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Manufacturer
VALEANT
SKU
24208031425

flurbiprofen 0.03% eye drop

Generic
$7.02 / drop btl
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Uses

Inhibition of Intraoperative Miosis

In ophthalmology, topical flurbiprofen sodium is used prophylactically before ocular surgery (e.g., cataract extraction) to prevent or reduce intraoperative miosis. 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).

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

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.

Other Uses

The value of topical flurbiprofen for the prevention and management of postoperative ocular inflammation remains to be more fully determined. 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 procedure and the occurrence and degree of post-procedural conjunctival injection; 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. 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. Further evaluation of the effects of topical flurbiprofen on intraocular inflammation is needed.

The value of topical NSAIAs, including flurbiprofen, 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 chemical or thermal burns or prolonged use of contact lenses. Controlled studies are needed to determine the value, if any, of topical NSAIAs in the inhibition of neovascularization in human corneal injuries.

For systemic uses of flurbiprofen, see 28:08.04.92.

Dosage and Administration

Administration

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

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.

Cautions

Flurbiprofen sodium ophthalmic solution is generally well tolerated following topical application to the eye.

Ocular Effects

Mild ocular stinging or burning and discomfort following instillation of the solution have been reported; these effects occur in most patients and usually are transient. Itching or foreign body sensation, and other minor symptoms of ocular irritation (e.g., tearing, dry eye sensation, dull eye pain, photophobia), fibrosis, miosis, and mydriasis also have been reported in some patients.

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

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

Systemic Effects

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

Precautions and Contraindications

The manufacturer cautions that topical flurbiprofen may slow or delay wound healing. (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, including those receiving drugs known to prolong bleeding time or with underlying bleeding tendencies, since the drug can inhibit platelet aggregation.

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. A severe, nearly fatal anaphylactic reaction to oral flurbiprofen has been reported in a patient with history of sensitivity to NSAIAs. NSAIAs generally are contraindicated in patients in whom urticaria, angioedema, bronchospasm, severe rhinitis, or shock is precipitated by aspirin or other NSAIAs, although the drugs have occasionally been used systemically in NSAIA-sensitive patients who have undergone desensitization. For further discussion of cross-sensitivity of NSAIAs, .

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); subsequently, however, all such cautionary information was removed from this labeling following completion by the same investigator of another study in rabbits that failed to demonstrate risk at usual concentrations of the drug. Some clinicians suggest that the drug might be used with extreme caution in patients with active epithelial herpes simplex keratitis.

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

Pediatric Precautions

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

Geriatric Precautions

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

Mutagenicity and Carcinogenicity

Long-term mutagenicity tests of flurbiprofen sodium in animals have not been performed to date. 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.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats, mice, and rabbits using oral flurbiprofen have not revealed evidence of teratogenicity. 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. 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.

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.

Lactation

It is not known whether flurbiprofen is distributed into milk after topical administration to the eye; however, the drug is distributed into milk after systemic administration. 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.

Drug Interactions

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

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.

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.

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.

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. 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.

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. 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). 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.

Following topical application to the eye of 50 mcL 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. 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. The extent of ocular absorption and peak aqueous humor concentrations of flurbiprofen do not appear to increase proportionally with the dose. Following topical application to the eye of 50 mcL of a 0.03, 0.15, or 0.3% solution of flurbiprofen sodium (15, 75, or 150 mcg, respectively) in rabbits, the absolute ocular bioavailabilities averaged 4, 10, or 7%, respectively. 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. 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. 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.

Flurbiprofen is rapidly and almost completely absorbed following oral administration. 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. Peak plasma concentrations of flurbiprofen reportedly increase proportionally with single oral doses ranging from 50-300 mg. 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. In animals, the drug undergoes enterohepatic circulation.

Distribution

Distribution of flurbiprofen sodium into human ocular tissues and fluids has not been fully characterized to date. 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. Little, if any, drug distributes into the contralateral eye following topical or intracameral (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. Following oral administration of flurbiprofen in humans, the drug does not appear to be widely distributed.

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 (Vss) and during the terminal ocular elimination phase averaged 0.62 and 1.99 mL, respectively. Following oral administration of flurbiprofen in healthy adults, the apparent volume of distribution is approximately 9.1 L.

Flurbiprofen is at least 99% bound to plasma proteins, mainly albumin. In vitro at plasma flurbiprofen concentrations of 5-20 mcg/mL, only 1 primary protein-binding site has been identified; however, at very high plasma concentrations, secondary binding sites may contribute to the protein binding of the drug. Flurbiprofen apparently binds to a different albumin binding site than oral anticoagulants, sulfonamides, or phenytoin. Protein binding of the drug appears to be independent of pH in the range of 7-8. Flurbiprofen may also bind to erythrocytes.

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

Elimination

Following intracameral administration of flurbiprofen in rabbits, aqueous humor concentrations of the drug appear to decline in a biphasic manner. Following a single intracameral dose in rabbits, the half-life of flurbiprofen averaged about 15 minutes in the initial ocular distribution phase (t½α) and about 1.5 hours in the ocular elimination phase (t½β). Following IV administration in rabbits, plasma concentrations of flurbiprofen appear to decline in a biphasic manner. Following a single 6-mg IV dose in rabbits, the plasma half-life of flurbiprofen averaged about 12 minutes in the initial distribution phase (t½α) and 74 minutes in the terminal elimination phase (t½β). Following a single oral dose in healthy adults, the plasma half-life of flurbiprofen in the initial distribution phase (t½α) is about 3-4 hours, and the half-life in the terminal elimination phase (t½β) is about 6-10 hours.

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

Following a single oral dose of flurbiprofen in healthy adults, about 95% of the dose is excreted in urine within 24 hours. 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. The drug and its metabolites are excreted in urine mainly as glucuronide and sulfate conjugates.

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

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