Nepafenac CME - Post operative Pain & Inflammation

1. Post operative pain &
Inflammation Management
Nepafenac 0.1% In

2. Cataract : The Sneaky Blurry Villain
• WHO estimated that there were 95 million people visually impaired due to cataracts.1
• In India : 80.1% of people suffering from blindness due to cataract.2
• The current standard of management of visually significant cataract is surgical removal of
the cataractous lens & its replacement with an IOL.3
1,3. Yu-Chi Liu, Mark Wilkins Et.al Volume 390, Issue 10094,2017, Pages 600-612
2. Vajpayee RB, Joshi S, Saxena R, Gupta SK. Epidemiology of cataract in India: combating plans and strategies. Ophthalmic Res. 1999;31(2):86-92

3. Cataract Operations : Indian Data*
*The figures of physical performance for the year 2017-18 are based on reports received from States/Uts upto 20.09.2017.
https://dghs.gov.in/content/1354_3_NationalProgrammeforControlofBlindnessVisual.aspx

4. Advancements in surgical techniques have led to a significant reduction in the risk
of complications, elevating both patients and surgeons expectations for achieving
successful visual outcomes.
Phacoemulsification Cataract Surgery
https://eyepcr.com/what-is-cataract-and-how-is-cataract-surgery-performed/

5. Cell Membrane
phospholipids
Arachidonic acid
Prostaglandins
Leukotrienes
Phospholipase A2
COX -1/COX-2
LOX
Surgical Trauma
Chemotaxis
- Increased Vascular permeability
- Miosis
- Vasodilation
- IOP Change
- Disruption of ocular-blood barrier
Drugs.2007;67(9):1291-1308
Cataract Surgery : OCULAR INFLAMMATION PATHWAY

6. Cataract Surgery Induces : OCULAR INFLAMMATION
• Inflammation in the anterior segment may manifest as an early complication
after phacoemulsification surgery.1
• Postoperative inflammation continues to be a cause of
 Patient discomfort
 Delayed recovery
 In some cases suboptimal visual results.2
• Uncontrolled inflammation may lead to serious side effects such as posterior
synechia,uveitis & secondary glaucoma.3
• If left untreated, this inflammation could impede patients rehabilitation efforts
and potentially precipitate the emergence of additional complications, such as
Cystoid Macular Edema (CME).4
1. Bardoloi N, Sarkar S Et.al Indian J Ophthalmol. 2022 Mar;70(3):807-812
2. Malik A, Sadafale A Et.al Oman J Ophthalmol. 2016 Sep-Dec;9(3):150-156
3. Line Kessel, Britta Tendal Et.al Ophthalmology Volume 121, Issue 10, 2014,Pages 1915-1924
4. Colin J. The role of NSAIDs in the management of postoperative ophthalmic inflammation. Drugs. 2007;67(9):1291-308

7. Cystoid Macular Edema (CME)
• Development of CME after cataract surgery is the most common cause of visual
impairment.
• Although the exact pathogenesis of CME remains to be elucidated, disruption of the
blood-retinal barrier resulting from inflammation after cataract surgery may play a
causative role.
• Prostaglandins and other inflammatory mediators may increase capillary permeability
around the fovea, leading to fluid accumulation and cystoid changes in the retinal layers
Ophthalmology. 2015 Nov;122(11):2159-68

8. • Management of inflammation is a mainstay in modern cataract surgery.
• Selection of anti-inflammatory agent to use as standard in patients undergoing cataract
surgery is important to ensure a favorable outcome.
• Topical medications are frequently employed both pre- and post-operatively to assist in
the facilitation of this process.
• Two drug groups are available to control ocular inflammation:
1. Corticosteroids
2. Nonsteroidal anti-inflammatory drugs (NSAIDs)
Management of Postoperative ocular inflammation
Ophthalmology 2014;121:1915-1924

9. Corticosteroids are widely regarded as premier anti-inflammatory agents for the
treatment of ocular inflammations, characterized by their remarkable potency
and efficacy
BUT
Limitations of Topical Corticosteroids: Well-Known Side Effects
Corticosteroids exhibit significant ocular side effects, including:
1. Elevated Intraocular Pressure
2. Glaucoma
3. Cataracts
4. Increased susceptibility to infections
5. Impaired wound healing
Gaballa SA, Kompella UB Et.al Drug Deliv Transl Res. 2021 Jun;11(3):866-893.

11. Topical Ophthalmic NSAIDs
• NSAIDs have emerged as indispensable adjuncts for surgeons undertaking both routine
and intricate cataract surgeries.1
• These medications have been found to:
Alleviate pain,
Inhibit intraoperative miosis,
Regulate postoperative inflammation, and
Diminish the occurrence of cystoid macular edema (CME)1
• Whether given in monotherapy, in conjunction with corticosteroids, or tailored for eyes
with a higher risk of cystoid macular edema (CME), the effectiveness of these medications
are clinically compelling.1
• NSAIDs also had fewer treatment-related/serious ocular adverse events.2
1. J Cataract Refract Surg. 2016 September ; 42(9): 1368–1379 ; 2. Graefes Arch Clin Exp Ophthalmol. 2017 Apr;255(4):639-649.

12. Topical Ophthalmic NSAIDs
J Cataract Refract Surg. 2016 September ; 42(9): 1368–1379

13. Cell Membrane
phospholipids
Arachidonic acid
Prostaglandins
Leukotrienes
Phospholipase A2
COX -1/COX-2
LOX
Surgical Trauma
- Increased Vascular permeability
- Miosis
- Vasodilation
- IOP Change
- Disruption of ocular-blood barrier Drugs.2007;67(9):1291-1308
NSAIDs
MOA of Topical Ophthalmic NSAIDs
Chemotaxis

14. Mode of Delivery of NSAIDs
• NSAIDs can be administered systemically, topically, or intracamerally.
• Topical NSAIDs adequately penetrate the eye for both anterior and posterior segment
inflammation.
• The ocular penetration and efficacy of systemic NSAIDs compared to topical treatment
are uncertain, with systemic side effects being a concern.
• Intracameral NSAID formulations are newly available for cataract surgery, potentially
aiding in mydriasis and intraoperative pain reduction.
J Cataract Refract Surg. 2016 September ; 42(9): 1368–1379

15. Nepafenac : An Ophthalmic NSAIDs
• Nepafenac differs from other topical NSAIDs as it is a prodrug formulation, not a free
acid.1
• Other NSAIDs like flurbiprofen, diclofenac, ketorolac, and bromfenac are water-soluble
acids, potentially limiting corneal epithelial penetration.1
• Nepafenac, being less polar, reduces ionic influences on corneal absorption.1
• In vitro studies show nepafenac has nearly six times greater permeation coefficient
compared to diclofenac.2
1. Clin Ophthalmol. 2008 Jun; 2(2): 355–368.; 2. Pharmaceutics. 2020 Jun 19;12(6):570

16. Nepafenac : An Ophthalmic NSAIDs
• Nepafenac easily penetrates corneal and retinal tissues after topical ocular
administration.1
• Once the molecule enters the aqueous humor, it converts to amfenac by intraocular
hydrolases.2
• Amfenac, a potent COX-1 and COX-2 inhibitor, exhibits strong anti-inflammatory
properties for managing pain and inflammation post-cataract surgery.2
• In vitro studies comparing nepafenac, amfenac, ketorolac, and bromfenac show ketorolac
has the highest COX-1 inhibitory activity, while amfenac demonstrates the greatest COX-2
inhibitory potential.3
1. Clin Ophthalmol. 2008 Jun; 2(2): 355–368. ; 2 J Cataract Refract Surg. 2016 September ; 42(9): 1368–1379 ; 3. Pharmaceutics. 2020 Jun 19;12(6):570

17. Nepafenac : An Ophthalmic NSAIDs
• Nepafenac's activity begins approximately 15 minutes after topical application, with a
duration of action exceeding 8 hours.1
• In vivo studies in human, topical nepafenac achieves faster time to peak concentration
(Cmax) and higher aqueous humor levels compared to bromfenac or ketorolac.1
• Small measurable plasma concentrations of nepafenac and its active metabolite, amfenac,
persist 2-3 hours after topical administration.1
• Research suggests nepafenac may possess greater potency than ketorolac or diclofenac.2
1. Clin Ophthalmol. 2008 Jun; 2(2): 355–368. ; 2. J Cataract Refract Surg. 2016 September ; 42(9): 1368–1379

18. Nepafenac 0.1% Eye Drop Indication & Dosage
Indicated for the treatment of pain and inflammation associated with cataract surgery.
Recommended dosing : Adults, including the elderly
• For the prevention and treatment of pain and inflammation, the dose is 1 drop of
Nepafenac eye drops in the conjunctival sac of the affected eye(s) 3 times daily beginning
1 day prior to cataract surgery, continued on the day of surgery and for the first 2 weeks
of the postoperative period.
• For the reduction in the risk of postoperative macular oedema associated with cataract
surgery in diabetic patients, the dose is 1 drop of Nepafenac eye drops in the conjunctival
sac of the affected eye(s) 3 times daily beginning 1 day prior to cataract surgery,
continued on the day of surgery and up to 60 days of the postoperative period as directed
by the clinician.

20. Curr Eye Res. 2020 Sep;45(9):1089-1093

23. European Ophthalmic Review. 2018;12(1):32–8
Cumulative percentage of cures (A) and patients (B) who were pain free by visit in
a phase III study (n=1,636) comparing 0.1% and 0.3% nepafenac & vehicle to treat
ocular inflammation & pain after cataract surgery

26. • Patients with previously demonstrated hypersensitivity to any of the
ingredients in the formula or to other NSAIDs.
• Patients in whom attacks of asthma, urticaria, or acute rhinitis are
precipitated by acetylsalicylic acid or other NSAIDs
Contraindications

27. • Increased bleeding time : It is recommended that nepafenac eye drops be
used with caution in patients with known bleeding tendencies, or who are
receiving other medications, which may prolong bleeding time.
• Delayed healing: it is recommended that caution should be exercised if
nepafenac eye drops is administered concomitantly with corticosteroids,
particularly in patients at high risk for corneal adverse reactions.
• Corneal effect: Use of topical NSAIDs may result in keratitis. In some
susceptible patients, continued use of topical NSAIDs may result in
epithelial breakdown, corneal thinning, corneal erosion, corneal
ulceration, or corneal perforation
Warnings & Precautions

28. • Contact lens wear : Nepafenac eye drops should not be administered while
using contact lenses
• Cross-sensitivity : There is a potential for cross-sensitivity of nepafenac to
acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs.
Warnings & Precautions

29. In vitro studies have demonstrated a very low potential for interaction with other
medicinal products and protein binding interactions.
• Prostaglandin analogues : There are very limited data on the concomitant use of
prostaglandin analogues and Nepafenac. Considering their mechanism of action,
the concomitant use of these medicinal products is not recommended.
• Concomitant use of topical NSAIDs and topical steroids may increase the potential
for healing problems.
• Concomitant use of nepafenac with medications that prolong bleeding time may
increase the risk of haemorrhage
Drug Interactions

30. • Usage in Pregnancy: There are no adequate and well-controlled studies in
pregnant women. Nepafenac should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
• Women of childbearing potential : Nepafenac should not be used by
women of child bearing potential not using contraception.
• Usage in lactation : Caution should be exercised when nepafenac eye drop
is administered to a nursing woman.
Warnings & Precautions

31. • Pediatric use : The safety and effectiveness of nepafenac in children and
adolescents have not been established. No data are available. Its use is not
recommended in these patients until further data become available.
• Geriatric use : No overall differences in safety and effectiveness have been
observed between elderly and younger patients.
• Effects on ability to drive and use machines : Nepafenac has no or
negligible influence on the ability to drive and use machines. Temporary
blurred vision or other visual disturbances may affect the ability to drive or
use machines.
Special Populations

32. • The most common adverse reactions were punctate keratitis, foreign body
sensation and eyelid margin crusting which occurred in between 0.4% and
0.2% of patients.
Adverse Reactions

33. • Nepafenac ophthalmic suspension (0.1%) is a distinct topical ophthalmic pro-drug NSAID.
• Nepafenac exhibits enhanced corneal permeability characteristics compared to traditional NSAIDs.
• Metabolized into its active form, amfenac, within ocular tissues including the iris, ciliary body, retina, and
choroid.
• Amfenac exerts potent anti-inflammatory effects by strongly inhibiting prostaglandin synthesis.
• Nepafenac's mechanism of action involves stabilizing both the blood-retina and blood-aqueous barriers.
• Nepafenac stands out as a therapeutic agent capable of targeting inflammation in both the anterior and
posterior segments of the eye.
Summary

34. • Nepafenac demonstrates efficacy in reducing postoperative pain in patients
undergoing routine clear corneal phacoemulsification under topical anesthesia.
• Preoperative administration of Nepafenac enhances patient comfort during the
surgical procedure.
• Nepafenac exhibits a significant role in mitigating postoperative cystoid macular
edema (CME) development, particularly in high-risk populations such as individuals
with diabetes mellitus.
• The safety profile of Nepafenac is favorable, with high tolerability among patients.
Summary