AHFS Class:

• Nonsteroidal Anti-inflammatory Agents 52:08.20

Generic Name(s):

• Ketorolac Tromethamine

• Ketorolac

Ketorolac, a pyrrolizine carboxylic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA).1,2,3,4,14,21,22,25,26,27,28

Conjunctivitis

In ophthalmology, topical ketorolac tromethamine 0.5% is used for its anti-inflammatory effect in the symptomatic treatment of seasonal allergic (hay fever, pollinosis) conjunctivitis.1,141,142,143 Results from a limited number of controlled studies indicate that ketorolac tromethamine ophthalmic solution is more effective than vehicle in providing short-term relief of ocular itching associated with such conjunctivitis.1,141,142,143 Topically applied NSAIAs also may provide some relief of other ocular inflammatory manifestations of this condition but additional study and experience are needed to clarify the role of these agents in the management of seasonal allergic conjunctivitis.72,137,143

Avoidance of allergen and other triggering factors (e.g., irritants) and application of cold compresses and lubricating eye drops are the initial means of managing allergic conjunctivitis.72,74,77,144,145,146 Drug therapy generally is reserved for use when such avoidance is not possible or is ineffective, and can include both prophylactic (e.g., topical mast-cell stabilizers such as cromolyn sodium, lodoxamide tromethamine) and symptomatic (e.g., topical and/or systemic antihistamines, topical vasoconstrictors, topical steroidal and nonsteroidal anti-inflammatory agents [NSAIAs]) therapy.72,74,77,144,145,146 The specific therapy(ies) employed will depend on the characteristics and severity of the allergic conjunctivitis.72,74,77,144,145,146 For patients with seasonal allergic conjunctivitis, prophylaxis with a mast-cell stabilizer often is initiated before and maintained throughout the pollen season, and symptomatic therapy with other agents (e.g., topical antihistamines, topical NSAIAs) generally is initiated as necessary to provide acute relief.72,77,144,145,146 Topical steroids usually are reserved for short-term use in patients with moderate to severe symptoms of allergic conjunctivitis.72,144,145,146

While the efficacy of topical NSAIAs versus corticosteroids for the relief of inflammatory manifestations of allergic conjunctivitis remains to be established, NSAIAs generally are considered less toxic (e.g., absence of predisposition to superinfection, absence of adverse effect on IOP and cataract formation) than corticosteroids and therefore may be preferred as initial topical anti-inflammatory therapy in certain patients.72,74,77,141,142 An initial trial with topical NSAIA therapy may be particularly suited for mild to moderately severe conjunctivitis and when the risk of topical corticosteroid therapy, particularly prolonged therapy (which rarely is indicated), is of concern.72,74 However, because NSAIAs do not share the full range of anti-inflammatory and immunologic effects of corticosteroids,8,72,81,116 response may be limited.74,137 Regardless of the therapy employed (antihistamine, NSAIA, corticosteroid, vasoconstrictors), relief of all of the clinically important manifestations of allergic conjunctivitis may not be possible despite combined topical and/or systemic administration.72,74,77,137 In general, the least toxic therapy providing adequate relief should be employed.72,74,77,137

Results from a limited number of controlled studies indicate short-term administration (up to 1 week) of ketorolac tromethamine 0.5% ophthalmic solution is more effective than vehicle in providing short-term symptomatic relief of seasonal allergic conjunctivitis.1,141,142,143 In these studies, administration of ketorolac tromethamine ophthalmic solution was associated with decreased conjunctival inflammation and ocular itching.1,141,142,143 In some patients, improvement in other ocular allergic manifestations (e.g., swollen eye, discharge or tearing, foreign body sensation) also was reported.1,141,142,143

Topical NSAIAs also have been used for their anti-inflammatory activity in the symptomatic treatment of vernal or atopic keratoconjunctivitis†77,82,84,86 and contact lens-associated giant papillary conjunctivitis†.83,86,88 However, management of these ocular allergic conditions often is more complex than that of seasonal allergic conjunctivitis.74,77,88,104,105 Because of the severity of manifestations, topical corticosteroids, topical cromolyn sodium, and systemic antihistamines often are necessary for the management of acute episodes in patients with vernal or atopic keratoconjunctivitis.74,77,104,105 For patients with contact lens-associated giant papillary conjunctivitis, meticulous lens care, frequent replacement of lenses (e.g., switching to disposable lenses), changing the type of lens, and/or temporary or permanent discontinuance of contact lens use are the mainstay of management of this condition.74,77,88 However, despite the current paucity of efficacy data in either condition, a trial with topical NSAIA therapy may be attempted to provide some symptomatic relief since the risk of such therapy, at least in adults, appears minimal.74,83,84,137,138

Postoperative and Posttraumatic Ocular Inflammation

In ophthalmology, topical ketorolac tromethamine 0.5% also has been used prophylactically after ocular surgery (e.g., cataract extraction, with or without implantation of an intraocular lens) to prevent or relieve postoperative ocular inflammation.1,11,17,18,19,61,85,110,147 Because NSAIAs inhibit prostaglandin formation rather than the effects of these autacoids once formed, efficacy of the drugs may be reduced if administration is delayed until inflammation is established.11,17,18,19,81,89,90,111 Therefore, some clinicians advocate that topical NSAIA therapy be initiated prior to surgery.11,17,18,19,81,111,137,147 However, optimal timing of such therapy remains to be established.11,17,18,19,20,24,81,85,86,87,101,137,139

In controlled studies, perioperative topical application to the eye of ketorolac tromethamine 0.5% reduced lid edema, conjunctival vasodilation, ciliary flush, and the number of anterior chamber cells and flare as determined by slit-lamp biomicroscopic or fluorophotometric evaluation.11,17,81,147 The drug also has reduced postoperative disruption of the blood-aqueous barrier.17,18,147 While topical corticosteroids were used concomitantly in some patients, the need for these drugs was less in ketorolac-treated patients than in those receiving placebo.11,81 In addition, there is evidence of ketorolac's efficacy from a placebo-controlled study in which concomitant corticosteroid therapy was not permitted.17,81 There also is some evidence that ketorolac tromethamine 0.5% may be at least as effective as dexamethasone sodium phosphate 0.1% (of dexamethasone phosphate) or prednisolone acetate 1% in the management of postoperative ocular inflammation and in restabilization of the blood-aqueous barrier,18,19,81,147 and evidence from studies with various NSAIAs suggests that the drugs actually may be more effective than corticosteroids in restabilizing the barrier.18,81,91,110,147 Additive or synergistic ocular anti-inflammatory activity may occur when a topical NSAIA and a corticosteroid are used concomitantly, and some patients may benefit from such combined therapy to the eye.11,18,81,90

Postoperative Ocular Pain

In ophthalmology, topical ketorolac tromethamine 0.5% as a preservative-free solution is used after ocular incisional refractive surgery to reduce ocular pain and photophobia.154 Results from 2 double-blind, multicenter, placebo-controlled studies in over 300 patients indicate that short-term application (up to 3 days) of ketorolac tromethamine 0.5% (as a preservative-free solution) is more effective than vehicle in reducing ocular pain and photophobia following ocular incisional refractive surgery.154

In ophthalmology, topical ketorolac tromethamine 0.4% is used following corneal refractive surgery to reduce ocular pain and burning/stinging.155,156 Ketorolac tromethamine 0.5% also provides analgesic and anti-inflammatory effects; however, use of the preparation is associated with ocular irritation, mainly burning and stinging on instillation.1,154,156 Ketorolac tromethamine 0.4% ophthalmic solution (Acular LS^®) is formulated with a lower concentration of the drug and certain inactive ingredients (i.e., benzalkonium chloride, edetate disodium) to reduce the incidence of adverse effects while maintaining clinical efficacy.156 Ketorolac tromethamine 0.4% ophthalmic solution has been evaluated for the treatment of ocular pain in patients undergoing photorefractive keratectomy (PRK), a procedure associated with severe postoperative ocular pain.156 In 2 multicenter, randomized, double-blind studies in over 300 patients undergoing PRK surgery, short-term therapy (up to 4 days) with ketorolac tromethamine 0.4% ophthalmic solution was more effective than placebo (vehicle) in reducing ocular pain and burning/stinging following surgery.155,156

Cystoid Macular Edema

NSAIAs,61,81,87,93,94,95,96,97,98,99,100,101,102,103,110 including ketorolac tromethamine,61 also have been applied topically to the eye, with or without concomitant topical corticosteroid therapy, to prevent or relieve postoperative cystoid macular edema associated with cataract extraction†. The drugs also have been used for the active treatment of chronic aphakic or pseudophakic cystoid macular edema†.14,20,23 While prophylactic therapy with the drugs has effectively prevented or reduced angiographic evidence of cystoid macular edema for up to several months after cataract surgery,81,93,102,103,110 there is less evidence for improvement in visual acuity.61,81,137 The potential benefit on visual acuity of active treatment of cystoid macular edema also is unclear.23,61,81,93,94,98,103 There is limited evidence indicating that topical ketorolac therapy (without concomitant corticosteroid therapy) may improve distance acuity in many patients when used for the active treatment of chronic aphakic or pseudophakic cystoid macular edema but such improvement may not be permanent.20,23,137

The comparative efficacy of topical NSAIAs, topical corticosteroids, topical NSAIAs combined with topical corticosteroids, or other agents for the prevention or active treatment of cystoid macular edema remains to be established.81,137 Most experience to date has involved combined therapy with a topical NSAIA and a topical corticosteroid.81,101,102,103 While there is limited evidence that NSAIAs alone can effectively prevent or relieve cystoid macular edema,20,23,61,81,110 there also is limited evidence that combined topical NSAIA and corticosteroid therapy may have an additive or synergistic effect in this condition.81,101,102,103 In addition, some clinicians state that the need for the development or identification of more effective therapy persists.137

Inhibition of Intraoperative Miosis

In ophthalmology, NSAIAs also have been used prophylactically before ocular surgery (e.g., cataract extraction) to prevent or reduce intraoperative miosis†, which may occur secondary to surgery-induced trauma despite preoperative induction of mydriasis.53,81,106,107,108,110,137,139 However, the clinical value of such therapy remains controversial, in part because of the variability and degree of the effect.81,92,109,137

For systemic uses of ketorolac tromethamine, see 28:08.04.92.

Administration

Ketorolac tromethamine is applied topically to the eye as an ophthalmic solution.1,154,155 To prevent contamination of the solution, patients should be instructed to avoid allowing the tip of the dispensing container to contact any surface, the eyelids, or surrounding structures.154 Contact lenses should be removed prior to administration of ketorolac tromethamine ophthalmic solution.1,154,155 The preservative-free solution is for single use only in one or both eyes; the preservative-free solution should be used immediately after opening and any unused portion should be discarded immediately after administration.154

Dosage

Conjunctivitis

For relief of ocular itching associated with seasonal allergic conjunctivitis, the usual adult dosage of ketorolac tromethamine is 1 drop of a 0.5% solution (250 mcg) in the affected eye(s) 4 times daily.1,141,142

Postoperative and Posttraumatic Ocular Inflammation

For the prevention and relief of postoperative ocular inflammation in patients undergoing cataract extraction, the usual dosage of ketorolac tromethamine is 1 drop of a 0.5% solution (250 mcg) in the eye(s) undergoing surgery 4 times daily beginning 24 hours after surgery.1 Ketorolac tromethamine therapy usually is continued at this dosage for 2 weeks after surgery.1

Postoperative Ocular Pain

To reduce ocular pain and photophobia in patients undergoing ocular incisional refractive surgery, the usual dosage of ketorolac tromethamine 0.5% (as a preservative-free solution) is 1 drop (250 mcg) 4 times daily in the operated eye(s) as needed for up to 3 days after surgery.154

To reduce pain and burning/stinging in patients undergoing corneal refractive surgery, the usual dosage of ketorolac tromethamine is 1 drop of a 0.4% solution (200 mcg) 4 times daily in the operated eye(s) as needed for up to 4 days.155

Cystoid Macular Edema

For the prevention and relief of postoperative cystoid macular edema associated with cataract extraction†, 1 or 2 drops of a 0. 5% ketorolac tromethamine solution (250 or 500 mcg) have been applied topically to the eye(s) undergoing surgery every 6-8 hours beginning 24 hours before surgery and continuing for 3-4 weeks after surgery.11,17,18,19,61,85

For the active treatment of chronic aphakic or pseudophakic cystoid macular edema†, 1 or 2 drops of a 0. 5% ketorolac tromethamine solution (250 or 500 mcg) have been applied topically to the affected eye(s) 4 times daily for 2-3 months.20,23 Occasionally, such therapy has been continued for longer periods, but the long-term risks versus benefits remain to be established.

Ketorolac tromethamine ophthalmic solution generally is well tolerated following topical application to the eye.1,4,19,20,23,72,74,85,147,154,155

Ocular Effects

The most frequent adverse effects of topical ketorolac tromethamine are stinging and burning following instillation of the solution; these effects have occurred in about 20-40% of patients receiving the drug in some clinical studies and usually are transient.1,85,141,142,143,154,155 Ocular irritation, allergic reactions, superficial ocular infections, superficial keratitis, ocular inflammation, corneal edema, and iritis have occurred in 1-10% of patients receiving ketorolac ophthalmic solutions.1,139,154,155 Conjunctival hyperemia, corneal infiltrates, ocular edema, or ocular pain has been reported in 1-5% of patients receiving ketorolac tromethamine 0.5% (as a preservative-free solution) or ketorolac tromethamine 0.4% solution in clinical studies.154,155 Ocular dryness,1,154,155 corneal ulcer,1,154,155 or visual disturbance (blurred vision)1,154,155 has occurred rarely in patients receiving ketorolac tromethamine ophthalmic solutions. Corneal erosion, corneal perforation, corneal thinning, and epithelial breakdown have been reported during postmarketing surveillance.1,154,155 (See Cautions: Precautions and Contraindications.)

In patients receiving ketorolac tromethamine 0.5% ophthalmic solution for the prevention or relief of postoperative inflammation associated with cataract surgery, most ocular complaints reported in clinical studies could not be distinguished from those associated with the trauma of surgery and/or implantation of an intraocular lens.85 In such patients, the most common adverse ocular effects were conjunctivitis (erythema, scratchiness, foreign body sensation), ocular pain (pain, ache, burning), and ptosis, occurring in 5-10% of patients.85 Keratitis was reported in 3% of patients, and iritis, corneal lesion, photophobia, pupillary disorder, blepharitis, and glaucoma were reported in 2% of patients.85,139 Postsurgical atonic mydriasis, which is resistant to reversal with parasympathomimetic agents, also has been reported in patients receiving topical NSAIAs prior to cataract surgery;81 however, this effect also has been reported following such surgery in patients who did not receive NSAIAs.81 In a controlled study of ketorolac tromethamine ophthalmic solution for the prevention or treatment of cystoid macular edema, the incidence and severity of ocular complaints also were similar in patients receiving the drug or placebo.23

There is some evidence that topically applied ketorolac tromethamine to the eye is less likely than topically applied corticosteroids to predispose to various ocular infections.1,12,13,14,15,19,83 In studies in rabbits, topically applied ketorolac tromethamine did not exacerbate ocular bacterial (e.g., Pseudomonas aeruginosa ),12,14,85 fungal (e.g., Candida albicans ),13,14,85 or viral (e.g., herpes simplex type 1) infections,14,15,85 while similarly applied corticosteroids did.

Topically applied ketorolac tromethamine does not appear to adversely affect intraocular pressure (IOP).1,4,14,17,154,155 However, changes in IOP may occur following cataract surgery.1

The effect of ketorolac tromethamine on ocular wound healing remains to be fully elucidated, although topical application to the eye in rabbits of ketorolac tromethamine 0.5% did not delay healing in corneal wounds.85,140 The manufacturers of ketorolac tromethamine ophthalmic solutions and some other ophthalmic NSAIAs (e.g., flurbiprofen, diclofenac) caution that topical application of NSAIAs to the eye may slow or delay wound healing;1,24,53,154,155 however, early corneal epithelialization rather than corneal stromal healing appears to be affected.112,137 The possibility that a similar effect might occur with ketorolac tromethamine should be considered.137,139

Topical NSAIAs can inhibit platelet aggregation and therefore may increase bleeding (e.g., hyphemas) of ocular tissues in patients undergoing ocular surgery.1,24,53,106,154,155

Systemic Effects

Since systemic absorption may occur following topical application of ketorolac tromethamine to the eye, the possibility of adverse systemic effects may exist.1,142,154,155 However, some evidence suggests that the risk of systemic effects following topical application to the eye in usual dosages is low.85,139,141,142 Headache has been reported rarely following instillation of ketorolac tromethamine ophthalmic solution.1,142,154,155 For additional information on adverse systemic effects of the drug, see Cautions in Ketorolac 28:08.04.92.

Precautions and Contraindications

The manufacturer cautions that topical application of NSAIAs may slow wound healing.1,154,155 Because topical application of corticosteroids also may interfere with wound healing, concomitant use of these agents with topical NSAIAs, including ophthalmic ketorolac tromethamine, may increase the potential for healing problems.1,154,155

Use of topical NSAIAs may result in keratitis.1,154,155 In some susceptible patients, continued use of topical NSAIAs also may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration, or corneal perforation; these events may be sight-threatening.1,154 The manufacturer states that patients presenting with evidence of corneal epithelial breakdown should be advised to discontinue topical NSAIA therapy immediately and should be closely monitored for corneal health.1,154,155

Postmarketing experience with topical NSAIAs suggests that 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 may be at increased risk of developing adverse corneal effects that may become sight-threatening.1,154,155 Therefore, the manufacturer states that topical NSAIAs should be used with caution in these patients.1,154,155

Postmarketing experience suggests that use of topical NSAIAs more than 24 hours prior to surgery or use beyond 14 days postoperatively may precipitate or exacerbate adverse corneal effects.1,154,155

Ketorolac tromethamine 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,1,154,155 since the drug inhibits platelet aggregation.137

Since there is potential for cross-sensitivity between ketorolac and other NSAIAs (including aspirin), ketorolac tromethamine ophthalmic solution should be used with caution in patients in whom asthma, rhinitis, or urticaria is precipitated by aspirin or other NSAIAs.1,54,55,56,57,58,59,85,117,118,154,155 For further discussion of cross-sensitivity of NSAIAs, see Cautions: Sensitivity Reactions, in the Salicylates General Statement 28:08:04.24.

The manufacturer of one NSAIA ophthalmic solution (suprofen [no longer commercially available]) states that the drug is contraindicated in patients with active epithelial herpes simplex keratitis (dendritic keratitis).106 This contraindication previously was included in the labeling of another NSAIA (flurbiprofen) based on findings in a study in rabbits in which the drug at a concentration more than 3 times the usual concentration exacerbated the infection (increased severity of corneal ulceration and conjunctivitis) and delayed healing;113,115 subsequently, however, all such cautionary information was removed from this labeling53 following completion by the same investigator of another study in rabbits that failed to demonstrate risk at usual concentrations of the drug.114 This contraindication also currently is not included in the labeling of ketorolac tromethamine1 or diclofenac,24 and studies with these topically applied drugs to the eye in rabbits revealed no evidence of exacerbation of viral or certain other microbial infections at usual concentrations of the drugs.1,12,13,14,15,110,114 Therefore, appropriate use of ketorolac tromethamine ophthalmic solution in patients with ocular infections currently is not precluded, although caution would be prudent.1,85,139

Patients who wear contact lenses should remove their lenses prior to receiving a dose of ketorolac tromethamine ophthalmic solution.1,154,155 (See Dosage and Administration: Administration.)

Ketorolac tromethamine ophthalmic solution is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1,85,154,155

Pediatric Precautions

Safety and efficacy of ketorolac tromethamine ophthalmic solution in children younger than 3 years of age have not been established.1,154,155

Geriatric Precautions

The manufacturer states that no overall differences in safety or efficacy have been observed between geriatric and younger patients.1,154,155

Mutagenicity and Carcinogenicity

Ketorolac tromethamine was not mutagenic in vitro in the Ames assay or in forward mutation assays.1,154,155 In addition, the drug did not result in an increase in unscheduled DNA synthesis in vitro or an increase in chromosome breakage in mice.1,154,155 However, ketorolac tromethamine did produce an increased incidence of chromosomal aberrations in Chinese hamster ovary cells.1,154,155

No evidence of carcinogenic potential was seen in an 18-month study in mice receiving oral ketorolac tromethamine dosages of 2 mg/kg daily (approximately equivalent to 60 times the maximum recommended human topical ophthalmic dosage of ketorolac tromethamine 0.5% on a mg/kg basis).1,21,154 There also was no evidence of carcinogenic potential in a 24-month study in rats receiving oral ketorolac tromethamine dosages up to 5 mg/kg daily (approximately 151 times the maximum recommended human topical ophthalmic dosage of ketorolac tromethamine 0.5% on a mg/kg basis).1,21,22,154

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rabbits and rats receiving oral ketorolac tromethamine dosages up to 109 and 303 times the maximum recommended human topical ophthalmic dosage of ketorolac tromethamine 0.5% (on a mg/kg basis), respectively, have not revealed evidence of harm to the fetus.1,21,22,154 However, oral dosages exceeding 45 times the maximum recommended human topical ophthalmic dosage of ketorolac tromethamine 0.5% (on a mg/kg basis) in rats produced dystocia and was associated with an increased neonatal death rate.1,154 There are no adequate and controlled studies to date using ophthalmic ketorolac tromethamine in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risk to the fetus.1,154,155 Ketorolac tromethamine ophthalmic solution should not be used during late pregnancy, since inhibitors of prostaglandin synthesis may have adverse effects on the fetal cardiovascular system (e.g., premature closure of the ductus arteriosus).1,24,60,85,137,139,154,155

Fertility

Ketorolac tromethamine did not impair fertility when administered orally to male and female rats at dosages up to 272 and 484 times the maximum recommended human topical ophthalmic dose of ketorolac tromethamine 0.5%, respectively, on a mg/kg basis.1,154

Lactation

Because ketorolac is distributed into milk following systemic administration (see Pharmacokinetics: Distribution, in Ketorolac 28:08.04.92),2,14,21,22,48,85 the ophthalmic solution should be used with caution in nursing women.1,85,154,155

The manufacturer states that ketorolac tromethamine ophthalmic solution has been used safely in conjunction with other ophthalmic agents, including antibiotics, β-adrenergic blocking agents, carbonic anhydrase inhibitors, cycloplegics, and/or mydriatics.1,85,155 The ophthalmic solution also has been used in conjunction with injectable sedatives (e.g., diazepam, hydroxyzine, lorazepam, promethazine hydrochloride), hyaluronidase, and/or local anesthetics (bupivacaine hydrochloride, lidocaine hydrochloride, tetracaine hydrochloride).17,19,85

Corticosteroids

Ophthalmic NSAIAs, including ketorolac tromethamine, have been used concomitantly with ophthalmic corticosteroids.11,18,81,101,102,103,110 While NSAIAs and corticosteroids both can inhibit prostaglandin synthesis, the drugs appear to act principally at different sites in the synthetic pathway8,72,80,81,116 and corticosteroids can affect leukotriene synthesis as well as possibly other mediators of inflammation.72,81,116 Additive or synergistic ocular anti-inflammatory activity may result when a topical NSAIA and corticosteroid are used concomitantly.81,90 This effect has been used to therapeutic advantage in some patients for the management of postoperative ocular inflammation,11,18,81 including cystoid macular edema.81,101,102,103 However, because administration of topical NSAIAs and corticosteroids may slow wound healing, the manufacturer states that concomitant use of these agents may increase the potential for healing problems.1,154,155 (See Cautions: Precautions and Contraindications.)

Acute Toxicity

There currently is no information available on overdosage of topical ketorolac tromethamine in humans.1 The acute lethal dose of ketorolac tromethamine in humans is not known.2,21 The oral LD₅₀ of the drug is 200 mg/kg in mice.10 Ocular toxicity studies in dogs, monkeys, and rats revealed no evidence of local irritation at topically applied ketorolac tromethamine concentrations up to 0.5%.16,138

It has been suggested by a few manufacturers that oral fluids be administered following acute ingestion of an ophthalmic NSAIA preparation in order to dilute the drug.24,85,106

Pharmacology

Ketorolac tromethamine has pharmacologic actions similar to those of other prototypical NSAIAs.1,2,3,4,10,21,25,154,155 The drug exhibits anti-inflammatory, analgesic, and antipyretic activity.1,2,3,4,10,14,21,25,27,154,155 The exact mechanisms have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis.1,2,4,10,21,28,80,81,110 Ketorolac tromethamine inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase;4,10,14,21,27,28,76,119,137 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.148,149,150,151,152,153 Ketorolac, like other prototypical NSAIAs, inhibits both COX-1 and COX-2.148,149,150,151,152,153,8,14,21,32,33,76,77,80,81,110 Ketorolac does not appear to inhibit lipoxygenase21,81 and therefore would not be expected to inhibit aspects of inflammation mediated by leukotrienes.81,119,137

Generally, the anti-inflammatory effect of NSAIAs appears to be correlated positively with their ability to inhibit prostaglandin synthesis; however, the relative contribution of this and other mechanisms of action remains to be determined. 8,32,33,34,35,36,37,76,77,80,81,110 On a weight basis, the anti-inflammatory potency of oral ketorolac tromethamine has been shown to be 2-3 times that of indomethacin10 or naproxen10,14 and about 36 times that of phenylbutazone,3,4,10,14 as determined by inhibition of carrageenan-induced paw edema in rats.4,10 However, when determined by inhibition of cotton pellet-induced granuloma in rats, the anti-inflammatory potency of ketorolac tromethamine was comparable to that of indomethacin.10,14

It appears that ketorolac tromethamine does not suppress phagocytic activity of mononuclear macrophages.9 In addition, the drug does not possess glucocorticoid or mineralocorticoid activity.10

Ocular Effects

Following topical application to the eye, NSAIAs, including ketorolac tromethamine, can reduce certain manifestations of ocular inflammation induced by ocular trauma (e.g., ocular surgery)4,11,17,80,81,110,123,124,125,127,128,131,132,133,134,135 or external agents (e.g., allergens, bacteria).1,12,13,14 The mechanisms of ocular inflammatory reactions are complex and involve a variety of mediators (e.g., cytokines, histamine, leukotrienes, prostaglandins). 73,74,75,80,81,110,129,130,131,132,133,134,135,136,137 The synthesis and release of prostaglandins into aqueous humor have been shown to be increased with ocular trauma (e.g., surgery) and inflammation in animals.80,81,110,121,122,123,126 The principal source of these prostaglandins appears to be the iris-ciliary body,80,110 although other ocular tissues also appear to contribute to concentrations of these and other arachidonic acid metabolites in aqueous humor.80 Trauma involving the anterior segment of the eye is associated with an influx of protein into aqueous humor secondary to disruption of the blood-aqueous barrier and with other inflammatory changes, increases in intraocular pressure (IOP), and anticholinergic-resistant miosis.80,81,110,124,125,126,127,131,132,133,134,135 These effects are mediated in part by prostaglandins.80,110,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136 In addition to effects on the blood-aqueous barrier, endogenous prostaglandins may contribute to the manifestations of intraocular inflammation by stimulating vasodilation and increasing vascular permeability.110,124,127,129,130

The exact mechanism(s) of the ocular effects of NSAIAs has not been clearly established, but these actions appear to be associated principally with the inhibition of ocular prostaglandin synthesis.1,4,6,31,40,62,63,64,65,66,67,68,69,72,73,77,80,81,110,121,122,123,124,125,126,127,128,131,133,135,154,155 NSAIAs inhibit the synthesis of certain prostaglandins (e.g., PGE₂) in iris, ciliary body, and conjunctiva by inhibiting cyclooxygenase.1,6,40,62,66,68,69,70,71,72,73,77,80,81,110 Aqueous humor concentrations of these prostaglandins are reduced substantially following topical application to the eye or systemic administration of NSAIAs.1,80,81,110,121,122,123,126,128 In patients undergoing cataract extraction, the concentration of PGE₂ in aqueous humor is reduced by 65% following topical application of ketorolac tromethamine 0.5% ophthalmic solution compared with administration of vehicle.1,139 By reducing ocular production of prostaglandins, the drugs can inhibit ocular inflammation and other reactions mediated primarily or secondarily by prostaglandins.73,74,75,77,80,81,110,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136 Thus, pretreatment with NSAIAs can inhibit ocular inflammatory manifestations such as conjunctival erythema, chemosis, and mucous discharge73 and the prostaglandin-mediated breakdown of the blood-aqueous barrier17,18,81,110,121,122,123,124,125,131,132,135 and resultant changes (e.g., perifoveal capillary dilatation, capillary leakage) associated with the development of cystoid macular edema.20,23,61,81,123,124,125 Likewise, the drugs can inhibit or reduce corneal neovascularization4,38,39,138 and ocular trauma-induced miosis53,81,110 as well as relieve ocular manifestations of seasonal allergic conjunctivitis (possibly secondary to reductions in PGD₂ production) such as itching.1 However, the intraocular anti-inflammatory action of NSAIAs may be limited by their apparent inability to inhibit the synthesis and/or activity of other mediators of inflammation (e.g., leukotrienes).80,81,110,136

Topically applied ketorolac tromethamine does not appear to adversely affect intraocular pressure (IOP).1,4,14,17,154,155 Application of ketorolac tromethamine to the eye also does not exacerbate ocular bacterial,12,14 fungal,13,14 or viral infections.14,15 Like other NSAIAs, topically applied ketorolac tromethamine may increase bleeding of ocular tissue in patients undergoing ocular surgery.1,24,53,79

Systemic Effects

Although ketorolac shares the systemic activity of other NSAIAs (e.g., following oral or parenteral administration),2,4,8,10 the risk of systemic effects appears to be minimal following topical ophthalmic administration of the drug.1,11,14,17,20,23,81

Ketorolac can inhibit collagen- and arachidonic acid-induced platelet aggregation and may prolong bleeding time.2,14,21,27,41,42,43,44

Pharmacokinetics

Absorption

The extent of ocular and systemic absorption of ketorolac tromethamine following topical application to the eye in humans has not been fully elucidated;1 however, only limited concentrations are achieved systemically following such application relative to usual oral or parenteral doses of the drug.1,14,16,18 Following topical application to the eyes of 2 drops (100 µL) of a 0.5% solution (500 mcg) of ketorolac tromethamine 12 hours and 1 hour before surgery in a limited number of patients undergoing cataract extraction, measurable aqueous humor concentrations of the drug were detected in almost all patients, averaging 95 ng/mL (range: 40-170 ng/mL) during surgery.1 Following topical application to one eye of 1 drop (50 µL) of a 0.5% solution (250 mcg) of the drug 3 times daily for 10 days in a limited number of healthy adults, plasma concentrations of drug were detectable (range: 10.7-22.5 ng/mL) in about 20% of these individuals.1,154,155 Following topical application to the eye of a 250-mcg dose of ketorolac tromethamine in rabbits, peak plasma concentrations of approximately 200 ng/mL occurred within about 15 minutes.16 In these rabbits, mean aqueous humor concentrations of the drug exceeded those of plasma 13-fold.16 In healthy adults, steady-state plasma concentrations of ketorolac average approximately 600-800 or 1300-1500 ng/mL with IM ketorolac tromethamine dosages of 15 or 30 mg, respectively, 4 times daily.2,21,27

Distribution

Distribution of ketorolac tromethamine into human ocular tissues and fluids has not been fully characterized to date.1,14,78 Following topical application to the eye of a 0.5% solution of ketorolac tromethamine in rabbits, the drug distributes throughout ocular tissues and fluids, including cornea, external tissues (e.g., sclera), intraocular tissues (e.g., aqueous humor, choroid-retina, iris, ciliary body), lens, and vitreous humor;14,16,78 concentrations are highest in scleral and corneal tissues and lowest in the lens.14,16,78 Following topical application of 50 µL of a 0.5% solution (250 mcg) of ketorolac tromethamine to each eye in anesthetized rabbits, peak anterior chamber ketorolac concentrations of 19 mcg/mL were reached within 3.4 hours; the relative bioavailability in aqueous humor following topical application to the eye was about 4% of that following intracameral injection.6,16

Following oral, IM, or IV administration of ketorolac tromethamine in humans, ketorolac does not appear to be distributed widely.2,14,27,28,49,78 (See Pharmacokinetics: Distribution, in Ketorolac 28:08.04.92.) Ketorolac is more than 99% bound to plasma proteins,2,14,28,45,49,78 but does not appear to bind irreversibly to ocular tissues.16

Ketorolac crosses the placenta.21,28,46,47,78 The drug also is distributed into milk, but in relatively small amounts.2,14,21,22,48,78

Elimination

Ketorolac tromethamine dissociates into ketorolac (anion) and tromethamine (cation) at physiologic pH.14,45,49 Following topical application to the eye or intracameral injection of a single dose of ketorolac tromethamine in rabbits, aqueous humor concentrations of drug decline with an average half-life of 3.8 or 2.1 hours, respectively.16 The principal mechanism of elimination from the eye of ocularly absorbed drug in these rabbits is thought to be via distribution into the iris-ciliary body and subsequent elimination via intraocular venous circulation.16 It is likely that substantial portions of a topically applied dose to the eye also are eliminated via systemic absorption from the conjunctiva.16

Following single oral, IM, or IV doses of ketorolac tromethamine in healthy adults, plasma concentrations of the drug appear to decline in a biphasic manner with a terminal elimination half-life of about 4-6 hours (range: 3.8-6.3 hours).2,14,21,27,28,45,49,50,51,52,78 Similar plasma half-lives have been reported following ocular administration.16

The exact metabolic fate of systemically absorbed ketorolac is not clearly established, but the drug undergoes hydroxylation in the liver21 to form p -hydroxyketorolac.14,21,45,50,78 This hydroxy metabolite exhibits limited pharmacologic activity, having less than 20% of the anti-inflammatory potency of the parent drug.45,50,78 Systemically absorbed ketorolac also undergoes conjugation with glucuronic acid45,49,78 and is metabolized to unidentified polar metabolites.21 Ketorolac reportedly does not undergo metabolism in the eye of rabbits and is present in plasma mainly as unchanged drug following ocular administration.16

Following oral, IM, or IV administration, ketorolac and its metabolites are excreted mainly in the urine; only small amounts of the drug and its metabolites are excreted in feces,2,14,45,78 probably via biliary elimination.6,45,78

Chemistry and Stability

Chemistry

Ketorolac, a pyrrolizine carboxylic acid derivative, is a prototypical nonsteroidal anti-inflammatory agent (NSAIA).1,2,3,4,14,21,22,25,26,27,28,154,155 The drug is structurally and pharmacologically related to tolmetin, zomepirac, and indomethacin,3,14,28,29,30 but unlike these pyrrole acetic acid derivatives, ketorolac is a cyclic propionic acid derivative.3,10

Ketorolac is commercially available as the tromethamine salt.1,2,22,26,154,155 The tromethamine moiety enhances the aqueous solubility of ketorolac.4,28,29,30 Ketorolac tromethamine is commercially available as a racemic mixture.1,2,5,6,31,78,154,155 The anti-inflammatory activity of the drug results principally from the levorotatory ( l ) isomer, which has approximately twice the pharmacologic activity of the racemic mixture.5

Ketorolac tromethamine occurs as an off-white crystalline powder1,21 and has solubilities of 3 mg/mL in alcohol and more than 500 mg/mL in water at 23°C.6,7 The pK_a of the drug in water is 3.54.1,2,3,21,25,26,28

Ketorolac tromethamine ophthalmic solutions are sterile, isotonic solutions of the drug in purified water having an osmolality of 290 mOsm/kg; hydrochloric acid and/or sodium hydroxide may be added to adjust pH to 7.4.1,154,155 The commercially available ophthalmic solutions are clear and colorless;139 the preserved solution also contains octoxynol 40, benzalkonium chloride, and edetate disodium but the preservative-free solution does not contain these excipients.1,154,155 Sodium chloride is added to the solutions to adjust tonicity.1

Stability

Ketorolac tromethamine 0.5% ophthalmic solutions should be stored at 15-25°C in tight, light-resistant containers.1,154 Ketorolac tromethamine 0.4% ophthalmic solution should be stored at 15-25°C in tight, light-resistant containers.155 Prolonged exposure of the drug to light can result in degradation of ketorolac and discoloration of the solution;1,139 discolored solutions should be discarded.139 The preservative-free ophthalmic solution is intended for single use only in one or both eyes immediately after opening; any unused portion from an opened container should be discarded.154

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.

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