Ketorolac (EENT)

Introductory Information
Prototypical NSAIA; a pyrrolizine carboxylic acid derivative.1, 2, 3, 4, 14, 21, 22, 25, 26, 27, 28
Class: 52:08.20 Nonsteroidal Anti-inflammatory Agents; op300 (VA primary)
Brands: Acular
Generic Name: Ketorolac Tromethamine
CAS Number: 74103-07-4
Generic Name: Ketorolac
CAS Number: 74103-06-3
Investigational Drug Number: RS 37619
Uses
Conjunctivitis
Temporary relief of ocular itching due to seasonal allergic (hay fever, pollinosis)
conjunctivitis.1, 141, 142, 143
Postoperative Ocular Inflammation
Management of postoperative inflammation associated with cataract extraction.1, 11, 17, 18, 19, 61,
85, 110, 147

Postoperative Ocular Pain

Reduction of ocular pain and burning/stinging following corneal refractive surgery and
photorefractive keratectomy (PRK).155, 156
Ketorolac tromethamine 0.5% preservative-free ophthalmic solution is used for the reduction
of ocular pain and photophobia following incisional refractive surgery.154
Cystoid Macular Edema
Treatment, with or without concomitant topical corticosteroid therapy, to prevent or relieve
postoperative cystoid macular edema associated with cataract extraction
.61

Has been used for the active treatment of chronic aphakic or pseudophakic cystoid macular
edema
.14, 20, 23

Inhibition of Intraoperative Miosis

Has been used prophylactically before ocular surgery to prevent or reduce intraoperative
miosis
.53, 81, 106, 107, 108, 110, 137, 139

Dosage and Administration

Administration
Ophthalmic Administration
Apply topically to the eye as an ophthalmic solution.1, 154, 155
Avoid contamination of the solution container.154
Do not administer while wearing contact lenses.1, 154, 155
Preservative-free solution is for single use only in one or both eyes; use immediately after
opening and discard any unused portion immediately after administration.154
Has been safely administered with other ophthalmic medications (e.g., antibiotics, -blockers,
carbonic anhydrase inhibitors, cycloplegics, mydriatics).1
Dosage
Available as ketorolac tromethamine; dosage expressed in terms of the salt.154, 155
Pediatric Patients
Conjunctivitis
>Ophthalmic
Children 3 years of age: 1 drop (250 mg) of a 0.5% solution in the affected eye(s) 4 times
daily.1, 141, 142
Postoperative Ocular Inflammation
>Ophthalmic
Children 3 years of age: 1 drop (250 mcg) of a 0.5% solution in the eye(s) undergoing
surgery 4 times daily beginning 24 hours after surgery and typically continuing for 2 weeks
after surgery.1
Postoperative Ocular Pain
>Ophthalmic
Children 3 years of age undergoing ocular incisional refractive surgery: 1 drop (250 mcg) of
a 0.5% preservative-free solution 4 times daily in the eye(s) that underwent surgery as needed
for up to 3 days after surgery.154
Children 3 years of age undergoing corneal refractive surgery: 1 drop (200 mcg) of a 0.4%
solution 4 times daily in the eye(s) that underwent surgery as needed for up to 4 days after
surgery.155
Adults
Conjunctivitis
>Ophthalmic
1 drop (250 mg) of a 0.5% solution in the affected eye(s) 4 times daily.1, 141, 142

Postoperative Ocular Inflammation

>Ophthalmic
1 drop (250 mcg) of a 0.5% solution in the eye(s) undergoing surgery 4 times daily beginning
24 hours after surgery and typically continuing for 2 weeks after surgery.1
Postoperative Ocular Pain
>Ophthalmic
Patients undergoing ocular incisional refractive surgery: 1 drop (250 mcg) of a 0.5%
preservative-free solution 4 times daily in the eye(s) that underwent surgery as needed for up
to 3 days after surgery.154
Patients undergoing corneal refractive surgery: 1 drop (200 mcg) of a 0.4% solution 4 times
daily in the eye(s) that underwent surgery as needed for up to 4 days after surgery.155
Cystoid Macular Edema
>Postoperative Cystoid Macular Edema
Ophthalmic: 1-2 drops (250-500 mcg) of a 0.5% solution in the eye(s) undergoing surgery
every 6-8 hours beginning 24 hours prior to surgery and continuing for 3-4 weeks after
surgery.11, 17, 18, 19, 61, 85
>Chronic Aphakic or Pseudophakic Cystoid Macular Edema
Ophthalmic: 1-2 drops (250-500 mcg) of a 0.5% solution in the affected eye(s) 4 times daily
for 2-3 months.20, 23
Cautions
Contraindications
Known hypersensitivity to ketorolac tromethamine or any ingredient in the formulation.1, 154,
155

Warnings/Precautions
Warnings
Hematologic Effects
May inhibit platelet aggregation and prolong bleeding time.1, 137, 154, 155
May increase bleeding (e.g., hyphemas) of ocular tissues in patients undergoing ocular
surgery.1, 24, 53, 106, 154, 155
Use with caution in patients with underlying bleeding tendencies or in those receiving drugs
known to prolong bleeding time.1, 154, 155
Sensitivity Reactions
Cross-sensitivity
Possible cross-sensitivity with aspirin, phenylacetic acid derivatives, and other NSAIAs.1, 154,
155
Use with caution in patients with history of hypersensitivity to these drugs.1, 54, 55, 56, 57, 58, 59,
85, 117, 118, 154, 155

General Precautions

Wound Healing Complications

Possible slow or delayed wound healing; may be potentiated with concomitant adminsitration
of topical NSAIAs or topical corticosteroids.1, 154, 155 (See Specific Drugs under Interactions.)
Ocular Effects
Use may result in keratitis.1, 85, 139, 154, 155 In susceptible patients, continued use may result in
epithelial breakdown, corneal thinning, erosion, ulceration, or perforation, which may be
sight-threatening.1, 154, 155
If manifestations of corneal epithelial breakdown occur, discontinue immediately and closely
monitor corneal health.1, 154, 155
Increased risk of sight-threatening, adverse corneal effects in patients with complicated
ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular
surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries
within a short period of time; use with caution in such patients.1, 154, 155
Use >24 hours prior to surgery or >14 days postoperatively may precipitate or exacerbate
adverse corneal effects.1, 154, 155
Specific Populations
Pregnancy
Category C.1, 154, 155 Avoid use in the third trimester because of possible premature closure of
the ductus arteriosus.1, 154, 155
Lactation
Distributed into milk after systemic administration.2, 14, 21, 22, 48, 85 Caution if used in nursing
women.1, 154, 155
Pediatric Use
Safety and efficacy not established in children <3 years of age.1, 154, 155
Geriatric Use
No substantial differences in safety and efficacy relative to younger adults.1, 154, 155
Common Adverse Effects
Ocular stinging and burning.1, 154, 155
Interactions
No formal drug interaction studies to date.1, 154, 155
Specific Drugs
Drug
Corticosteroids,
ophthalmic

Interaction
Possible additive effects on
delaying wound healing1, 154,
155

Additive ocular antiinflammatory activity1, 154, 155

Comments
Concomitant use may increase the
potential for wound healing
complications1, 154, 155
Potential for additive effects used to
therapeutic advantage11, 18, 81

Pharmacokinetics
Absorption
Bioavailability
Extent of ocular and systemic absorption not fully elucidated;1 however, limited
concentrations are achieved systemically following topical application to the eye relative to
usual oral or parenteral doses.1, 14, 16, 18
Following topical application to the eye, plasma ketorolac concentrations were detectable
(range: 10.7-22.5 ng/mL) in about 20% of patients.1, 154, 155
Distribution
Extent
Distribution into human ocular tissues and fluids not fully characterized to date.1, 14, 78
Ketorolac crosses the placenta21, 28, 46, 47, 78 and is distributed into milk following systemic
administration.2, 14, 21, 22, 48, 78
Plasma Protein Binding
>99%.2, 14, 28, 45, 49, 78
Stability
Storage
Ophthalmic
0.4% Solution
15-25C.155
0.5% Solution
Light-resistant containers at 15-30C.1, 154
Actions
Inhibits synthesis of certain ocular prostaglandins (e.g., PGE2) in iris, ciliary body, and
conjunctiva by inhibiting cyclooxygenase-1 (COX-1) and -2 (COX-2).1, 2, 4, 6, 10, 21, 28, 40, 62, 66, 68,
69, 70, 71, 72, 73, 77, 80, 81, 110, 154, 155

Substantially reduces aqueous humor concentrations of these prostaglandins.1, 80, 81, 110, 121, 122, 123,
126, 128

Does not appear to inhibit lipoxygenase;21, 81 does not inhibit aspects of inflammation mediated
by leukotrienes.81, 119, 137
Advice to Patients
Importance of learning and adhering to proper administration techniques to avoid
contamination of the product.1, 154, 155
Importance of removing contact lenses before administration.1, 154, 155
Importance of women informing clinicians if they are or plan to become pregnant or plan to
breast-feed.1, 154, 155

 Importance of informing clinicians of existing or contemplated concomitant therapy, including

prescription and OTC drugs, as well as concomitant illnesses.1, 154, 155
Importance of informing patients of other important precautionary information.1, 154, 155 (See
Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects
in some individuals; consult specific product labeling for details.
Ketorolac Tromethamine
Routes
Dosage Forms Strengths Brand Names
Manufacturer

Ophthalmic Solution
0.4%
Acular LS (with benzalkonium chloride) Allergan
0.5%
Acular (with benzalkonium chloride)
Allergan

Acular PF (preservative-free)
Allergan
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This
pricing information was updated 03/2011. For the most current and up-to-date pricing
information, please visit www.drugstore.com. Actual costs to patients will vary depending on
the use of specific retail or mail-order locations and health insurance copays.
Acular 0.5% Solution (ALLERGAN): 3/$59.34 or 9/$158.96
Acular 0.5% Solution (ALLERGAN): 5/$132.07 or 15/$370.21
Acular 0.5% Solution (ALLERGAN): 10/$236.03 or 30/$687.45
Acular LS 0.4% Solution (ALLERGAN): 5/$133.52 or 15/$400.6
Acuvail 0.45% Solution (ALLERGAN): 30/$133.11 or 90/$374.39
Ketorolac Tromethamine 0.4% Solution (FALCON PHARMACEUTICALS): 5/$75.99 or
15/$199.96
Use is not currently included in the labeling approved by the US Food and Drug

Administration.
References
1. Allergan. Acular (ketorolac tromethamine) ophthalmic solution 0.5% sterile prescribing
information. Irvine, CA; 2002 Feb.
2. Syntex Laboratories Inc. Toradol (ketorolac tromethamine) tablets and injection prescribing
information. Physicians' desk reference. 47th ed. Montvale, NJ: Medical Economics
Company Inc; 1993:2411-5.

3. Muchowski JM, Unger SH, Ackrell J et al. Synthesis and antiinflammatory and analgesic
activity of 5-aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole -1-carboxylic acids and related
compounds. J Med Chem. 1985; 28: 1037-49. [PubMed 4020827]
4. Rooks WH II, Maloney PJ, Shott LD et al. The analgesic and anti-inflammatory profile of
ketorolac and its tromethamine salt. Drugs Exp Clin Res. 1985; 11:479-92. [PubMed
3879752]
5. Guzman A, Yuste F, Toscano RA et al. Absolute configuration of (-)-5-benzoyl-1,2-dihydro3H-pyrrolo[1,2-a]pyrrole -1-carboxy lic acid, the active enantiomer of ketorolac. J Med
Chem. 1986; 29:589-91. [PubMed 3959034]
6. Syntex Laboratories Inc, Palo Alto, CA: Personal communication on ketorolac 28:08.04.
7. Gu L, Strickley RG. Preformulation salt selection: physical property comparisons of the
tris(hydroxymethyl)aminomethane (THAM) salts of four analgesic/antiinflammatory agents
with the sodium salts and the free acids. Pharm Res. 1987; 4:255-7. [PubMed 3509292]
8. Insel PA. Analgesic-antipyretics and antiinflammatory agents: drugs employed in the
treatment of rheumatoid arthritis and gout. In: Gilman AG, Rall TW, Nies AS, et al, eds.
Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York:
Pergamon Press; 1990:638-81.
9. Fraser-Smith EB, Matthews TR. Effect of ketorolac on phagocytosis of Candida albicans by
peritoneal macrophages. Immunopharmacology. 1988; 16:151-5. [PubMed 3075603]
10. Rooks WH II, Tomolonis AJ, Maloney PJ et al. The analgesic and anti-inflammatory profile
of ()-5-benzoyl-1,2-dihydro-3 H-pyrrolo[1,2a]pyrrole-1-carboxylic acid (rS -37619). Agents
Actions. 1982; 12:684-90. [PubMed 6984594]
11. Flach AJ, Lavelle CJ, Olander KW et al. The effect of ketorolac tromethamine solution 0.5%
in reducing postoperative inflammation after cataract extraction and intraocular lens
implantation. Ophthalmology. 1988; 95:1279-84. [PubMed 3062540]
12. Fraser-Smith EB, Matthews TR. Effect of ketorolac on Pseudomonas aeruginosa ocular
infection in rabbits. J Ocul Pharmacol. 1988; 4:101-9. [PubMed 3262701]
13. Fraser-Smith EB, Matthews TR. Effect of ketorolac on Candida albicans ocular infection in
rabbits. Arch Ophthalmol. 1987; 105:264-7. [PubMed 3492994]
14. Buckley MMT, Brogden RN. Ketorolac: a review of its pharmacodynamic and
pharmacokinetic properties, and therapeutic potential. Drugs. 1990; 39:86-109. [PubMed
2178916]
15. Fraser-Smith EB, Matthews TR. Effect of ketorolac on herpes simplex virus type one ocular
infection in rabbits. J Ocul Pharmacol. 1988; 4:321-6. [PubMed 3246566]
16. Ling TL, Combs DL. Ocular bioavailability and tissue distribution of [14C]ketorolac
tromethamine in rabbits. J Pharm Sci. 1987; 76:289-94. [PubMed 3598886]

17. Flach AJ, Graham J, Kruger LP et al. Quantitative assessment of postsurgical breakdown of
the blood-aqueous barrier following administration of 0.5% ketorolac tromethamine solution.
Arch Ophthalmol. 1988; 106:344-7. [IDIS 239148] [PubMed 3345153]
18. Flach AJ, Kraff MC, Sanders DR et al. The quantitative effect of 0.5% ketorolac
tromethamine solution and 0.1% dexamethasone sodium phosphate solution on postsurgical
blood-aqueous barrier. Arch Ophthalmol. 1988; 106:480-3. [IDIS 240262] [PubMed
3355415]
19. Flach AJ, Jaffe NS, Akers WA. The effect of ketorolac tromethamine in reducing
postoperative inflammation: double-mask parallel comparison with dexamethasone. Ann
Ophthalmol. 1989; 21:407-11. [PubMed 2619149]
20. Flach AJ, Dolan BJ, Irvine AR. Effectiveness of ketorolac tromethamine 0.5% ophthalmic
solution for chronic aphakic and pseudophakic cystoid macular edema. Am J Ophthalmol.
1987; 103:479-86. [IDIS 228104] [PubMed 3551617]
21. Syntex Laboratories Inc. Toradol product monograph. Palo Alto, CA; 1990 Mar.
22. Syntex Laboratories Inc. Toradol pharmacy information. Palo Alto, CA; 1990 Mar.
23. Flach AJ, Jampol LM, Weinberg D et al. Improvement in visual acuity in chronic aphakic
and pseudophakic cystoid macular edema after treatment with topical 0.5% ketorolac
tromethamine. Am J Ophthalmol. 1991; 112:514-9. [IDIS 290630] [PubMed 1951587]
24. CIBA Vision Ophthalmics. Voltaren Ophthalmic (diclofenac sodium) 0.1% sterile
ophthalmic solution prescribing information. Physicians' desk reference for ophthalmology.
21st ed. Montvale, NJ: Medical Economics Company Inc; 1993:273-4.
25. Budavari S, ed. The Merck index. 11th ed. Rahway, NJ: Merck & Co, Inc; 1989:836.
26. Syntex Laboratories Inc. Toradol formulary facts. Palo Alto, CA; 1990.
27. Anon. Ketorolac tromethamine. Med Lett Drugs Ther. 1990; 32:79- 82. [PubMed 2199809]
28. Gannon R. Focus on ketorolac: a nonsteroidal, anti-inflammatory agent for the treatment of
moderate to severe pain. Hosp Formul. 1989; 24:695-702.
29. Yee JP, Koshiver JE, Allbon C et al. Comparison of intramuscular ketorolac tromethamine
and morphine sulfate for analgesia of pain after major surgery. Pharmacotherapy. 1986;
6:253-61. [IDIS 394443] [PubMed 3540877]
30. Bloomfield SS, Mitchell J, Cissell GB et al. Ketorolac versus aspirin for postpartum uterine
pain. Pharmacotherapy. 1986; 6:247-52. [IDIS 394442] [PubMed 3540876]
31. Reviewers' comments (personal observations) on ketorolac.
32. Robinson DR. Prostaglandins and the mechanism of action of anti-inflammatory drugs. Am
J Med. 1983; 10:26-31.

33. Koch-Weser J. Nonsteroidal antiinflammatory drugs (first of two parts). N Engl J Med.
1980; 302:1179-85. [IDIS 113555] [PubMed 6988717]
34. Abramson S, Edelson H, Kaplan H et al. Inhibition of neutrophil activation by nonsteroidal
anti-inflammatory drugs. Am J Med. 1984; 10:3-6.
35. Deraedt R, Jouquey S, Benzoni J et al. Inhibition of prostaglandin biosynthesis by nonnarcotic analgesic drugs. Arch Int Pharmacodyn Ther. 1976; 224:30-42. [PubMed 13749]
36. Atkinson DC, Collier HOJ. Salicylates: molecular mechanism of therapeutic action. Adv
Pharmacol Chemother. 1980; 17:233-88. [PubMed 7004141]
37. Hart FD. Rheumatic disorders. In: Avery GS, ed. Drug treatment: principles and practice of
clinical pharmacology and therapeutics. 2nd ed. New York: ADIS Press; 1987:846-61.
38. Haynes WL, Proia AD, Klintworth GK. Effect of inhibitors of arachidonic acid metabolism
on corneal neovascularization in the rat. Invest Ophthalmol Vis Sci. 1989; 30:1588-93.
[PubMed 2473047]
39. Mahoney JM, Waterbury LD. Drug effects on the neovascularization response to silver
nitrate cauterization of the rat cornea. Curr Eye Res. 1985; 4:531-5. [PubMed 2410194]
40. Havener WH. Ocular pharmacology. 5th ed. St. Louis: The CV Mosby Company; 1983:1843,223-35.
41. Conrad KA, Fagan TC, Mackie MJ et al. Effects of ketorolac tromethamine on hemostasis in
volunteers. Clin Pharmacol Ther. 1988; 43:542-6. [IDIS 242096] [PubMed 3259170]
42. Spowart K, Greer IA, McLaren M et al. Haemostatic effects of ketorolac with and without
concomitant heparin in normal volunteers. Thromb Haemost. 1988; 60:382-6. [PubMed
3266379]
43. Roe RL, Bruno JJ, Ellis DJ. Effects of a new nonsteroidal anti-inflammatory agent on
platelet function in male and female subjects. Clin Pharmacol Ther. 1981; 29:277.
44. Bruno JJ, Yang D, Taylor LA. Differing effects of ticlopidine and two prostaglandin
synthetase inhibitors on maximum rate of ADP-induced aggregation. Thromb Haemost. 1981;
46:412.
45. Mroszczak EJ, Lee FW, Combs D et al. Ketorolac tromethamine absorption, distribution,
metabolism, excretion, and pharmacokinetics in animals and humans. Drug Metab Dispos.
1987; 15:618-26. [IDIS 235471] [PubMed 2891477]
46. Walker JJ, Johnstone J, Lloyd J et al. The transfer of ketorolac tromethamine from maternal
to foetal blood. Eur J Clin Pharmacol. 1988; 34:509-11. [IDIS 244072] [PubMed 3264528]
47. Greer IA, Johnston J, Tulloch I et al. Effect of maternal ketorolac administration on platelet
function in the newborn. Eur J Obstet Gynecol Reprod Biol. 1988; 29:257-60. [PubMed
3265921]

48. Wischnik A, Manth SM, Lloyd J. The excretion of ketorolac tromethamine into breast milk
after multiple oral dosing. Eur J Clin Pharmacol. 1989; 36:521-4. [IDIS 255985] [PubMed
2787750]
49. Jung D, Mroszczak E, Bynum L. Pharmacokinetics of ketorolac tromethamine in humans
after intravenous, intramuscular and oral administration. Eur J Clin Pharmacol. 1988;
35:423-5. [IDIS 247775] [PubMed 3264245]
50. Jung D, Mroszczak EJ, Wu A et al. Pharmacokinetics of ketorolac and p-hydroxyketorolac
following oral and intramuscular administration of ketorolac tromethamine. Pharm Res.
1989; 6:62-5. [PubMed 2717521]
51. Jallad NS, Garg DC, Martinez JJ et al. Pharmacokinetics of single-dose oral and
intramuscular ketorolac tromethamine in the young and elderly. J Clin Pharmacol. 1990;
30:76-81. [IDIS 262959] [PubMed 2303585]
52. Sarnquist FH, Mroszczak EJ, Sevelius H. Absorption and metabolism of a new antiinflammatory, analgesic agent. Clin Pharmacol Ther. 1981; 29:280.
53. Allergan Medical Optics. Ocufen Liquifilm (flurbiprofen sodium) 0.03% sterile
ophthalmic solution prescribing information. Physicians' desk reference for ophthalmology.
Montvale, NJ: Medical Economics Company Inc; 1993:236-7.
54. Weinberger M. Analgesic sensitivity in children with asthma. Pediatrics. 1978;
62(Suppl):910-5. [IDIS 118712] [PubMed 103067]
55. Pleskow WW, Stevenson DD, Mathison DA et al. Aspirin desensitization in aspirin-sensitive
asthmatic patients: clinical manifestations and characterization of the refractory period. J
Allergy Clin Immunol. 1982; 69(1 Part 1):11-9. [IDIS 144037] [PubMed 7054250]
56. VanArsdel PP Jr. Aspirin idiosyncrasy and tolerance. J Allergy Clin Immunol. 1984; 73:4313. [IDIS 183975] [PubMed 6423718]
57. Stevenson DD. Diagnosis, prevention, and treatment of adverse reactions to nonsteroidal
anti-inflammatory drugs. J Allergy Clin Immunol. 1984; 74(4 Part 2):617-22. [IDIS 193318]
[PubMed 6436354]
58. Stevenson DD, Mathison DA. Aspirin sensitivity in asthmatics: when may this drug be safe?
Postgrad Med. 1985; 78:111-3,116-9.
59. Settipane GA. Aspirin and allergic diseases: a review. Am J Med. 1983; 74(Suppl):102-9.
[IDIS 171763] [PubMed 6344621]
60. Indocin (indomethacin) capsules, oral suspension, and suppositories prescribing
information. In: Barnhart ER, ed. Physicians' desk reference. 44th ed. Oradell, NJ: Medical
Economics Company Inc; 1990:1395-8.
61. Flach AJ, Stegman RC, Graham J et al. Prophylaxis of aphakic cystoid macular edema
without corticosteroids. A paired-comparison, placebo-controlled double -masked study.
Ophthalmology. 1990; 97:1253-8. [PubMed 2243674]

62. Bhattacherjee P. Prostaglandins and inflammatory reactions in the eye. Methods Find Exp
Clin Pharmacol. 1980; 2:17-31. [PubMed 6803089]
63. Eakins KE. Prostaglandin and non-prostaglandin mediated breakdown of the blood-aqueous
barrier. Exp Eye Res. 1977; 25(Suppl):483-98. [PubMed 338326]
64. Podos SM, Becker B. Comparison of ocular prostaglandin synthesis inhibitors. Invest
Ophthalmol. 1976; 15:841-4. [PubMed 977253]
65. Duffin RM, Camras CB, Gardner SK et al. Inhibitors of surgically induced miosis.
Ophthalmology. 1982; 89:966-78. [PubMed 7133642]
66. Kulkarni PS, Srinivasan BD. Comparative in vivo inhibitory effects of nonsteroidal antiinflammatory agents on prostaglandin synthesis in rabbit ocular tissues. Arch Ophthalmol.
1985; 103:103-6. [PubMed 3919694]
67. Leopold IH, Murray D. Noncorticosteroidal anti-inflammatory agents in ophthalmology.
Ophthalmology. 1979; 86:142-55. [PubMed 394060]
68. van Alphen GWHM, Dutilh CE, de Deckere EAM. The high yield of prostacyclin
biosynthesis by the iris and its effects on the intraocular muscles. Prostaglandins Med. 1978;
1:151-8. [PubMed 362455]
69. Hall DWR, Bonta IL. Prostaglandins and ocular inflammation. Doc Ophthalmol. 1977;
2:421-34.
70. Kass MA, Holmberg NJ. Prostaglandin and thromboxane synthesis by microsomes of rabbit
ocular tissues. Invest Ophthalmol Vis Sci. 1979; 18:166-71. [PubMed 761971]
71. Sawa M, Masuda K. Topical indomethacin in soft cataract aspiration. Jpn J Ophthalmol.
1976; 20:514-9.
72. Ciprandi G, Buscaglia S, Cerqueti PM et al. Drug treatment of allergic conjunctivitis: a
review of the evidence. Drugs. 1992; 43:154-76. [IDIS 360840] [PubMed 1372215]
73. Abelson MB, Butrus SI, Kliman GH et al. Topical arachidonic acid: a model for screening
anti-inflammatory agents. J Ocul Pharmacol. 1987; 3:63-75. [PubMed 3141537]
74. Friedlaender MH. Current concepts in ocular allergy. Ann Allergy. 1991; 67:5-10,13. [IDIS
312766] [PubMed 1859041]
75. Helleboid L, Khatami M, Wei ZG et al. Histamine and prostacyclin: primary and secondary
release in allergic conjunctivitis. Invest Ophthalmol Vis Sci. 1991; 32:2281-9. [PubMed
1712764]
76. Abramson SB, Weissmann G. The mechanisms of action of nonsteroidal antiinflammatory
drugs. Arthritis Rheum. 1989; 32:1-9. [IDIS 250500] [PubMed 2643434]

77. Trocme SD. Medical therapy for ocular allergy. Mayo Clin Proc. 1992; 67:557-65. [IDIS
296611] [PubMed 1359206]
78. Brocks DR, Jamali F. Clinical pharmacokinetics of ketorolac tromethamine. Clin
Pharmacokinet. 1992; 23:415-27. [PubMed 1458761]
79. Sabiston D, Tessler H, Sumers K et al. Reduction of inflammation following cataract surgery
by the nonsteroidal anti-inflammatory drug, flurbiprofen. Ophthalmic Surg. 1987; 18:873-7.
[PubMed 3502173]
80. Bhattacherjee P. The role of arachidonate metabolites in ocular inflammation. Prog Clin Biol
Res. 1989; 312:211-27. [PubMed 2508125]
81. Flach AJ. Cyclo-oxygenase inhibitors in ophthalmology. Surv Ophthalmol. 1992; 36:259-84.
[PubMed 1549810]
82. Buckley DC, Caldwell DR, Reaves TA Jr. Treatment of vernal conjunctivitis with suprofen,
a topical nonsteroidal anti-inflammatory agent. Invest Ophthalmol Vis Sci. 1986; 27:29. [IDIS
213714] [PubMed 3941035]
83. Wood TS, Stewart RH, Bowman RW et al. Suprofen treatment of contact lens-associated
giant papillary conjunctivitis. Ophthalmology. 1988; 95:822-6. [PubMed 3211485]
84. Gupta S, Khurana AK, Ahluwalia BK et al. Topical indomethacin for vernal
keratoconjunctivitis. Acta Opthalmol (Copenh). 1991; 69:95-8.
85. Allergan. Acular (ketorolac tromethamine) prescribing information. In: Krogh CME, ed.
Compendium of pharmaceuticals and specialties 1993. 28th ed. Ottawa, Ontario: Canadian
Pharmaceutical Association; 1993:23.
86. CIBA Vision. Voltaren Ophthalmic (diclofenac sodium) prescribing information. In: Krogh
CME, ed. Compendium of pharmaceuticals and specialties 1993. 28th ed. Ottawa, Ontario:
Canadian Pharmaceutical Association; 1993:1333-4.
87. Merck Sharp and Dohme. Indocid (indomethacin) ophthalmic suspension prescribing
information. In: Krogh CME, ed. Compendium of pharmaceuticals and specialties 1993. 28th
ed. Ottawa, Ontario: Canadian Pharmaceutical Association; 1993:583.
88. Asbell PA, Torres MA. Therapeutic dilemmas in external ocular diseases. Drugs. 1991;
42:606-15. [PubMed 1723363]
89. Leibowitz HM, Ryan WJ, Kupferman A et al. Bioavailability of corneal anti-inflammatory
effect of topical suprofen. Invest Ophthalmol Vis Sci. 1986; 27:628-31. [PubMed 3957583]
90. Leibowitz HM, Ryan WJ, Kupferman A et al. Effect of concurrent topical corticosteroid and
NSAID therapy of experimental keratitis. Invest Ophthalmol Vis Sci. 1986; 27:1226-9.
[PubMed 3733368]

91. Kraff MC, Sanders DR, McGuigan L et al. Inhibition of blood-aqueous humor barrier
breakdown with diclofenac: a fluorophotometric study. Arch Ophthalmol. 1990; 108:380-3.
[IDIS 296047] [PubMed 2178597]
92. Bito LZ. Surgical miosis: have we been misled by a bunch of rabbits? Ophthalmology. 1990;
97:1-2. Letter.
93. Kraff MC, Sanders DR, Jampol LM et al. Factors affecting pseudophakic cystoid macular
edema: five randomized trials. J Am Intraocul Implant Soc. 1985; 11:380-5. [PubMed
4030486]
94. Gnad HD, Paroussis P, Skorpik C. Treatment of cystoid macular edema after intracapsular
cataract extraction and implantation of the Binkhorst 4-loop lens. (German; with English
abstract.) Wien Klin Wochenschr. 1985; 97:625-7.
95. Alpar JJ. Posterior capsulotomy in sulcus-fixated versus bag-fixated intraocular lenses in
diabetic patients. J Am Intraocul Implant Soc. 1985; 11:577-80. [PubMed 4077672]
96. Jampol LL. Pharmacologic therapy of aphakic and pseudophakic cystoid macular edema.
1985 update. Ophthalmology. 1985; 92:807-10. [PubMed 3897936]
97. Lambrix K. Cystoid macular edema: a postoperative complication. J Ophthalmic Nurs
Technol. 1990; 9:152-4. [PubMed 2374166]
98. Peterson M, Yoshizumi MO, Hepler R et al. Topical indomethacin in the treatment of
chronic cystoid macular edema. Graefes Arch Clin Exp Ophthalmol. 1992; 230:401-5.
[PubMed 1521802]
99. Sears ML. Aphakic cystoid macular edema. The pharmacology of ocular trauma. Surv
Ophthalmol. 1984; 28(Suppl):525-34. [PubMed 6379950]
100. Yannuzzi LA. A perspective on the treatment of aphakic cystoid macular edema. Surv
Ophthalmol. 1984; 28(Suppl):540-53. [PubMed 6379952]
101. Yannuzzi LA, Landau AN, Turtz AL. Incidence of aphakic cystoid macular edema with the
use of topical indomethacin. Ophthalmolgy. 1981; 88:947-54.
102. Kraff MC, Sanders DR, Jampol LM et al. Prophylaxis of pseudophakic cystoid macular
edema with topical indomethacin. Ophthalmology. 1982; 89:885-90. [PubMed 6752799]
103. Miyake K, Sakamura S, Miura H. Long-term follow-up study on the prevention of aphakic
cystoid macular edema by topical indomethacin. Br J Ophthalmol. 1980; 64:324-8. [PubMed
7437393] [Free Fulltext PMC]
104. Foster CS, Calonge M. Atopic keratoconjunctivitis. Ophthalmology. 1990; 97:992-100.
[PubMed 1976238]
105. Foster CS, Rice BA, Dutt JE. Immunopathology of atopic keratocomjunctivitis.
Ophthalmology. 1991; 98:1190-6. [PubMed 1923355]

106. Alcon Laboratories. Profenal (suprofen) 1% sterile ophthalmic solution prescribing

information. In: Physicians' desk reference for ophthalmology. 21st ed. Montvale, NJ:
Medical Economics Company; 1993;233-5.
107. Stark WJ, Fagadau WR, Stewart RH et al. Reduction of pupillary constriction during
cataract surgery using suprofen. Arch Ophthalmol. 1986; 104:364-6. [IDIS 212468] [PubMed
3513744]
108. Keates RH, McGowan KA. Clinical trial of flurbiprofen to maintain pupillary dilation
during cataract surgery. Ann Ophthalmol. 1984; 16:919-21. [PubMed 6391333]
109. Camras CR, Miranda OC. The putative role of prostaglandins in surgical miosis. Prog Clin
Biol Res. 1989; 312:197-210. [PubMed 2508124]
110. Goa KL, Chrisp P. Ocular diclofenac: a review of its pharmacology and clinical use in
cataract surgery, and potential in other inflammatory ocular conditions. Drugs Aging. 1992;
2:473-86. [PubMed 1493352]
111. Green K, Cheeks L, Luxenberg MN. Topical indomethacin and prostaglandins in normal
and aphakic rabbit eyes. Curr Eye Res. 1988; 7:1105-11. [PubMed 3243084]
112. Hersh PS, Rice BA, Baer JC et al. Topical nonsteroidal agents and corneal wound healing.
Arch Ophthalmol. 1990; 108:577-83. [PubMed 2322160]
113. Trousdale MD, Dunkel EC, Nesburn AB. Effect of flurbiprofen on herpes simplex keratitis
in rabbits. Invest Ophthalmol Vis Sci. 1980; 19:267-70. [PubMed 7358477]
114. Trousdale MD, Barlow WE, McGuigan LJB. Assessment of diclofenac on herpes keratitis
in rabbit eyes. Arch Ophthalmol. 1989; 107: 1664-6.
115. Allergan Medical Optics. Ocufen Liquifilm (flurbiprofen sodium) 0.03% sterile
ophthalmic solution prescribing information. Physicians' desk reference for ophthalmology.
20th ed. Montvale, NJ: Medical Economics Company Inc; 1992:236-7.
116. Haynes RC Jr. Adrenocorticotropic hormone: adrenocortical steroids and their synthetic
analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In: Gilman AG,
Rall TW, Nies AS, et al, eds. Goodman and Gilman's the pharmacological basis of
therapeutics. 8th ed. New York: Pergamon Press; 1990:1431-62.
117. Haddow GR, Riley E, Isaacs R et al. Ketorolac, nasal polyposis, and bronchial asthma: a
cause for concern. Anesth Analg. 1993; 76:420-2. [IDIS 310160] [PubMed 8424525]
118. Zikowski D, Hord AH, Haddox JD et al. Ketorolac-induced bronchospasm. Anesth Analg.
1993; 76:417-9. [IDIS 310159] [PubMed 8424524]
119. Campbell WB. Lipid-derived autacoids: eicosanoids and platelet -activating factor. In:
Gilman AG, Rall TW, Nies AS, et al, eds. Goodman and Gilman's the pharmacological basis
of therapeutics. 8th ed. New York: Pergamon Press; 1990:600 -605.

120. Flower RJ, Blackwell GJ. Anti-inflammatory steroids induce biosynthesis of a

phospholipase A2 inhibitor which prevents PG production. Nature. 1979; 278:456 -9.
[PubMed 450050]
121. Kremer M, Baikoff G, Charbonnel B. The release of prostaglandins in human aqueous
humour following intraocular surgery: effect of indomethacin. Prostaglandins. 1982; 23:695702. [PubMed 6956947]
122. Kremer M, Baikoff G, Charbonnel B. Prostaglandin E2 in side effects of ocular surgery in
man: preventive action of indomethacin. Adv Prostaglandin Thromboxane Leukot Res. 1983;
12:121-6. [PubMed 6221587]
123. Miyake K, Sugiyama S, Norimatsu I et al. Prevention of cystoid macular edema after lens
extraction by topical indomethacin (III) radioimmunoassay measurement of prostaglandins in
the aqueous during and after lens extraction procedures. Graefes Arch Klin Exp Ophthalmol.
1978; 209:83-8.
124. Miyake K. Prevention of cystoid macular edema after lens extraction by topical
indomethacin (I): a preliminary report. Graefes Arch Klin Exp Ophthalmol. 1977; 203:81-8.
125. Miyake K. Prophylaxis of aphakic cystoid macular edema using topical indomethacin. J
Am Intraocul Implant Soc. 1978; 4:174-9. [PubMed 748308]
126. Paterson CA, Eakins KE, Paterson E et al. The ocular hypertensive response following
experimental acid burns in the rabbit eye. Invest Ophthalmol Vis Sci. 1979; 18:67-74.
[PubMed 32151]
127. Rowland JM, Ford CJ, Della Puca RA et al. Effects of topical diclofenac sodium in a rabbit
model of ocular inflammation and leukotaxis. J Ocul Pharmacol. 1986; 2:23-9. [PubMed
3509726]
128. Bhattercherjee P, Eakins KE. Inhibition of the ocular effects of sodium arachidonate by
anti-inflammatory compounds. Prostaglandins. 1975; 9:175-82. [PubMed 1135434]
129. Neufeld AH, Sears ML. Prostaglandin and the eye. Prostaglandins. 1973; 4:157-75.
[PubMed 4199679]
130. Waitzman MB. Possible new concepts relating prostaglandins to various ocular functions.
Surv Ophthalmol. 1970; 14:301-26. [PubMed 4984791]
131. van Haeringen NJ, Glasium E, Oosterhuis JA et al. Drug prevention of blood -aqueous
barrier disruption. Ophthalmic Res. 1983; 15:180-4. [PubMed 6634053]
132. van Haeringen NJ, Osterhuis JA, van Delft JL et al. A comparison of the effects of nonsteroidal compounds on the disruption of the blood -aqueous barrier. Exp Eye Res. 1982;
35:271-7. [PubMed 7117419]
133. Eakins KE. Prostaglandin and non-prostaglandin mediated breakdown of the bloodaqueous barrier. Exp Eye Res. 1977; 25(Suppl):483-98. [PubMed 338326]

134. Neufeld AH, Sears ML. The site of action of prostaglandin E2 on the disruption of the
blood-aqueous barrier in the rabbit eye. Exp Eye Res. 1973; 17:445-8. [PubMed 4783182]
135. Oosterhuis JA, van Haeringen NJ, Glasius E et al. The effect of indomethacin on the
anterior segment of the eye after paracentesis. Doc Ophthalmol. 1981; 50:303-13. [PubMed
7227171]
136. Eakins KE, Bhattacherjee P. Histamine, prostaglandins and ocular inflammation. Exp Eye
Res. 1977; 24:299-305. [PubMed 852527]
137. Reviewers' comments (personal observations).
138. Mahoney JM, Waterbury LD. (+)-5 Benzoyl-1,2-dihydro-3H -pyrrolo(1,2a)pyrrole-1carboxlic acid (rS-37619)a non-irritating ophthalmic anti -inflammatory agent. Invest
Ophthalmol Vis Sci. 1983; 24(Suppl):151.
139. Allergan, Irvine, CA: Personal communication.
140. Waterbury L, Kunysz EA, Beuerman R. Effects of steroidal and non -steroidal antiinflammatory agents on corneal wound healing. J Ocul Pharmacol. 1987; 3:43-54. [PubMed
3503908]
141. Tinkelman DG, Rupp G, Kaufman H et al. Double-masked, paired-comparison clinical
study of ketorolac tromethamine 0.5% ophthalmic solution compared with placebo eyedrops
in the treatment of seasonal allergic conjunctivitis. Surv Ophthalmol. 1993; 38(Suppl): 133140. [PubMed 8236004]
142. Ballas Z, Blumenthal M, Tinkeman DG et al. Clinical evaluation of ketorolac tromethamine
0.5% ophthalmic solution for the treatment of seasonal allergic conjunctivitis. Surv
Ophthalmol. 1993; 38(Suppl): 141-8.
143. Anonymous. Ketorolac for seasonal allergic conjunctivitis. Med Lett Drugs Ther. 1993; 35:
88-9.
144. Morrow GL, Abbott RL. Conjunctivitis. Am Fam Physician. 1998; 57:735-46. [IDIS
418448] [PubMed 9490996]
145. Titi MJ. A critical look at ocular allergy drugs. Am Fam Physician. 1996; 53:2637-42.
[IDIS 367250] [PubMed 8644576]
146. Galindez OA, Kaufman HE. Coping with the itchy-burnies: the management of allergic
conjunctivitis. Ophthalmology. 1996; 103:1335-6. [IDIS 373485] [PubMed 8841290]
147. Ostrov CS, Sirkin SR, Deutsch WE et al. Ketorolac, prednisolone, and dexamethasone for
postoperative inflammation. Clin Ther. 1997; 19:259-72. [IDIS 387651] [PubMed 9152565]
148. Hawkey CJ. COX-2 inhibitors. Lancet. 1999; 353:307-14. [IDIS 418284] [PubMed
9929039]

149. Kurumbail RG, Stevens AM, Gierse JK et al. Structural basis for selective inhibition of
cyclooxygenase-2 by anti-inflammatory agents. Nature. 1996; 384:644-8. [PubMed 8967954]
150. Riendeau D, Charleson S, Cromlish W et al. Comparison of the cyclooxygenase-1
inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2
inhibitors, using sensitive microsomal and platelet assays. Can J Physiol Pharmacol. 1997;
75:1088-95. [PubMed 9365818]
151. DeWitt DL, Bhattacharyya D, Lecomte M et al. The differential susceptibility of
prostaglandin endoperoxide H synthases-1 and -2 to nonsteroidal anti-inflammatory drugs:
aspirin derivatives as selective inhibitors. Med Chem Res. 1995; 5:325-43.
152. Cryer B, Dubois A. The advent of highly selective inhibitors of cyclooxygenasea review.
Prostaglandins Other Lipid Mediators. 1998; 56:341-61. [PubMed 9990677]
153. Simon LS. Role and regulation of cyclooxygenase-2 during inflammation. Am J Med.
1999; 106(Suppl 5B):37-42S.
154. Allergan. Acular PF (ketorolac tromethamine) ophthalmic solution 0.5% preservative free
sterile prescribing information. Irvine, CA; 2002 Feb.
155. Allergan. Acular LS (ketorolac tromethamine) ophthalmic solution 0.4% prescribing
information. Irvine, CA; 2003 May.
156. Solomon KD, Donnenfeld ED, Raizman M et al. Safety and efficacy of ketorolac
tromethamine 0.4% ophthalmic solution in post-photorefractive keratectomy patients. J
Cataract Refract Surg. 2004; 30:1653-60. [PubMed 15313287]