ACULAR  LS  ophthalmic  solution  is  indicated  for  the  reduction  of  ocular  pain  and burning/stinging following corneal refractive surgery.

The recommended dose of ACULAR LS ophthalmic solution is one drop four times a day in the operated eye as needed for pain and burning/stinging for up to 4 days following corneal refractive surgery.

The safety and effectiveness of ACULAR LS in post-cataract surgery patients has not been established.

Pediatric Use:

Safety and effectiveness of ketorolac tromethamine 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 patients.

Delayed Healing

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.

Cross-Sensitivity or Hypersensitivity

There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs.  There  have been reports of bronchospasm or exacerbation of asthma associated with the use of ketorolac tromethamine ophthalmic solution in patients who have either a known hypersensitivity to aspirin/non-steroidal anti-inflammatory drugs or a past medical history of asthma. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.

Increased Bleeding Time

With some NSAIDs, 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.

It is recommended that ACULAR LS ophthalmic solution be used with caution in patients with known bleeding tendencies or who are receiving other medications, which may prolong bleeding time.

 Corneal Effects

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 1 day prior to surgery or use beyond 14 days post-surgery may increase patient risk for the occurrence and severity of corneal adverse events.

Risk of Contamination

Do not allow the tip of the bottle to contact the eye or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

Contact Lens Wear

ACULAR LS should not be administered while wearing contact lenses.

Information for Patients:

ACULAR LS may cause irritation in the eye due to its benzalkonium chloride content.  Avoid contact with soft contact lenses. Remove contact lenses before application and allow at least 15 minutes before reinserting them. Benzalkonium chloride is known to potentially cause discolouration of soft contact lenses.

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures to avoid injury and contamination of eye drops.

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. Drops should be administered at least 5 minutes apart.

There is the potential  for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other nonsteroidal anti-inflammatory agents (see section 4.4).

Concomitant use of topical NSAIDS and topical steroids may increase the  potential for healing problems (see section 4.4).

Fertility:

Ketorolac tromethamine did not impair fertility when administered orally to male and female rats at doses up to 280 and 499 times the maximum recommended human topical ophthalmic dose, respectively, on a mg/kg basis, assuming 100% absorption in humans and animals.

Pregnancy :

Ketorolac tromethamine, administered during organogenesis, was not teratogenic in rabbits or rats at oral doses up to 112 times and 312 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 46 times the maximum recommended human topical ophthalmic dose 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. ACULAR LS ophthalmic solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Because of the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), the use of ACULAR LS ophthalmic solution during late pregnancy should be avoided.

Nursing Mother:

It is not known whether ketorolac when given topically is present in human milk. Because    many drugs are excreted in human milk, caution should be exercised when ACULAR LS is  administered to a nursing woman.

There are no reported effects of topical ophthalmic drugs on driving or using machinery. However, caution should be exercised. If transient blurred vision occurs during installation, the patient should wait until the vision is restored.

The most frequently reported adverse reactions for ACULAR LS ophthalmic solution occurring in approximately 1 to 5% of the overall study population were;

•   conjunctival hyperemia

•   corneal infiltrates

•   headache

•   ocular edema

•   ocular pain

The most frequent adverse reactions reported with the use of ketorolac tromethamine ophthalmic solutions have been transient stinging and burning on instillation. These reactions were reported by up to 40% of patients participating in clinical trials.

Other adverse reactions occurring approximately 1% - 10% of the time during treatment with other ketorolac tromethamine ophthalmic solutions included;

•   allergic reactions (including eye swelling, eyelid edema, and hyperemia)

•   corneal edema

•   iritis

•   ocular inflammation

•   ocular irritation

•   superficial keratitis

•   superficial ocular infections

     Other adverse reactions reported rarely with the use of ketorolac tromethamine ophthalmic  solutions included: corneal ulcer, eye dryness, and visual disturbance (blurry vision).

Clinical Practice:

The following adverse reactions have been identified during postmarketing use of ketorolac tromethamine ophthalmic  solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to topical ketorolac tromethamine ophthalmic solutions, or a combination of these factors, include;

•   Bronchospasm or exacerbation of asthma

•   corneal erosion

•   corneal perforation

•   corneal thinning

•   corneal melt

•   epithelial breakdown (see section 4.4)

To report any side effect(s) :

•   Saudi Arabia:

•         Other GCC States:

No overdosage has been reported after ophthalmic use. In case of an overdosage, symptomatic and supportive treatment should be instituted and must be diluted with plenty of water.

Pharmacotherapeutic group: Non-steroidal anti-inflammatory (NSAID) ATC Code: S01BC05

Mechanism of Action:

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.

Clinical Studies

In two double-masked, multi-centered, parallel-group studies, 313 patients who had undergone photorefractive keratectomy received ACULAR LS 0.4% or its vehicle QID for up to 4 days. Significant differences favored ACULAR LS for the reduction of ocular pain and burning/stinging following photorefractive keratectomy surgery.

Results from clinical studies indicate that ketorolac tromethamine has no significant effect upon intraocular pressure.

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 healthy subjects. Only 5 of 26 subjects had a detectable amount of ketorolac in their plasma (range 11 to 23 ng/mL) at day 10 during topical ocular treatment.

Two drops of 0.5% ketorolac tromethamine ophthalmic solution instilled into the eyes of patients 12 hours and 1 hour prior to cataract extraction achieved a mean ketorolac concentration of 95 ng/mL in the aqueous humor of 8 of 9 eyes tested (range 40 to 170 ng/mL).

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Ketorolac tromethamine was neither 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, 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.

Sodium chloride

Edetate disodium 0.015%

Octoxynol 40

Hydrochloric acid and/or sodium hydroxide to adjust pH Purified water

Not known.

Do not store above 25°C.

ACULAR LS (ketorolac tromethamine ophthalmic solution) 0.4% is supplied sterile in an opaque white LDPE plastic bottle with a white dropper with a gray high impact polystyrene (HIPS) cap as follows:

5 mL in 10 mL bottle

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements