ACULAR® PF (ketorolac tromethamine ophthalmic solution) Preservative-Free is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs (NSAIDs) for ophthalmic use. Ketorolac tromethamine' chemical name is (±)-5-benzoyl-2,3-dihydro-1 H pyrrolizine-1-carboxylic acid compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1).
ACULAR® PF 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 ACULAR® PF is 290 mOsmol/kg.
Each ml of ACULAR® PF contains: Active ingredient: ketorolac tromethamine 0.5%. Inactives: sodium chloride; hydrochloric acid and/or sodium hydroxide to adjust the pH to 7.4; and purified water.
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.
One drop (0.05 mL) of ketorolac tromethamine (preserved) 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.
In two double-masked, multi-centered, parallel-group studies, 340 patients who had undergone incisional refractive surgery received ACULAR® PF or its vehicle QID for up to 3 days. Significant differences favored ACULAR® PF for the treatment of ocular pain and photophobia.
Results from clinical studies indicate that ketorolac tromethamine has no significant effect upon intraocular pressure.
ACULAR® PF ophthalmic solution is indicated for the reduction of ocular pain and photophobia following incisional refractive surgery.
ACULAR® PF 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: It is recommended that ACULAR® PF be used with caution in surgical patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time.
Wound healing may be delayed with the use of ACULAR® PF.
Information for Patients: ACULAR® PF should not be administered while wearing contact lenses.
The solution from one individual single-use vial is to be used immediately after opening for administration to one or both eyes, and the remaining contents should be discarded immediately after administration. To avoid contamination, do not touch tip of unit-dose vial to eye or any other surface.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: An 18-month study in mice at oral doses of ketorolac tromethamine equal to the parenteral MRHD (Maximum Recommended Human Dose) and a 24-month study in rats at oral doses 2.5 times the parenteral MRHD, showed no evidence of tumorigenicity.
Ketorolac tromethamine was not mutagenic in the Ames test, unscheduled DNA synthesis and repair, and forward mutation assays. Ketorolac did not cause chromosome breakage in the in vivo mouse micronucleus assay. At 1590 µg/mL (approximately 1000 times the average human plasma levels) and at higher concentrations, ketorolac tromethamine increased the incidence of chromosomal aberrations in Chinese hamster ovarian cells.
Impairment of fertility did not occur in male or female rats at oral doses of 9 mg/kg and 16 mg/kg, respectively.
Pregnancy: Teratogenic Effects: Pregnancy Category C: Reproduction studies have been performed in rabbits, using daily oral doses at 3.6 mg/kg and in rats at 10 mg/kg during organogenesis. Results of these studies did not reveal evidence of teratogenicity to the fetus. Oral doses of ketorolac tromethamine at 1.5 mg/kg, which was half of the human oral exposure, administered after gestation day 17 caused dystocia and higher pup mortality in rats. There are no adequate and well-controlled studies in pregnant women. Ketorolac tromethamine 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 ACULAR® PF during late pregnancy should be avoided.
Nursing Mothers: Caution should be exercised when ACULAR® PF is administered to a nursing woman.
Pediatric Use: Safety and efficacy in pediatric patients below the age of 12 years have not been established.
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 approximately 20% of patients participating in clinical trials.
Other adverse events occurring 1%-10% of the time during treatment with ketorolac tromethamine ophthalmic solutions included ocular irritation, allergic reactions, superficial ocular infections, superficial keratitis, ocular inflammation, corneal edema, and iritis.
Other adverse events reported rarely with the use of ketorolac tromethamine ophthalmic solutions include: eye dryness, corneal infiltrates, corneal ulcer, visual disturbance (blurry vision), and headaches.
The recommended dose of ACULAR® PF Preservative-Free is one drop (0.25 mg) four times a day in the operated eye as needed for pain and photophobia for up to 3 days after incisional refractive surgery.
ACULAR® PF (ketorolac tromethamine ophthalmic solution) 0.5% Preservative-Free is available as a sterile solution supplied in single-use vials as follows: ACULAR® PF 12 Single-Use Vials 0.4 mL each - NDC 0023-9055-04. Store ACULAR® PF between 15°C-30°C (59°F-86°F) with protection from light.
U.S. Patent Nos. 4,089,969; 4,454,151; 5,110,493
ALLERGAN ©1997 Allergan, Irvine, CA 92612, U.S.A.
ACULAR® is a registered trademark of SYNTEX (U.S.A.) Inc. ACULAR® PF is manufactured and distributed by ALLERGAN under license from its developer, SYNTEX (U.S.A.) Inc., Palo Alto, California, U.S.A.November 1997