Better ophthalmic surgery outcomes in recent years have created more Demanding Patients.

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1 By Alaa EL Zawawi Prof. of Ophthalmology Alexandria - Egypt Launch Better ophthalmic surgery outcomes in recent years have created more Demanding Patients. 1

2 NSAIDs can play a pivotal role in facilitating cataract surgeries, getting a better visual outcome with a rapid and safe convalescence. NSAIDs can optimize the surgical experience for patients undergoing PRK and LASIK. 2

3 1. Maintain pupillary dilatation during cataract surgery. 2. Prevention and management of post operative inflammation. 3. Prevention and management of post operative cystoid macular edema. 4. Management of pain in PRK patients. Phospholipids Inhibited by Corticosteroids Phospholipase A 2 Arachidonic Acid Inhibited by NSAIDs Cyclooxygenase Lipoxygenases Endoperoxides (PGG 2 PGH 2 ) Leukotrienes Thromboxane A 2 PGE 2 PGF 2α PGD 2 Prostacyclin (PGI 2 ) Jampol LM. Pharmacologic therapy of aphakic cystoid macular edema. Ophthalmology. 1982; 80:

4 NSAIDs help to maintain pupillary dilatation during cataract surgery. Miosis may obstruct surgeon s view during cataract surgery, thus creating a hindrance to the surgical procedure 1 Miosis associated with increased complications and posterior capsular rupture 1 When dosed preoperatively, NSAIDs play significant role in decreasing intraoperative miosis 2 Courtesy of University of Pittsburgh Visual Imaging 1. Guzek JP, Holm M, Cotter JB, et al. Risk factors for intraoperative complications in 1000 extracapsular cataract cases. Ophthalmology. 1987; 94: Stewart R, Grosserode R, et al. Efficacy and safety profile of ketorolac 0.5% ophthalmic solution in the prevention of surgically induced miosis during cataract surgery. Clin Ther. 1999; 21:

5 Recommended NSAID Dosing At-Risk Patients Preoperative: 1 week Postoperative: 4 weeks to several months Not At-Risk Patients Preoperative: 1-2 Days Postoperative: 4 weeks CME is the most frequent cause of visual decline following uncomplicated cataract surgery Normally occurs 4 to 6 weeks post-op Studies show CME occurs in up to 12% of cases 1. O Brien TP. Emerging guidelines for use of NSAID therapy to optimized cataract surgery patient care. Curr Med Res & Opin. 2005;21:

6 Angiographic CME May not be associated with significant visual loss, but fluorescein angiographic evidence of macular edema Clinical CME Described as vessel leakage associated with visual acuity of 20/40 or worse Today s definition is becoming stricter (20/25 or worse) due to higher patient expectation. Heier JS, Topping TM, et al. Ketorolac vs prednisolone vs combination therapy in treatment of acute pseudophakic cystoid macular edema. American Academy of Ophthalmology. 2000;107: Can measure even subtle postoperative retinal thickening Gaining popularity for diagnosis of CME Along with contrast sensitivity test Heier, JS. Preventing post-cataract extraction CME: Early identification of patients at risk and prophylactic treatment may avert vision loss. Ophthalmology Management. 2004; Courtesy of University of Pittsburgh Visual Imaging 6

7 Pre-existing ocular inflammation Epi-retinal or vitreo-retinal interface membrane problems Diabetic retinopathy Patients suffering from ocular vascular or cardiovascular disease Patients with history of retinitis pigmentosa Prophylaxis should be started earlier and extended longer for high-risk patients 1 1. Heier, JS. Preventing post-cataract extraction CME: Early identification of patients at risk and prophylactic treatment may avert vision loss. Ophthalmology Management. 2004; Operative Irritation/Inflammation Aging Systemic Vasculopathy Glaucoma Prostaglandins in Aqueous & Vitreous Breakdown of the Blood Aqueous Barrier & Blood Retina Barrier Cystoid Macular Edema Adapted from Miyake K, et al. Jpn J Ophthalmol. 2000;44:

8 Patients expectation have changed. They now expect excellent vision immediately. In the era of multifocal IOLs even a very mild CME will reduce the performance of the lens, thus it is mandatory with these IOLs to avoid CME in the post operative period. 8

9 Topical NSAIDs are effective in preventing postsurgical angiographic CME 1 NSAID therapy also shown to have beneficial effect on visual function 1 Critical to achieve therapeutic concentrations in posterior chamber to maximize effect of NSAID therapy on target tissue - retina 2 Steroids alone do not effectively prevent or treat CME 3 1. Samiy N, Foster CS. The role of nonsteroidal antiinflammatory drugs in ocular inflammation. Int Ophthalmol Clin. 1996;36: Gaynes ESOIRS BI, Fiscella 2012 R. Topical nonsteroidal antiinflammatory drugs for ophthalmic use: a safety review. Drug Saf. 2002;25: McColgin AZ, Raizman MB. Efficacy of topical Voltaren in reducing the incidence of post operative cystoid macular edema. Invest Ophthmol Vis Sci. 1999;40:S289. Patients undergoing cataract surgery (N = 60) Group 1: Post-Op NSAID + Corticosteroid NSAID + NSAID Corticosteroid -2 Day -1 Day Day of Surgery Week 1 Week 2 Week 3 Week 4 Group 2: Post-Op Corticosteroid alone NSAID Corticosteroid -2 Day -1 Day Day of Surgery Week 1 Week 2 Week 3 Week 4 McColgin AZ, Raizman MB. Efficacy of topical Voltaren in reducing the incidence of post operative cystoid macular edema. Invest Ophthalmol Vis Sci.1999;40:S289. 9

10 Proper dosing of NSAIDs maximizes success and minimizes complications Proper dosing includes: Dosing 4 weeks post-op in cataract patients to prevent CME Limit dosing in a compromised cornea... this includes PRK In PRK, NSAIDs should be dosed 3-4 times a day while the patient experiences pain (2-3 days) and then discontinued Avoid NSAIDs in patients with severe dry eye Routine-Risk Patients Preoperative 4 times daily for 2-3 days. Post operative: 4 times daily for 4 weeks. Higher-Risk Patients Preoperative 4 times daily for 1 week. Post operative: 4 times daily for 4 weeks to several months. 10

11 They are excellent pain control for PRK and PTK patients. Recommended NSAID Dosing LASIK Dry stromal bed for 1 minute, Remove speculum, Dose post-operatively Surface Ablation Dose after bandage contact lens Dose post-operatively for 2-3 days NSAIDs in refractive surgery used primarily for analgesic effect Immediate post-op use NOT to be dosed for the entire epithelial wound healing process 1. Colin J, Paquette B. Comparison of the analgesic efficacy of nepafenac ophthalmic suspension compared with diclofenac ophthalmic solution for ocular pain and photophobia after excimer laser surgery: A phase II, randomized, double-masked trial. Clinical Therapeutics. 2006, in press. 2. Yee RW, Ketorolac ESOIRS Radial Keratotomy 2012 Study Group. Analgesic efficacy and safety of nonpreserved ketorolac ophthalmic solution following radial keratotomy. Am J Ophthalmol 1998;125: VOLTAREN* US Prescribing Information *Trademark is the property of its owner. 11

12 Ability to penetrate target intraocular tissues at therapeutic levels: Aqueous humor: cell/flare reduction Posterior segment: CME prevention Excellent anti-inflammatory efficacy Excellent analgesic properties Safe and comfortable A Novel Class of Non-Steroidal Anti-Inflammatory Therapy 12

13 Indication: Treatment of pain and inflammation following cataract surgery Dosing: One drop TID one day pre-op, DOS, 14 days post-op Formulation: First and only ophthalmic non-steroidal prodrug Preservative: 0.005% BAK ph: 7.4 (physiologic) Nepafenac Amfenac Nepafenac is converted to a potent cyclooxygenase inhibitor, amfenac, by intraocular hydrolases Ke TL, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: II. In vitro bioactivation and permeation of external ocular barriers. Inflammation. 2000;24:

14 Optimizes Activation Upon ocular dosing, nepafenac metabolized by intraocular tissues 1 Target-Specific Efficacy Nepafenac is converted into amfenac for optimal efficacy 2 Retina/choroid» iris ciliary body > cornea 2 Amfenac Amfenac Amfenac 1. Gamache DA, et al. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: I. assessment of antiinflammatory efficacy. Inflammation. 2000;24: Ke TL, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: II. In vitro bioactivation and permeation of external ocular barriers. Inflammation. 2000;24: Minimizes toxicity Ocular surface complications associated with conventional NSAID therapies may be minimized Drug rapidly distributes into anterior and posterior segments 1 Cornea, anterior and posterior chamber safety demonstrated in vivo via slit-lamp biomicroscopic examination in two long-term pre-clinical studies 2,3 3-month study and 6-month study Minimal systemic absorption 4 1,700x less than single oral dose 1. O Brien TP. Emerging guidelines for use of NSAID therapy to optimized cataract surgery patient care. Curr Med Res & Opin. 2005; 21: Walker et al. Ocular effects of nepafenac ophthalmic suspension following three months of topical ocular administration to cynomolgus monkeys, presented at The Association for Research in Vision and Ophthalmology, May 2005, Fort Lauderdale, Florida 3. Heaton et al. Ocular effects of nepafenac ophthalmic suspension following six months of topical ocular administration to pigmented rabbits presented at The Association for Research in Vision and Ophthalmology, May 2005, Fort Lauderdale, Florida. 4. NEVANAC Suspension US Prescribing Information 14

15 Degree of Corneal Permeation of Various NSAIDs Ketorolac Bromfenac Diclofenac Nepafenac Corneal Permeability (cm/sec x 10-5 ) Lindstrom R, Kim T. Nepafenac: ocular permeation and inhibition of retinal inflammation: an examination of data and opinion of clinical utility. Curr Med Res & Opin.2006;22: Evaluation of Analgesic Effect Following PRK Purpose Evaluation of safety/efficacy of nepafenac 0.1% ophthalmic suspension vs. diclofenac 0.1% Reduction of pain associated with PRK Methods 60 patient, multi-center, randomized, doublemasked, parallel groups Dosing: 2 drops preoperatively, 1 drop one hour after surgery, QID postoperatively for 2 days Colin J, Paquette B. Comparison of the analgesic efficacy of nepafenac ophthalmic suspension compared with diclofenac ophthalmic solution for ocular pain and photophobia after excimer laser surgery: A phase II, randomized, double-masked trial. Clinical Therapeutics. 2006, in press. 15

16 Percentage of Patients with Complete Reepithelization Pain Scores 6/10/2012 Severe None Day 1 - am Day 1 - noon Day 1 - pm Day 1 - Bedtime Day 2- am Day 2 - noon * Day 2 - pm n=20 n=20 * Day 2 - Bedtime Nepafenac 0.1% Diclofenac 0.1% *p = Colin J, Paquette B. Comparison of the analgesic efficacy of nepafenac ophthalmic suspension compared with diclofenac ophthalmic solution for ocular pain and photophobia after excimer laser surgery: A phase II, randomized, double-masked trial. Clinical Therapeutics. 2006, in press. 100 PRK Epithelial Healing Results Nepafenac 0.1% Diclofenac 0.1% Day 3 Day 7 Colin J, Paquette B. Comparison of the analgesic efficacy of nepafenac ophthalmic suspension compared with diclofenac ophthalmic solution for ocular pain and photophobia after excimer laser surgery: a phase II, randomized, double-masked trial. Clinical Therapeutics. 2006, in press. 16

17 Inhibition & Treatment of Post-Operative Inflammation Results demonstrate the superior pharmacodynamics and longer duration of action of nepafenac 0.1% Covalently bound nepafenac molecule increases corneal permeability coefficient and drug distribution within ocular tissue Overall, nepafenac 0.1% exhibits superior anti-inflammatory properties vs conventional NSAIDs such as diclofenac 0.1% Gamache DA, et al. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of traumainduced ocular inflammation: I. assessment of anti-inflammatory efficacy. Inflammation. 2000;24:

18 % Cures by Visit 6/10/2012 Purpose Efficacy evaluation of NEVANAC Ophthalmic Suspension in decreasing pain and inflammation following cataract surgery Methods Multi-center, vehicle-controlled, randomized, doublemasked (n=476) Dosing: TID 1 day preoperatively, day of surgery, 14 days postoperatively Additional topical or systemic anti-inflammatory medications excluded from protocol Lane SS, Modi SS, Holland EJ, et al. Nepafenac ophthalmic suspension 0.1% before and after surgery for postoperative anterior segment inflammation. Paper presented at: American Society of Cataract and Refractive Surgery; April 18, 2005, Washington, DC. 70% 60% 50% 40% 30% 20% 10% 0% * * * * * * Day 1 Day 3 Day 7 Day 14 NEVANAC Suspension Placebo *P Lane SS, Modi SS, Holland EJ, et al. Nepafenac ophthalmic suspension 0.1% before and after surgery for postoperative anterior segment inflammation. Paper ESOIRS presented 2012 at: American Society of Cataract and Refractive Surgery; April 18, 2005, Washington, DC. 18

19 % of Patients Pain-Free Concentration (ng/m 6/10/ % 80% * * * * 60% 40% 20% 0% Day 1 Day 3 Day 7 Day 14 NEVANAC Suspension Placebo *P < 0.05 Lane SS, Modi SS, Holland EJ, et al. Nepafenac ophthalmic suspension 0.1% before and after surgery for postoperative anterior segment inflammation. Paper presented at: American Society of Cataract and Refractive Surgery; April 18, 2005, Washington, DC hr 0.5 hr 1 hr 2 hr 3 hr 4 hr Bromfenac Ketorolac Amfenac Nepafenac Nepafenac + Amfenac Commercial nepafenac 0.1% suspension (amfenac plus nepafenac) demonstrated significantly greater ocular bioavailability of drug than either ketorolac 0.4% or bromfenac 0.09% solutions Walters TR, Raizman M, Ernest P, Gayton J, et al. In Vivo Pharmacokinetics and In Vitro Pharmacodynamics of Nepafenac, Amfenac, Ketorolac, and Bromfenac. Journal of Cataract and Refractive Surgery. September 2007 Trademark is the property of its owner 19

20 Prevention of Cystoid Macular Edema Uniform potent inhibition Uniformly targets cyclooxygenase of intraocular tissue Affects all ocular blood barriers Arachidonic acid pathway similarity Uniformly inhibits all prostaglandins of the ICB Inhibits retina PGE 2 synthesis Inhibits BRB breakdown Gamache DA, et al. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: I. assessment of anti-inflammatory efficacy. Inflammation. 2000;24:

21 Change in Vitreous Humor PGE 2 pg/ml 6/10/ Nepafenac 0.1% Diclofenac 0.1% Ketorolac 0.5% * *p< Lindstrom R, Kim T. Nepafenac: ocular permeation and inhibition of retinal inflammation: an examination of data and opinion of clinical utility. Curr Med Res & Opin. 2006;22: Kapin MA, Yanni JM, Brady MT, et al. Inflammation-mediated retinal edema in the rabbit is inhibited by topical nepafenac. Inflammation. 2003;27: Conclusions Nepafenac 0.1% exhibits superior pharmacodynamic properties in the posterior segment following ocular dosing Unique therapeutic potential for a variety of conditions associated with retinal edema Diclofenac 0.1% and Ketorolac 0.5% were ineffective in reducing inflammation in the posterior segment. Kapin MA, Yanni JM, Brady MT, et al. Inflammation-mediated retinal edema in the rabbit is inhibited by topical nepafenac. Inflammation. 2003;27:

22 NEVANAC Suspension has been proven safe and well tolerated throughout ocular tissues with no delays in wound healing compared to placebo in animal models 1,2,3 Ocular safety of Nepafenac has been confirmed in pre-clinical studies 1,2,3 : Concentrations up to 1.5% (15x commercial concentration) Dosing regimens up to 2 drops QID Treatment duration up to 6 months 11 completed clinical studies to date n = 891 across all Nepafenac patients Low incidence of adverse events Occurred at rate similar to vehicle No burning or stinging reported in phase III trials 4,5 1. Walker et al. Ocular effects of nepafenac ophthalmic suspension following three months of topical ocular administration to cynomolgus monkeys. Poster presented at Association for Research in Vision and Opthalmology; May 3, 2005, Fort Lauderdale, Florida. 2. Heaton et al. Ocular effects of nepafenac ophthalmic suspension following six months of topical ocular administration to pigmented rabbits. Poster presented at Association for Research in Vision and Opthalmology; May 3, 2005, Fort Lauderdale, Florida. 3. McGee et al. Ocular effects of nepafenac ophthalmic suspension in new zealand white rabbits undergoing partial corneal incisions. Poster presented at Association for Research in Vision and Opthalmology; May 3, 2005, Fort Lauderdale, Florida. 4. Lane, Holland et al. Nepafenac ophthalmic suspension 0.1% before and after surgery for postoperative anterior segment inflammation. Poster presented at: American Society of Cataract and Refractive Surgery; April 18, 2005, Washington, DC. 5. Stewart WC et al. Preoperative and postoperative clinical evaluation of nepafenac 0.1% ophthalmic suspension for postcataract inflammation. Poster presented at: American Society of Cataract and Refractive Surgery; April 18, 2005, Washington, DC. 22

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