfa drugs!! • Diarrhea • Dosage question – BID or TID? • Aplastic anemia
• Are they useful as stand alone drugs? • These are virtually non existent with drops
CAI directory CAIs make wonderful partners
• Trusopt – Dorzolamide 2% • Feldman, et al 2006 – • 1.5 1.8 mm lower IOP as compared to • Azopt Brinzolamide 1% brimonidine 0.15% when added to travaprost • Oral CAI • This significance was present at all time points – Acetazolamide – Diamox 250, 500mg – Methazolamide – 25, 50mg • BID dosing
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Companion study #2 Combination drugs
• When compared to brimonidine 2% adding • Cosopt – timolol dorzolamide them to Travaprost... • Timolol ½%, Dorzolamide 2% • IOP lowered by 13% w/ brimonidine • This drop works better than either timolol • IOP lowered by 23% w/ brinzolamide or dorzolamide does on their own • Cosopt is not as effective as if you were using both timolol and dorzolamide • Same side effects as beta blockers and CAIs • Capice? Kapeesh?
Companion study #3 New Combo Drugs
• Stewart et al, 2006 • Extravan – Travaprost 0.004%/Timolol • Compared to timolol 0.5% as additive to 0.5% travaprost • No difference at all between the 2 drugs • Combigan – Bimatoprost/Timolol 0.5% • CAI is effective at controlling night IOP spikes (TID?) • What do we know about these?
Oral CAI Extravan
• Is there still a place for them? • Dosed QD – generally in AM • Barneby study • What is the correct dosage? – Lowered IOP 2 3mm more than T ½ alone – Lowered IOP 1 2mm more than Trav alone • Are there precautions we need to take? – Statistically significant in 7 0f 9 time points
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The Glaucoma Treatment Universe Extravan 2008 • Schuman Study • Prostaglandins • Beta blockers – QD dosing in AM • Alpha –agonist • Cardioselective beta – Lowered IOP 7 9mm • CAI blockers – Similar IOP drop if used Travatan and T ½ • Combo drugs • ALT/SLT concommitantly • Ginkgo , etc • Trabeculectomy – Consistent throughout day and for 3 months • Nutrition issues – Hyperemia – 14.3% w/ Extravan – 23.4% w/ T ½ and Trav concommitantly
Eric’s 7 Simple Rules For Regarding Prostaglandins: Treatment 1. Choose 30% IOP decrease as initial • Generally the 1 st line of treatment target • There are interindividual differences in 2. Squash the diurnal curve (Keep IOP peak efficacy <18mm) • Are there racial differences? 3. Assess risk factors for progression and • If at first one fails; try, try , try again (with rate of progression another prostaglandin) (CT<555, IOP >26,C/D 0.5) • Why wouldn’t you use a prostaglandin 1 st ?
Eric’s Rules cont. Treatment paradigm – Step 2
4. If you are going to treat; treat aggressively • Prostaglandins 1 st • If not successful – try another agent by 5. KISS itself: Brimonidine bid or timolol • If neither of these get IOP to desired level 6. Be mindful of perfusion issues then add
7. Above all, do no harm
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Many Patients Require Treatment paradigm, part IV Adjunctive Therapy • If on 2 meds and target IOP not met • Ocular Hypertension Treatment Study (OHTS) 1 rd – 817 patients with OHT; target pressure reduction = 20% – 1. Consider 3 drop (Betoptic S or CAI) – At month 60 visit, 39.7% of patients in the medical treatment – 2. Substitute Combo drug for least successful drop group required 2 or more medications to reach the target IOP – 3. Consider ALT or SLT • Collaborative Initial Glaucoma Treatment Study • What is maximum medical therapy nowadays? (CIGTS) 2 – 307 newly diagnosed patients with mild to advanced • SLT/ALT and trabeculectomy should not be glaucoma; aggressive target pressures set per formula considered weapons of last choice or last – After first 2 years, >75% of patients required 2 or more chance medications to reach target IOP • Even patients on the most powerful IOP lowering medications often require adjunctive therapy 3
1. Kass et al. Arch Ophthalmol. 2002; 2. Lichter et al. Ophthalmology . 2001. 3. Robin et al. AGS . 2003.
Consider Mechanism of Action (MOA) When Adding Medications • Best chance of additivity by combining medications with different mechanisms • Hypotensive lipids lower IOP by increasing aqueous outflow (uveoscleral/trabecular) • Complement a hypotensive lipid by adding a drug that inhibits aqueous production – Brimonidine – CAI – Beta blocker
Treatment Paradigm, Part III
1.Prostaglandins alone 2. Brimonidine or beta blocker alone 3. Prostaglandin + beta blocker or brimonidine or CAI (unless 1 of these absolutely sucked!) 4. Consider Cosopt or Combigan if (3) is not successful
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