AHFS Class:

• Nonsteroidal Anti-inflammatory Agents 52:08.20

Generic Name(s):

• Flurbiprofen Sodium

Flurbiprofen, a propionic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA).1,2,3,4,16,17,18,19,20,21,23

Inhibition of Intraoperative Miosis

In ophthalmology, topical flurbiprofen sodium is used prophylactically before ocular surgery (e.g., cataract extraction)74,102 to prevent or reduce intraoperative miosis.1,74,102 Intraoperative miosis may decrease direct visualization of intraocular structures and increase the difficulty of the operative procedure (e.g., aspiration of lens material during cataract surgery and implantation of an intraocular lens).74,103

There currently is limited information available on the clinical use of topical flurbiprofen for the inhibition of intraoperative miosis.74,102 Results to date indicate that the drug can effectively reduce miosis occurring during cataract extraction.1,74,102 Flurbiprofen has been used topically in conjunction with phenylephrine, gentamicin, and tropicamide prior to cataract surgery.74 Further clinical evaluation is needed.74

Results of some studies indicate that use of a 0.1% topical solution of flurbiprofen sodium (not commercially available) before and after cataract surgery may prevent or reduce disruption of the blood-aqueous humor barrier that occurs during the surgery.48,50

Other Uses

The value of topical flurbiprofen for the prevention and management of postoperative ocular inflammation† remains to be more fully determined.75,76,78 Limited data suggest that use of topical flurbiprofen before and after argon laser trabeculoplasty in patients with open-angle glaucoma may decrease the degree of conjunctival erythema present 24 hours after the procedure76 and the occurrence and degree of post-procedural conjunctival injection;78 however, the drug appears to have little or no effect on intraocular inflammation (anterior chamber cells or flare) or on the transient increase in IOP that occurs following the laser treatment.76,78 Based on limited data, use of topical flurbiprofen before and after cyclocryotherapy in patients with refractory glaucoma also appears to have little or no effect on postoperative intraocular inflammation.75 Further evaluation of the effects of topical flurbiprofen on intraocular inflammation is needed.74,75,76,78,103

The value of topical NSAIAs,35,48,71,97 including flurbiprofen,48 for the prevention of postoperative cystoid macular edema† in patients undergoing cataract surgery remains to be determined.

In animals, topical flurbiprofen has inhibited corneal neovascularization induced by chemical80 or thermal81 burns or prolonged use of contact lenses.79 Controlled studies are needed to determine the value, if any, of topical NSAIAs in the inhibition of neovascularization in human corneal injuries.103,105

For systemic uses of flurbiprofen, see 28:08.04.92.

Administration

Flurbiprofen sodium is applied topically to the eye as an ophthalmic solution.1,74 Care should be taken to avoid contamination of the solution container.94

Dosage

Inhibition of Intraoperative Miosis

For the inhibition of intraoperative miosis, the recommended dosage of flurbiprofen sodium is 1 drop of a 0.03% solution in the eye(s) undergoing surgery beginning 2 hours before the surgery and repeated thereafter at approximately 30-minute intervals for a total of 4 drops per affected eye.1

Flurbiprofen sodium ophthalmic solution is generally well tolerated following topical application to the eye.1,74,76,78,101

Ocular Effects

Mild ocular stinging1,74,101 or burning1,76,78,101 and discomfort78 following instillation of the solution have been reported; these effects occur in most patients101 and usually are transient.1,74,101 Itching78,101,105 or foreign body sensation,78,105 and other minor symptoms of ocular irritation1 (e.g., tearing, dry eye sensation, dull eye pain, photophobia),101,103,105 fibrosis,1 miosis,1 and mydriasis1 also have been reported in some patients.

Topical flurbiprofen may slow corneal wound healing;1,84 however, the drug did not affect corneal re-epithelialization by conjunctival epithelium in rabbits following partial or complete corneal denudation.88

Topical NSAIAs can inhibit platelet aggregation and therefore may increase bleeding (e.g., hyphemas) of ocular tissues in patients undergoing ocular surgery.1

Systemic Effects

Use of flurbiprofen sodium ophthalmic solution has not been associated with adverse systemic effects to date;1,74,75,76,78,101 however, since systemic absorption may occur following ophthalmic application of the drug,65,66,101 the possibility of adverse systemic effects (e.g., increase in bleeding time) may exist.1

Precautions and Contraindications

The manufacturer cautions that topical flurbiprofen may slow or delay wound healing.1,84 (See Cautions: Ocular Effects.)

Flurbiprofen ophthalmic solution should be used with caution in patients who may be affected adversely by a prolongation of bleeding time,1 including those receiving drugs known to prolong bleeding time or with underlying bleeding tendencies,1 since the drug can inhibit platelet aggregation.1,4,28,29,30,31,32,33

Since there is potential for cross-sensitivity between flurbiprofen and aspirin or other NSAIAs, flurbiprofen ophthalmic solution should be used with particular caution in patients with a history of hypersensitivity to these drugs and in those in whom asthma, rhinitis, or urticaria is precipitated by aspirin or other NSAIAs.1,3 A severe, nearly fatal anaphylactic reaction to oral flurbiprofen has been reported in a patient with history of sensitivity to NSAIAs.86 NSAIAs generally are contraindicated in patients in whom urticaria, angioedema, bronchospasm, severe rhinitis, or shock is precipitated by aspirin or other NSAIAs,82,89,90,91,92 although the drugs have occasionally been used systemically in NSAIA-sensitive patients who have undergone desensitization.83,89,90,91,92 For further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08.04.24.

Active epithelial herpes simplex keratitis (dendritic keratitis) previously was included as a contraindication in the manufacturer's prescribing information (labeling) for flurbiprofen ophthalmic solution based on findings in a study in rabbits in which the drug at a concentration more than 30 times the usual concentration exacerbated the infection (increased severity of corneal perforation and clouding and conjunctivitis);1,85 subsequently, however, all such cautionary information was removed from this labeling1 following completion by the same investigator of another study in rabbits that failed to demonstrate risk at usual concentrations of the drug.114 Some clinicians suggest that the drug might be used with extreme caution in patients with active epithelial herpes simplex keratitis.103

Flurbiprofen ophthalmic solution is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1

Pediatric Precautions

Safety and efficacy of flurbiprofen sodium ophthalmic solution in children have not been established.1

Geriatric Precautions

No overall differences in safety and efficacy have been observed between geriatric and younger patients.1

Mutagenicity and Carcinogenicity

Long-term mutagenicity tests of flurbiprofen sodium in animals have not been performed to date.1 No evidence of carcinogenic potential was seen in mice or rats receiving oral flurbiprofen dosages of up to 12 mg/kg daily for 24 or 18 months, respectively.101

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats, mice, and rabbits using oral flurbiprofen have not revealed evidence of teratogenicity.4,101 Reproduction studies in rats using oral flurbiprofen dosages of 0.4 mg/kg daily (approximately 300 times the human topical daily dose) and higher have shown that the drug is embryocidal and can delay parturition; prolong gestation; produce uterine hemorrhage, gastric damage, death of dams and offspring during labor, and an increased incidence of stillbirths; reduce fetal weight; and/or slightly retard fetal growth.1,4,101 There are no adequate and controlled studies to date using ophthalmic flurbiprofen in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1

Fertility

Reproduction studies in male and female rats using oral flurbiprofen dosages of 2.25 mg/kg daily for up to 65 days before mating have not revealed evidence of impaired fertility.4,101

Lactation

It is not known whether flurbiprofen is distributed into milk after topical administration to the eye;1 however, the drug is distributed into milk after systemic administration.117,118 Because of the potential for serious adverse reactions from flurbiprofen sodium in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1

The interactions between flurbiprofen sodium ophthalmic solution and other ophthalmic drugs have not been fully evaluated.1

Acetylcholine Chloride

Although clinical and animal studies with acetylcholine chloride revealed no interference, and there is no known pharmacologic basis for an interaction, acetylcholine chloride has been reported to be ineffective when used in some patients who were concurrently receiving ophthalmic flurbiprofen.1,115

Carbachol

Although animal studies with carbachol revealed no interference and there is no known pharmacologic basis for an interaction, carbachol has been reported to be ineffective when used in patients who were concurrently receiving ophthalmic flurbiprofen.1,115,116

Drugs that Prolong Bleeding Time

Because an increased bleeding tendency of ocular tissues in conjunction with ocular surgery has been reported in patients receiving flurbiprofen sodium ophthalmic solution and other ophthalmic NSAIAs, the drugs should be used with caution in patients concurrently receiving other drugs known to prolong bleeding time.1

Local Anesthetics

In animals, concomitant administration of topical flurbiprofen and some topical local anesthetics (e.g., benoxinate, capsaicin) produces greater miotic inhibition during ocular surgery than topical flurbiprofen alone.40 Experimental data suggest that some topical local anesthetics may exhibit ocular effects similar to those of topical flurbiprofen (e.g., inhibition of intraoperative miosis, decreased disruption of the blood-aqueous humor barrier), although different mechanisms of action appear to be involved.40,61,62,63

Acute Toxicity

There currently is no information available on overdosage of topical flurbiprofen in humans.103 Acute and subacute ocular toxicity studies in rabbits using topical flurbiprofen sodium solutions containing up to 1.1% of the drug revealed no evidence of toxicity other than slight to moderate ocular discomfort.101 The oral LD₅₀ of flurbiprofen in mice and rats is approximately 750 and 600 mg/kg, respectively.4,101 The IV LD₅₀ of the drug in rats is 150 mg/kg.101

In general, overdosage of flurbiprofen may be expected to produce effects associated with inhibition of prostaglandin synthesis.4,103 The manufacturers state that topical overdosage usually should not cause acute difficulties.1

Following acute ingestion, the manufacturer recommends drinking fluids to dilute the drug.1

Pharmacology

Flurbiprofen sodium has pharmacologic actions similar to those of other prototypical NSAIAs.1,3,4,6,16,17,18,19,21,23,24 The drug exhibits anti-inflammatory, analgesic, and antipyretic activity.1,3,16,17,21 The exact mechanisms have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis.1,3,4,18,19,20,21,23,24,25 Like other NSAIAs, flurbiprofen inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase;1,3,18,35 at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and -2 (COX-2) (also referred to as prostaglandin G/H synthase-1 [PGHS-1] and -2 [PGHS-2], respectively), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway.107,108,109,110,111,112 Flurbiprofen, like other prototypical NSAIAs, inhibits both COX-1 and COX-2.107,108,109,110,111,112 Flurbiprofen is one of the most potent NSAIAs currently available.4,16,17,18,19,20,21,23,24,35,101 In vitro studies indicate that the prostaglandin inhibitory activity of flurbiprofen on a molar basis is approximately 1-20 times that of indomethacin,18,19,23,101 10-200 times that of ibuprofen,18,21,101 and 200-5600 times that of aspirin.3,19,101

Generally, the anti-inflammatory effect of NSAIAs appears to be positively correlated with their ability to inhibit prostaglandin synthesis;7,9,10,12,13,18,20 however, the relative contribution of this and other mechanisms of action remains to be determined.4,8,9,10,13,20 Flurbiprofen also inhibits the migration of leukocytes, including polymorphonuclear leukocytes, into sites of inflammation, although the mechanism has not been clearly established.4,20,21,22,24,25

Flurbiprofen does not possess glucocorticoid or adrenocorticoid-stimulating properties.17

Ocular Effects

Following topical application to the eye, flurbiprofen sodium inhibits or reduces miosis1,35,40,74,102 and possibly some manifestations of ocular inflammation75,76,78,84,120 induced by ocular trauma (e.g., ocular surgery). When administered prophylactically, topical flurbiprofen may effectively reduce intraoperative trauma-induced miosis,1,74,102 but the drug has little, if any, effect if administered once trauma-induced miosis is present.103 Flurbiprofen does not inhibit or reduce light-induced miosis.103,105 The exact mechanism of the ocular effects of the drug has not been clearly established, but many of the actions appear to be associated principally with the inhibition of ocular prostaglandin synthesis.1,35,36,37,39,40,43,45,51,52,74,101 Topical NSAIAs inhibit the synthesis of prostaglandins in the iris, ciliary body, and conjunctiva by inhibiting cyclooxygenase.35,36,37,43,51,52,59,64 Flurbiprofen does not appear to affect intraocular pressure (IOP)1,35,49,76,78,101 or tonographic aqueous outflow resistance.35,49 Flurbiprofen also does not prevent increases in IOP or decreases in outflow facility induced by topical corticosteroids.49

It has been postulated that trauma to the eye (e.g., ocular surgery) may cause release of prostaglandins into the aqueous humor.35,36,37,47,48,52 In animals, prostaglandins appear to cause miosis,1,35,36,37,40,44,52,53,56,64,74 intraocular1,35,36,37,39,40,52,58,74 and external ocular57,75,76 inflammation, transient elevation of IOP1,35,36,37,39,44,45,46,52,55,56,74 (which may be followed by ocular hypotension),35,52,55,60 and migration of leukocytes, including polymorphonuclear leukocytes, into tear fluid.41,57 Prostaglandins may also cause ocular vasodilation,1,36,37,44,54,56,74 increase vascular permeability,1,35,36,37,44,52,53,74 and disrupt the blood-aqueous humor barrier.1,36,37,44,52,53,56 Prostaglandins appear to produce a miotic response during ocular surgery by constricting the iris sphincter1,35,51,64,74 independently of cholinergic mechanisms.1,74 The degree of ocular inflammatory response is correlated with prostaglandin-induced increases in permeability of the ciliary epithelium.35,37,46 Transient increases in IOP may result from ocular vasodilation and/or consequent breakdown of the blood-aqueous humor barrier.36,37,44,52,53,56

Like other topical NSAIAs,36,37,39,45 topical flurbiprofen inhibits prostaglandin synthesis in the conjunctiva and uvea and thereby may prevent and/or decrease prostaglandin-associated miosis,1,40,74 vasodilation,74 disruption of the blood-aqueous humor barrier,48,50,93 and/or increases in IOP39,48 and possibly some other manifestations of prostaglandin-associated ocular inflammation.75,76,78,84,106 The ability of topical flurbiprofen to inhibit corneal neovascularization in animal models may also be related to its inhibition of prostaglandin synthesis.79,80,81 Flurbiprofen is 3, 16, or 33 times more potent than indomethacin, fenoprofen, or naproxen, respectively, in inhibiting arachidonic acid-induced increase in IOP in rabbits.39 Flurbiprofen may also inhibit migration of leukocytes, including polymorphonuclear leukocytes, into tear fluid.36,41,42

Systemic Effects

Flurbiprofen shares the systemic effects of other NSAIAs,3,7,8,10,11,12,14,15,26,27 although the risk of systemic effects appears to be minimal following topical ophthalmic use of the drug.1,74,75,76,78,103,105

Flurbiprofen can inhibit platelet aggregation4,28,29,30,31,32,33 but does not appear to affect prothrombin time29,30 or bleeding time.28,29 Like other NSAIAs, these effects of flurbiprofen appear to be associated with inhibition of prostaglandin (thromboxane) synthesis.7,8,10 Unlike the irreversible action of aspirin on platelets and the resultant prolonged effect on platelet aggregation, flurbiprofen has a transient effect on platelet function, and platelet aggregation usually returns to normal within 24 hours following discontinuance of systemically administered drug.28,29 In vitro, flurbiprofen inhibits the platelet response to thrombin or collagen28,29,30,31,32 and the second phase of platelet aggregation induced by adenosine diphosphate28,29,31 or epinephrine.31 It appears that only the d -isomer and not the l -isomer of flurbiprofen inhibits collagen-induced platelet aggregation.32,33

In vitro, flurbiprofen also inhibits dextran-induced erythrocyte aggregation and sedimentation.16

Pharmacokinetics

Absorption

The extent of ocular and systemic absorption of flurbiprofen sodium following topical application to the eye in humans has not been fully elucidated.1,101,104 Following topical application to the eye of 1 drop of a 0.03% solution of the drug every 30 minutes for 2 hours before surgery (total of 4 drops per affected eye) in patients undergoing cataract extraction, aqueous humor concentrations of the drug averaged 213 ng/mL (range: 90-320 ng/mL).101,104 Following oral administration of flurbiprofen 50 mg 3 times daily the day before and once 1 hour before cataract surgery, concentrations of the drug attained in aqueous humor were approximately 10% of those attained with topical application as recommended.101,104

Following topical application to the eye of 50 µL of a 0.03% solution of flurbiprofen sodium (15 mcg) in rabbits, peak drug concentrations in ocular tissues and fluids were reached within 0.5-1 hours and were approximately 6300, 600, 580, 500, 300, 200, 100, 90, 6, and 1 ng/g in the cornea, conjunctiva, nictitating membrane, sclera, aqueous humor, iris, choroid-retina, ciliary body, lens, and vitreous humor, respectively.66 Following topical application of flurbiprofen sodium to aphakic eyes in rabbits, ocular distribution of the drug was generally similar to that observed in normal eyes but drug concentrations in vitreous humor and choroid-retina were higher than in normal eyes.66,101 The extent of ocular absorption and peak aqueous humor concentrations of flurbiprofen do not appear to increase proportionally with the dose.65,101 Following topical application to the eye of 50 µL of a 0.03,66,101 0.15,65,101 or 0.3%65,101 solution of flurbiprofen sodium (15, 75, or 150 mcg, respectively) in rabbits, the absolute ocular bioavailabilities averaged 4, 10, or 7%, respectively.65,66,101 Compared with the 75-mcg dose of the 0.15% solution, the area under the aqueous humor concentration-time curve (AUC) increased by only 70% with the 150-mcg dose of the more concentrated solution.65 Following topical application to the eye of a 0.03, 0.15, or 0.3% solution of flurbiprofen sodium in rabbits, peak plasma concentrations occurred about 30 minutes after application and about 75-95% of the ocularly applied dose was absorbed systemically.65,66,101 Following IV administration of a single 6-mg dose of flurbiprofen sodium in rabbits, aqueous humor concentrations of the drug were approximately 1% of concurrent plasma concentrations.65

Flurbiprofen is rapidly and almost completely absorbed following oral administration.2,3,4,67,68 Following oral administration of a single 50-mg dose of flurbiprofen in healthy adults, peak plasma concentrations of about 5.5 mcg/mL occur within approximately 1-1.5 hours.2,67 Peak plasma concentrations of flurbiprofen reportedly increase proportionally with single oral doses ranging from 50-300 mg.3,68,70 Steady-state plasma concentrations of flurbiprofen were approximately 2.3 mcg/mL in healthy adults receiving oral flurbiprofen dosages of 50 mg 3 times daily.67 In animals, the drug undergoes enterohepatic circulation.3,67

Distribution

Distribution of flurbiprofen sodium into human ocular tissues and fluids has not been fully characterized to date.101,103,104 Following topical application to the eye in rabbits, flurbiprofen is rapidly distributed throughout ocular tissues and fluids, including cornea, external tissues (e.g., sclera, conjunctiva, nictitating membrane), intraocular tissues (e.g., aqueous humor, choroid-retina, iris, ciliary body), lens, and vitreous humor.66 Little,66 if any,65 drug distributes into the contralateral eye following topical66 or intracameral65 (into the anterior chamber of the eye) administration in rabbits. Following oral administration in animals, flurbiprofen is distributed into many tissues, including liver, kidneys, heart, intestines, adrenals, thyroid, stomach, eyes, and bile, but only minimally into CSF.3,67,99 Following oral administration of flurbiprofen in humans, the drug does not appear to be widely distributed.68

Following intracameral administration in rabbits, flurbiprofen is rapidly distributed into aqueous humor; the apparent initial ocular volume of distribution averaged 0.47 mL (range: 0.26-0.62 mL), and the ocular volume of distribution at steady state (V_ss) and during the terminal ocular elimination phase averaged 0.62 and 1.99 mL, respectively.65 Following oral administration of flurbiprofen in healthy adults, the apparent volume of distribution is approximately 9.1 L.68

Flurbiprofen is at least 99% bound to plasma proteins,3,67,69 mainly albumin.3,67,69 In vitro at plasma flurbiprofen concentrations of 5-20 mcg/mL, only 1 primary protein-binding site has been identified;3,67 however, at very high plasma concentrations, secondary binding sites may contribute to the protein binding of the drug.67 Flurbiprofen apparently binds to a different albumin binding site than oral anticoagulants, sulfonamides, or phenytoin.3,73 Protein binding of the drug appears to be independent of pH in the range of 7-8.69 Flurbiprofen may also bind to erythrocytes.68

It is not known whether flurbiprofen crosses the placenta103 or is distributed into milk following ophthalmic administration;1 however, the drug is distributed into milk after systemic administration.117,118

Elimination

Following intracameral administration of flurbiprofen in rabbits, aqueous humor concentrations of the drug appear to decline in a biphasic manner.65 Following a single intracameral dose in rabbits, the half-life of flurbiprofen averaged about 15 minutes in the initial ocular distribution phase (t_½α) and about 1.5 hours in the ocular elimination phase (t_½β).65 Following IV administration in rabbits, plasma concentrations of flurbiprofen appear to decline in a biphasic manner.65 Following a single 6-mg IV dose in rabbits, the plasma half-life of flurbiprofen averaged about 12 minutes in the initial distribution phase (t_½α) and 74 minutes in the terminal elimination phase (t_½β).65 Following a single oral dose in healthy adults, the plasma half-life of flurbiprofen in the initial distribution phase (t_½α) is about 3-4 hours,67,68 and the half-life in the terminal elimination phase (t_½β) is about 6-10 hours.67,68

The exact metabolic fate of flurbiprofen is not fully established.3,4,67,68,69 Following systemic absorption, the drug is extensively metabolized, probably in the liver,67 to 3 major metabolites3,4,66,67,68 and to at least 3 unidentified minor metabolites.67 Two major metabolites, 4'-hydroxyflurbiprofen and 3',4'-dihydroxyflurbiprofen, are formed by hydroxylation, and the third major metabolite, 3'-hydroxy-4'-methoxyflurbiprofen, is formed by hydroxylation and methylation.67,68 The principal metabolite, 4'-hydroxyflurbiprofen, has weak prostaglandin inhibitory activity.3,98 Flurbiprofen and its metabolites undergo extensive glucuronide and sulfate conjugation.67,68 Following oral administration in humans, metabolites have not been detected in plasma; however, substantial amounts of the metabolites are found in urine.4,67 Following topical application of flurbiprofen to the eye in rabbits, only unchanged drug was found in ocular tissues;66,101 however, metabolites and unchanged drug were found in urine, indicating systemic absorption.66 Metabolism of topical flurbiprofen apparently occurs after the drug has been absorbed systemically and not in ocular tissues.66,105 Flurbiprofen apparently does not induce or inhibit its own metabolism.4,67

Following a single oral dose of flurbiprofen in healthy adults, about 95% of the dose is excreted in urine within 24 hours.68 In healthy individuals, about 20-25% of an oral dose is excreted in urine as unchanged drug, 40-45% as 4'-hydroxyflurbiprofen, 5% as 3',4'-dihydroxyflurbiprofen, and 20-30% as 3'-hydroxy-4'-methoxyflurbiprofen.67,68 The drug and its metabolites are excreted in urine mainly as glucuronide and sulfate conjugates.67,68

Following intracameral administration of flurbiprofen in rabbits, ocular clearance of flurbiprofen averaged 0.0144 mL/minute (range: 0.0114-0.0157 mL/minute).65 Following oral administration of flurbiprofen in healthy adults, the apparent total plasma clearance of flurbiprofen was approximately 20 mL/minute.68

Chemistry and Stability

Chemistry

Flurbiprofen, a propionic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA).1,2,3,4,16,17,18,19,20,21,23 The drug is structurally and pharmacologically related to fenoprofen, ibuprofen, and ketoprofen.3,4,16,23 The presence and proximity of the fluorine atom and carboxylic acid group in flurbiprofen are associated with the drug's time-dependent inhibition of prostaglandin synthesis.95

The commercially available flurbiprofen ophthalmic solution contains the sodium dihydrate salt of the drug.1 Flurbiprofen occurs as white4 or colorless2,17 crystals.2,4,17 The sodium salt of the drug has a solubility of 4 mg/mL in water (pH 7) at 26°C.105 Flurbiprofen has a pK_a of 4.22.100

Flurbiprofen sodium ophthalmic solution is a sterile, isotonic solution of the drug in purified water;1 hydrochloric acid and/or sodium hydroxide is added to adjust pH to 6-7.1,105 The ophthalmic solution also contains thimerosal as a preservative, potassium chloride and sodium chloride to adjust tonicity, polyvinyl alcohol to adjust viscosity, and sodium citrate and citric acid as a buffer.1

Stability

Flurbiprofen sodium ophthalmic solution should be stored in tight, light-resistant containers105 at 15-25°C.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Allergan Pharmaceuticals, Inc. Ocufen^® (flurbiprofen sodium ophthalmic solution) 0.03% prescribing information. Irvine, CA; 2004 May.

2. Reynolds JEF, ed. Martindale: the extra pharmacopoeia. 28th ed. London: The Pharmaceutical Press; 1982:255.

3. Brogden RN, Heel RC, Speight TM et al. Flurbiprofen: a review of its pharmacological properties and therapeutic use in rheumatic diseases. Drugs . 1979; 18:417-38. [PubMed 391529]

4. Adams SS, Buckler JW. Ibuprofen and flurbiprofen. Clin Rheum Dis . 1979; 5:359-79.

5. Mimnaugh MN, Gearien JE. Nonsteroidal anti-inflammatory agents. In: Foye WO, ed. Principles of medicinal chemistry. 2nd ed. Philadelphia: Lea & Febiger; 1981:561-90.

6. Flower RJ, Moncada S, Vane JR. Analgesic-antipyretics and anti-inflammatory agents; drugs employed in the treatment of gout. In: Gilman AG, Goodman LS, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:674-715.

7. Moncada S, Roderick JF, Vane JR. Prostaglandins, prostacyclin, thromboxane A2, and leukotrienes. In: Gilman AG, Goodman L, Rall TW et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 7th ed. New York: Macmillan Publishing Company; 1985:660-73.

8. Wolf RE. Nonsteroidal anti-inflammatory drugs. Arch Intern Med . 1984; 144:1658-60. [PubMed 6235791]

9. Abramson S, Edelson H, Kaplan H et al. Inhibition of neutrophil activation by nonsteroidal anti-inflammatory drugs. Am J Med . 1984; 77(Suppl 4B):3-6. [PubMed 6093509]

10. Robinson DR. Prostaglandins and the mechanism of action of anti-inflammatory drugs. Am J Med . 1983; 75(Suppl 4B):26-31. [PubMed 6416064]

11. O'Brien WM. Pharmacology of nonsteroidal anti-inflammatory drugs: practical review for clinicians. Am J Med . 1983; 75(Suppl 4B):32-9.

12. Hart FD, Huskisson EC. Non-steroidal anti-inflammatory drugs: current status and rational therapeutic use. Drugs . 1984; 27:232-55. [PubMed 6368185]

13. Simon LS, Mills JA. Nonsteroidal antiinflammatory drugs. N Engl J Med . 1980; 302:1179-85. [PubMed 6988717]

14. Robert A. Cytoprotection by prostaglandins. Gastroenterology . 1979; 77:761-7. [PubMed 38173]

15. Miller TA, Jacobson ED. Gastrointestinal cytoprotection by prostaglandins. Gut . 1979; 20:75-87. [PubMed 367886]

16. Glenn EM, Rohloff N, Bowman BJ et al. The pharmacology of 2-(2-fluoro-4-biphenylyl)propionic acid (flurbiprofen): a potent non-steroidal anti-inflammatory drug. Agents Actions . 1973; 3:210-6. [PubMed 4776365]

17. Adams SS, McCullough KF, Nicholson JS. Some biological properties of flurbiprofen, an anti-inflammatory, analgesic and antipyretic agent. Arzneimittelforschung . 1975; 25:1786-91. [PubMed 1081878]

18. Nozu K. Flurbiprofen: highly potent inhibitor of prostaglandin synthesis. Biochim Biophys Acta . 1978; 529:493-6. [PubMed 96864]

19. Crook D, Collins AJ, Rose AJ. A comparison of the effect of flurbiprofen on prostaglandin synthetase from human rheumatoid synovium and enzymatically active animal tissues. J Pharm Pharmacol . 1976; 28:535. [PubMed 7661]

20. Ford-Hutchinson AW, Walker JR, Connor NS et al. Separate anti-inflammatory effects of indomethacin, flurbiprofen and benoxaprofen. J Pharm Pharmacol . 1977; 29:372-3. [PubMed 18578]

21. Adams SS. Some aspects of the pharmacology and pharmacokinetics of flurbiprofen. Drugs Exp Clin Res . 1977; 2:27-33.

22. Ringrose PS, Parr MA, McLaren M. Effects of anti-inflammatory and other compounds on the release of lysosomal enzymes from macrophages. Biochem Pharmacol . 1975; 24:607-14. [PubMed 164870]

23. Fitzpatrick FA, Wynalda MA. In vivo suppression of prostaglandin biosynthesis by non-steroidal anti-inflammatory agents. Prostaglandins . 1976; 12:1037-51. [PubMed 1005736]

24. Blackham A, Owen RT. Prostaglandin synthetase inhibitors and leucocytic emigration. J Pharm Pharmacol . 1975; 27:201-3. [PubMed 238006]

25. Adams SS, Burrows CA, Skeldon N et al. Inhibition of prostaglandin synthesis and leucocyte migration by flurbiprofen. Curr Med Res Opin . 1977; 5:11-6. [PubMed 410589]

26. Vakil BJ, Kulkarni RD, Kulkarni VN et al. Estimation of gastro-intestinal blood loss in volunteers treated with non-steroidal anti-inflammatory agents. Curr Med Res Opin . 1977; 5:32-7. [PubMed 334471]

27. Vakil BJ, Shah PN, Dalal NJ et al. Endoscopic study of gastro-intestinal injury with non-steroidal anti-inflammatory drugs. Curr Med Res Opin . 1977; 5:38-42. [PubMed 334472]

28. Sim AK, McCraw AP, Sim MF. An evaluation of the effect of flurbiprofen [2-(2-fluoro-4-biphenylyl) propionic acid] on platelet behaviour. Thromb Res . 1975; 7:655-68. [PubMed 1198551]

29. Davies T, Lederer DA, Spencer AA et al. The effect of flurbiprofen [2-(2-fluoro-4-biphenylyl) propionic acid] on platelet function and blood coagulation. Thromb Res . 1974; 5:667-83. [PubMed 4445988]

30. Gupta KC, Manikeri S, Paul T et al. Effect of RH-8, flurbiprofen and aspirin on platelet function and coagulation. Ind J Med Res . 1979; 69:181-8.

31. Abe T, Goto H, Imaoka S et al. Influence of flurbiprofen on platelet aggregation. Part I: Metabolic and ultrastructural studies in vitro. Acta Haem Jap . 1978; 41:111-26.

32. Nishizawa EE, Wynalda DJ, Suydam DE et al. Flurbiprofen, a new potent inhibitor of platelet aggregation. Thromb Res . 1973; 3:577-88.

33. Nishizawa EE, Wynalda DJ, Suydam DE. Effect of flurbiprofen on platelet function. Thromb Diath Haemorrh . 1974; 60:415-23.

34. Cremoncini CM, Libroia A, Valente C et al. Flurbiprofen and thyroid function tests. Br J Clin Pract . 1984; 38:399-402. [PubMed 6397221]

35. Havener WH. Ocular pharmacology. 5th ed. St. Louis: The CV Mosby Company; 1983:18-43,223-35.

36. Bhattacherjee P. Prostaglandins and inflammatory reactions in the eye. Methods Find Exp Clin Pharmacol . 1980; 2:17-31. [PubMed 6803089]

37. Eakins KE. Prostaglandin and non-prostaglandin mediated breakdown of the blood-aqueous barrier. Exp Eye Res . 1977; 25(Suppl):483-98. [PubMed 338326]

38. van Alphen GWHM, Wilhelm P. Effect of prostaglandins on the blood-aqueous barrier of the perfused cat eye. Invest Ophthalmol Vis Sci . 1978; 17:60-3. [PubMed 621127]

39. Podos SM, Becker B. Comparison of ocular prostaglandin synthesis inhibitors. Invest Ophthalmol . 1976; 15:841-4. [PubMed 977253]

40. Duffin RM, Camras CB, Gardner SK et al. Inhibitors of surgically induced miosis. Ophthalmology . 1982; 89:966-78. [PubMed 7133642]

41. Srinivasan BD, Kulkarni PS. Polymorphonuclear leukocyte response: inhibition following corneal epithelial denudation by steroidal and nonsteroidal anti-inflammatory agents. Arch Ophthalmol . 1981; 99:1085-9. [PubMed 7236107]

42. Srinivasan BD, Kulkarni PS. The effect of indomethacin (INDO), flurbiprofen (F) and prednisolone acetate on conjunctival prostaglandin (PG) biosynthesis and polymorphonuclear leukocyte (PMN) release following corneal injury. Invest Ophthalmol Vis Sci . 1980; 19(Suppl):228-9.

43. Kulkarni PS, Srinivasan BD. Comparative in vivo inhibitory effects of nonsteroidal anti-inflammatory agents on prostaglandin synthesis in rabbit ocular tissues. Arch Ophthalmol . 1985; 103:103-6. [PubMed 3919694]

44. Beitch BR, Eakins KE. The effects of prostaglandins on the intraocular pressure of the rabbit. Br J Pharmacol . 1969; 37:158-67. [PubMed 4981000]

45. Leopold IH, Murray D. Noncorticosteroidal anti-inflammatory agents in ophthalmology. Ophthalmology . 1979; 86:142-55. [PubMed 394060]

46. Green K. Permeability properties of the ciliary epithelium in response to prostaglandins. Invest Ophthalmol . 1973; 12:752-8. [PubMed 4784282]

47. Miller JD, Eakins KE, Atwal M. The release of PGE₂-like activity into aqueous humor after paracentesis and its prevention by aspirin. Invest Ophthalmol . 1973; 12:939-42. [PubMed 4768600]

48. Araie M, Sawa M, Takase M. Topical flurbiprofen and diclofenac suppress blood-aqueous barrier breakdown in cataract surgery: a fluorophotometric study. Jpn J Ophthalmol . 1983; 27:535-42. [PubMed 6656015]

49. Gieser DK, Hodapp E, Goldberg I et al. Flurbiprofen and intraocular pressure. Ann Ophthalmol . 1981; 13:831-3. [PubMed 7027872]

50. Araie M, Takase M. Effects of S-596 and carteolol, new beta-adrenergic blockers, and flurbiprofen on the human eye: a fluorophotometric study. Graefes Arch Clin Exp Ophthalmol . 1985; 222:259-62. [PubMed 2579877]

51. 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]

52. Hall DWR, Bonta IL. Prostaglandins and ocular inflammation. Doc Ophthalmol . 1977; 2:421-34.

53. Waitzman MB. Possible new concepts relating prostaglandins to various ocular functions. Surv Ophthalmol . 1970; 14:301-26. [PubMed 4984791]

54. Starr MS. Effects of prostaglandin on blood flow in the rabbit eye. Exp Eye Res . 1971; 11:161-9. [PubMed 5001094]

55. Starr MS. Further studies on the effect of prostaglandin on intraocular pressure in the rabbit. Exp Eye Res . 1971; 11:170-7. [PubMed 5001095]

56. Eakins KE. Increased intraocular pressure produced by prostaglandins E₁ and E₂ in the cat eye. Exp Eye Res . 1970; 10:87-92. [PubMed 5456783]

57. Srinivasan BD, Kulkarni PS. The role of arachidonic acid metabolites in the mediation of the polymorphonuclear leukocyte response following corneal injury. Invest Ophthalmol Vis Sci . 1980; 19:1087-93. [PubMed 7409999]

58. Eakins KE, Whitelocke RAF, Bennett A et al. Prostaglandin-like activity in ocular inflammation. Br Med J . 1972; 3:452-3. [PubMed 5069222]

59. Kass MA, Holmberg NJ. Prostaglandin and thromboxane synthesis by microsomes of rabbit ocular tissues. Invest Ophthalmol Vis Sci . 1979; 18:166-71. [PubMed 761971]

60. Camras CB, Bito LZ, Eakins KE. Reduction of intraocular pressure by prostaglandins applied topically to the eyes of conscious rabbits. Invest Ophthalmol Vis Sci . 1977; 16:1125-34. [PubMed 924742]

61. Butler JM, Unger WG, Hammond BR. Sensory mediation of the ocular response to neutral formaldehyde. Exp Eye Res . 1979; 28:577-89. [PubMed 571810]

62. Unger WG, Cole DF, Bass MS. Prostaglandin and neurogenically mediated ocular response to laser irradiation of the rabbit iris. Exp Eye Res . 1977; 25:209-20. [PubMed 590365]

63. Jampol LM, Neufeld AH, Sears ML. Pathways for the response of the eye to injury. Invest Ophthalmol Vis Sci . 1975; 14:184-9.

64. Sawa M, Masuda K. Topical indomethacin in soft cataract aspiration. Jpn J Ophthalmol . 1976; 20:514-9.

65. Tang-Liu DDS, Liu SS, Weinkam RJ. Ocular and systemic bioavailability of ophthalmic flurbiprofen. J Pharmacokinet Biopharm . 1984; 12:611-26. [PubMed 6533296]

66. Anderson JA, Chen CC, Vita JB et al. Disposition of topical flurbiprofen in normal and aphakic rabbit eyes. Arch Ophthalmol . 1982; 100:642-5. [PubMed 7073585]

67. Risdall PC, Adams SS, Crampton EL et al. The disposition and metabolism of flurbiprofen in several species including man. Xenobiotica . 1978; 8:691-704. [PubMed 103331]

68. Kaiser DG, Brooks CD, Lomen PL. Pharmacokinetics of flurbiprofen. Am J Med . 1986; 80(Suppl 3A):10-5. [PubMed 3963013]

69. Aarons L, Khan AZ, Grennan DM et al. The binding of flurbiprofen to plasma proteins. J Pharm Pharmacol . 1985; 37:644-6. [PubMed 2867185]

70. Cardoe N, de-Silva M, Glass RC et al. Serum concentrations of flurbiprofen in rheumatoid patients receiving flurbiprofen over long periods of time. Curr Med Res Opin . 1977; 5:21-5. [PubMed 913119]

71. Miyake K. Prevention of cystoid macular edema after lens extraction by topical indomethacin. II: a control study in bilateral extractions. Jpn J Ophthalmol . 1978; 22:80-94.

72. BenEzra D. Neovasculogenic ability of prostaglandins, growth factors, and synthetic chemoattractants. Am J Ophthalmol . 1978; 86:455-61. [PubMed 707590]

73. Sudlow G, Birkett DJ, Wade DN. Further characterization of specific drug binding sites on human serum albumin. Mol Pharmacol . 1976; 12:1052-61. [PubMed 1004490]

74. Keates RH, McGowan KA. Clinical trial of flurbiprofen to maintain pupillary dilation during cataract surgery. Ann Ophthalmol . 1984; 16:919-21. [PubMed 6391333]

75. Hurvitz LM, Spaeth GL, Zakhour I et al. A comparison of the effect of flurbiprofen, dexamethasone, and placebo on cyclocryotherapy-induced inflammation. Ophthalmic Surg . 1984; 15:394-9. [PubMed 6374562]

76. Weinreb RN, Robin AL, Baerveldt G et al. Flurbiprofen pretreatment in argon laser trabeculoplasty of primary open-angle glaucoma. Arch Ophthalmol . 1984; 102:1629-32. [PubMed 6497745]

77. Hillman JS, Frank GJ, Kheskani MB. Flurbiprofen and human intraocular inflammation. Adv Prostaglandin Thromboxane Res . 1980; 8:1723-5. [PubMed 6990732]

78. Hotchkiss ML, Robin AL, Pollack IP et al. Nonsteroidal anti-inflammatory agents after argon laser trabeculoplasty: a trial with flurbiprofen and indomethacin. Ophthalmology . 1984; 91:969-76. [PubMed 6387568]

79. Duffin M, Weissman BA, Glasser DB et al. Flurbiprofen in the treatment of corneal neovascularization induced by contact lenses. Am J Ophthalmol . 1982; 93:607-14. [PubMed 6177247]

80. Cooper CA, Bergamini VW, Leopold IH. Use of flurbiprofen to inhibit corneal neovascularization. Arch Ophthalmol . 1980; 98:1102-5. [PubMed 6155898]

81. Robin JB, Regis-Pacheco LF, Kash RL et al. The histopathology of corneal neovascularization: inhibitor effects. Arch Ophthalmol . 1985; 103:284-7. [PubMed 2579632]

82. Weinberger M. Analgesic sensitivity in children with asthma. Pediatrics . 1978; 62(Suppl):910-5. [PubMed 103067]

83. 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. [PubMed 7054250]

84. Miller D, Gruenberg P, Miller R et al. Topical flurbiprofen or prednisolone: effect on corneal wound healing in rabbits. Arch Ophthalmol . 1981; 99:681-2. [PubMed 7224940]

85. Trousdale MD, Dunkel EC, Nesburn AB. Effect of flurbiprofen on herpes simplex keratitis in rabbits. Invest Ophthalmol . 1980; 19:267-70.

86. Cohen RD, Bateman ED, Potgieter PD. Near-fatal bronchospasm in an asthmatic patient following ingestion of flurbiprofen: a case report. S Afr Med J . 1982; 61:803. [PubMed 7079897]

87. Moebius UM. Adverse drug reactions. Lancet . 1986; 1:384.

88. Srinivasan BD, Kulkarni PS. The effect of steroidal and nonsteroidal anti-inflammatory agents on corneal re-epithelialization. Invest Ophthalmol Vis Sci . 1981; 20:688-91. [PubMed 7216684]

89. VanArsdel PP Jr. Aspirin idiosyncrasy and tolerance. J Allergy Clin Immunol . 1984; 73:431-3. [PubMed 6423718]

90. Stevenson DD. Diagnosis, prevention, and treatment of adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs. J Allergy Clin Immunol . 1984; 74(4 Part 2):617-22. [PubMed 6436354]

91. Stevenson DD, Mathison DA. Aspirin sensitivity in asthmatics: when may this drug be safe? Postgrad Med . 1985; 78:111-3,116-9. (IDIS 205854)

92. Settipane GA. Aspirin and allergic diseases: a review. Am J Med . 1983; 74(Suppl):102-9. [PubMed 6344621]

93. Van Haeringen NJ, Oosterhuis 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]

94. American Society of Health-System Pharmacists, Inc.. Medication teaching manual: a guide for patient counseling. 2nd ed. Bethesda, MD: American Society of Hospital Pharmacists; 1980:300.

95. Rome LH, Lands WEM. Structural requirements for time-dependent inhibition of prostaglandin biosynthesis by anti-inflammatory drugs. Proc Natl Acad Sci USA . 1975; 72:4863-5. [PubMed 1061075]

96. Bito LZ, Draga A, Blanco J et al. Long-term maintenance of reduced intraocular pressure by daily or twice daily topical application of prostaglandins to cat or rhesus monkey eyes. Invest Ophthalmol Vis Sci . 1983; 24:312-9. [PubMed 6572617]

97. Miyake K. Prophylaxis of aphakic cystoid macular edema using topical indomethacin. J Am Intraocul Implant Soc . 1978; 4:174-9. [PubMed 748308]

98. Adams SS, Bresloff P, Risdall PC. The contribution of metabolites to the anti-inflammatory activity of flurbiprofen. Curr Med Res Opin . 1975; 3(Suppl 4):27-30.

99. Ishii Y, Sakai Y, Masumoto S et al. Absorption, distribution, excretion and anti-inflammatory effects of flurbiprofen in animals after rectal administration. Curr Med Res Opin . 1975; 3:31-8.

100. Anderson BD, Conradi RA. Predictive relationships in the water solubility of salts of a nonsteroidal anti-inflammatory drug. J Pharm Sci . 1985; 74:815-20. [PubMed 4032262]

101. Allergan Pharmaceuticals, Inc. Ocufen^® (flurbiprofen topical ophthalmic solution). Irvine, CA; 1987 Jan.

102. Allergan Pharmaceuticals, Inc. Ocufen^® (flurbiprofen sodium 0.03% ophthalmic solution): inhibition of miosis during cataract surgery. Irvine, CA; 1987 Jan.

103. Reviewers' comments (personal observations); 1987.

104. Cheetham JK, Chen CC, Sabiston DW. The concentration of flurbiprofen in the aqueous humor of humans after multiple topical or oral dosing. Invest Ophthalmol Vis Sci . 1987; 28(Suppl):395.

105. Petrauskas J (Allergan Pharmaceuticals, Inc, Irvine, CA): Personal communication; 1987.

106. Bhattacherjee P, Williams RN, Eakins KE. A comparison of the ocular anti-inflammatory activity of steroidal and nonsteroidal compounds in the rat. Invest Ophthalmol Vis Sci . 1983; 24:1143-6. [PubMed 6874278]

107. Hawkey CJ. COX-2 inhibitors. Lancet . 1999; 353:307-14. [PubMed 9929039]

108. 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]

109. 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]

110. 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.

111. Cryer B, Dubois A. The advent of highly selective inhibitors of cyclooxygenase—a review. Prostaglandins Other Lipid Mediators . 1998; 56:341-61. [PubMed 9990677]

112. Simon LS. Role and regulation of cyclooxygenase-2 during inflammation. Am J Med . 1999; 106(Suppl 5B):37-42S.

113. Allergan Inc., Irvine, CA: Personal communication; 2007 Mar 28.

114. Trousdale MD, Barlow WE, McGuigan LJB. Assessment of diclofenac on herpes keratitis in rabbit eyes. Arch Ophthalmol . 1989; 107: 1664-6.

115. Holmes JM, Jay WM. The effect of preoperative flurbiprofen on miosis produced by acetylcholine during cataract surgery. Am J Ophthalmol . 1991; 111:735-8. [PubMed 2039045]

116. Jackson H, Patel CK, Westcott M et al. Does topical flurbiprofen affect the pupillary response to acetylcholine?. Eye . 1994; 8 (Part 3):329-31.

117. Cox SR, Forbes KK. Excretion of flurbiprofen into breast milk. Pharmacotherapy . 1987; 7:211-5. [PubMed 3444752]

118. Smith IJ, Hinson JL, Johnson VA et al. Flurbiprofen in post-partum women: plasma and breast milk disposition. J Clin Pharmacol . 1989; 29:174-84. [PubMed 2715375]

119. Gimbel H, Van Westenbrugge J, Cheetham JK et al. Intraocular availability and pupillary effect of flurbiprofen and indomethacin during cataract surgery. J Cataract Refract Surg . 1996; 22:474-9. [PubMed 8733853]

120. Solomon LD. Efficacy of topical flurbiprofen and indomethacin in preventing pseudophakic cystoid macular edema. Flurbiprofen-CME Study Group 1. J Cataract Refract Surg . 1995; 21:73-81. [PubMed 7722910]

121. Peyman GA, Kazi AA, Riazi-Esfahani M et al. The effect of combinations of flurbiprofen, low molecular weight heparin, and doxycycline on the inhibition of corneal neovascularization. Cornea . 2006; 25:582-5. [PubMed 16783147]