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ketorolac tromethamine solution
Ketorolac tromethamine ophthalmic solution is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs) for ophthalmic use. Its chemical name is (±)-5-benzoyl-2, 3-dihydro-1H pyrrolizine-1-carboxylic acid compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1) and it has the following structure:
Ketorolac tromethamine ophthalmic solution is supplied as a sterile isotonic aqueous 0.5% solution, with a pH of 7.4. Ketorolac tromethamine ophthalmic solution is a racemic mixture of R-(+) and S-(-)- ketorolac tromethamine. Ketorolac tromethamine may exist in three crystal forms. All forms are equally soluble in water. The pKa of ketorolac is 3.5. This white to off-white crystalline substance discolors on prolonged exposure to light. The molecular weight of ketorolac tromethamine is 376.41. The osmolality of ketorolac tromethamine ophthalmic solution is 290 mOsmol/kg.
Each mL of ketorolac tromethamine ophthalmic solution contains: Active: ketorolac tromethamine USP 0.5%.
Preservative: benzalkonium chloride solution (50%) USP-NF 0.02%. Inactives: edetate disodium USP 0.1%; octoxynol 40; water for
injection USP; sodium chloride USP; hydrochloric acid NF and/or sodium hydroxide
NF to adjust the pH.
Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug which, when administered systemically, has demonstrated analgesic, anti-inflammatory, and anti-pyretic activity. The mechanism of its action is thought to be due to its ability to inhibit prostaglandin biosynthesis. Ketorolac tromethamine given systemically does not cause pupil constriction.
Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular inflammation. In studies performed in animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilation, increased vascular permeability, leukocytosis, and increased intraocular pressure. Prostaglandins also appear to play a role in the miotic response produced during ocular surgery by constricting the iris sphincter independently of cholinergic mechanisms.
Two drops (0.1 mL) of 0.5% ketorolac tromethamine ophthalmic solution instilled into the eyes of patients 12 hours and 1 hour prior to cataract extraction achieved measurable levels in 8 of 9 patients’ eyes (mean ketorolac concentration 95 ng/mL aqueous humor, range 40 to 170 ng/mL). Ocular administration of ketorolac tromethamine reduces prostaglandin E2 (PGE2) levels in aqueous humor. The mean concentration of PGE2 was 80 pg/mL in the aqueous humor of eyes receiving vehicle and 28 pg/mL in the eyes receiving ketorolac tromethamine 0.5% ophthalmic solution.
One drop (0.05 mL) of 0.5% ketorolac tromethamine ophthalmic solution was instilled into one eye and one drop of vehicle into the other eye TID in 26 normal subjects. Only 5 of 26 subjects had a detectable amount of ketorolac in their plasma (range 10.7 to 22.5 ng/mL) at Day 10 during topical ocular treatment. When ketorolac tromethamine 10 mg is administered systemically every 6 hours, peak plasma levels at steady state are around 960 ng/mL.
Two controlled clinical studies showed that ketorolac tromethamine ophthalmic solution was significantly more effective than its vehicle in relieving ocular itching caused by seasonal allergic conjunctivitis.
Two controlled clinical studies showed that patients treated for two weeks with ketorolac tromethamine ophthalmic solution were less likely to have measurable signs of inflammation (cell and flare) than patients treated with its vehicle.
Results from clinical studies indicate that ketorolac tromethamine has no
significant effect upon intraocular pressure; however, changes in intraocular
pressure may occur following cataract surgery.
INDICATIONS AND USAGE
Ketorolac tromethamine ophthalmic solution is indicated for the
temporary relief of ocular itching due to seasonal allergic conjunctivitis.
Ketorolac tromethamine ophthalmic solution is also indicated for the treatment
of postoperative inflammation in patients who have undergone cataract
Ketorolac tromethamine ophthalmic solution is contraindicated in
patients with previously demonstrated hypersensitivity to any of the ingredients
in the formulation.
There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory agents. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.
With some nonsteroidal anti-inflammatory drugs, there exists the potential
for increased bleeding time due to interference with thrombocyte aggregation.
There have been reports that ocularly applied nonsteroidal anti-inflammatory
drugs may cause increased bleeding of ocular tissues (including hyphemas) in
conjunction with ocular surgery.
General: All topical nonsteroidal anti-inflammatory drugs (NSAIDs) may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems.
Use of topical NSAIDs may result in keratitis. In some susceptible patients, continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs and should be closely monitored for corneal health.
Postmarketing experience with topical NSAIDs 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 for corneal adverse events which may become sight threatening. Topical NSAIDs should be used with caution in these patients.
Postmarketing experience with topical NSAIDs also suggests that use more than 24 hours prior to surgery or use beyond 14 days post surgery may increase patient risk for the occurrence and severity of corneal adverse events.
It is recommended that ketorolac tromethamine ophthalmic solution be used
with caution in patients with known bleeding tendencies or who are receiving
other medications which may prolong bleeding time.
Information for Patients: Ketorolac
tromethamine ophthalmic solution should not be administered while wearing
Carcinogenesis, Mutagenesis, Impairment of Fertility: Ketorolac tromethamine was not carcinogenic in rats given up to 5 mg/kg/day orally for 24 months (151 times the maximum recommended human topical ophthalmic dose, on a mg/kg basis, assuming 100% absorption in humans and animals) nor in mice given 2 mg/kg/day orally for 18 months (60 times the maximum recommended human topical ophthalmic dose, on a mg/kg basis, assuming 100% absorption in humans and animals).
Ketorolac tromethamine was not mutagenic in vitro in the Ames assay or in forward mutation assays. Similarly, it did not result in an in vitro increase in unscheduled DNA synthesis or an in vivo increase in chromosome breakage in mice. However, ketorolac tromethamine did result in an increased incidence in chromosomal aberrations in Chinese hamster ovary cells.
Ketorolac tromethamine did not impair fertility when administered orally to
male and female rats at doses up to 272 and 484 times the maximum recommended
human topical ophthalmic dose, respectively, on a mg/kg basis, assuming 100%
absorption in humans and animals.
Pregnancy: Teratogenic Effects: Pregnancy
Category C. Ketorolac tromethamine, administered during organogenesis,
was not teratogenic in rabbits or rats at oral doses up to 109 times and 303
times the maximum recommended human topical ophthalmic dose, respectively, on a
mg/kg basis assuming 100% absorption in humans and animals. When administered to
rats after Day 17 of gestation at oral doses up to 45 times the maximum
recommended human topical ophthalmic dose, respectively, on a mg/kg basis,
assuming 100% absorption in humans and animals, ketorolac tromethamine resulted
in dystocia and increased pup mortality. There are no adequate and
well-controlled studies in pregnant women. Ketorolac tromethamine ophthalmic
solution should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.
Nonteratogenic Effects: Because of the
known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular
system (closure of the ductus arteriosus), the use of ketorolac tromethamine
ophthalmic solution during late pregnancy should be avoided.
Nursing Mothers: Caution should be
exercised when ketorolac tromethamine ophthalmic solution is administered to a
Pediatric Use: Safety and efficacy in
pediatric patients below the age of 3 have not been established.
Geriatric Use: No overall differences in
safety or effectiveness have been observed between elderly and younger
The most frequent adverse events reported with the use of ketorolac tromethamine ophthalmic solutions have been transient stinging and burning on instillation. These events were reported by up to 40% of patients participating in clinical trials.
Other adverse events occurring approximately 1 to 10% of the time during treatment with ketorolac tromethamine ophthalmic solutions included allergic reactions, corneal edema, iritis, ocular inflammation, ocular irritation, superficial keratitis, and superficial ocular infections.
Other adverse events reported rarely with the use of ketorolac tromethamine ophthalmic solutions included: corneal infiltrates, corneal ulcer, eye dryness, headaches, and visual disturbance (blurry vision).
Clinical Practice: The following events have been identified during
postmarketing use of ketorolac tromethamine ophthalmic solution 0.5% in clinical
practice. Because they are reported voluntarily from a population of unknown
size, estimates of frequency cannot be made. The events, which have been chosen
for inclusion due to either their seriousness, frequency of reporting, possible
causal connection to topical ketorolac tromethamine ophthalmic solution 0.5% or
a combination of these factors, include corneal erosion, corneal perforation,
corneal thinning, and epithelial breakdown (see PRECAUTIONS, General).
DOSAGE AND ADMINISTRATION
The recommended dose of ketorolac tromethamine ophthalmic solution is one drop (0.25 mg) four times a day for relief of ocular itching due to seasonal allergic conjunctivitis.
For the treatment of postoperative inflammation in patients who have undergone cataract extraction, one drop of ketorolac tromethamine ophthalmic solution should be applied to the affected eye(s) four times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period.
Ketorolac tromethamine ophthalmic solution has been safely administered in
conjunction with other ophthalmic medications such as antibiotics, beta
blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics.
Ketorolac tromethamine ophthalmic solution is supplied sterile in white opaque LDPE dropper bottles with white opaque plug and sealed with gray pantone opaque pilfer-proof caps as follows:
Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C
(59° and 86°F) [see USP Controlled Room Temperature] with protection from
Relabeling of "Additional Barcode Label" by:
PRINCIPAL DISPLAY PANEL
Ketorolac Tromethamine Ophthalmic Solution
Revised: 11/2010 Physicians Total Care, Inc.
Reproduced with permission of U.S. National Library of Medicine
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