DICLOFENAC SODIUM OPHTHALMIC SOLUTION 0.1%

Diclofenac sodium is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is thought to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins.

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.

Results from a bioavailability study established that plasma levels of diclofenac following ocular instillation of two drops of Diclofenac sodium ophthalmic solution, 0.1% to each eye were below the limit of quantification (10 ng/mL) over a 4-hour period. This study suggests that limited, if any, systemic absorption occurs with Diclofenac sodium ophthalmic solution.

Postoperative Anti-Inflammatory Effects
In two double-masked, controlled, efficacy studies of postoperative inflammation, a total of 206 cataract patients were treated with Diclofenac sodium ophthalmic solution and 103 patients were treated with vehicle placebo. Diclofenac sodium ophthalmic solution was favored over vehicle placebo over a 2-week period for the clinical assessments of inflammation as measured by anterior chamber cells and flare.

In double-masked, controlled studies of corneal refractive surgery (radial keratotomy (RK) and laser photorefractive keratectomy (PRK)) patients were treated with Diclofenac sodium ophthalmic solution and/or vehicle placebo. The efficacy of Diclofenac sodium ophthalmic solution, 0.1% given before and shortly after surgery was favored over vehicle placebo during the 6-hour period following surgery for the clinical assessments of pain and photophobia. Patients were permitted to use a hydrogel soft contact lens with Diclofenac sodium ophthalmic solution for up to three days after PRK.

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 infiltrates, corneal erosion, corneal ulceration, and 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 experiencing complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface disease (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 postsurgery may increase patient risk for occurrence and severity of corneal adverse events.

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

Results from clinical studies indicate that Diclofenac sodium ophthalmic solution has no significant effect upon ocular pressure. However, elevations in intraocular pressure may occur following cataract surgery.

Except for the use of a bandage hydrogel soft contact lens during the first 3 days following refractive surgery, diclofenac sodium ophthalmic solution should not be used by patients currently wearing soft contact lenses due to adverse events that have occurred in other circumstances.

Long-term carcinogenicity studies in rats given diclofenac in oral doses up to 2mg/kg/day (approximately 500 times the human topical ophthalmic dose) revealed no significant increases in tumor incidence. A 2-year carcinogenicity study conducted in mice employing oral diclofenac up to 2 mg/kg/day did not reveal any oncogenic potential. Diclofenac did not show mutagenic potential in various mutagenicity studies including the Ames test. Diclofenac administered to male and female rats at 4 mg/kg/day (approximately 1000 times the human topical ophthalmic dose) did not affect fertility.

No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.

Teratogenic Effects
Pregnancy Category C. Reproduction studies performed in mice at oral doses up to 5,000 times (20 mg/kg/day) and in rats and rabbits at oral doses up to 2,500 times (10 mg/kg/day) the human topical dose have revealed no evidence of teratogenicity due to diclofenac despite the induction of maternal toxicity and fetal toxicity. In rats, maternally toxic doses were associated with dystocia, prolonged gestation, reduced fetal weights and growth, and reduced fetal survival. Diclofenac has been shown to cross the placental barrier in mice and rats.

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Non-teratogenic Effects
Because of the known effects of prostaglandin biosynthesis inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), the use of diclofenac sodium ophthalmic solution during late pregnancy should be avoided.

Safety and effectiveness in pediatric patients have not been established.

The following reactions have been identified during postmarketing use of topical diclofenac sodium ophthalmic solution, 0.1% 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 diclofenac sodium ophthalmic solution, 0.1%, or a combination of these factors, include corneal erosion, corneal infiltrates, corneal perforation, corneal thinning, corneal ulceration and epithelilal breakdown (see PRECAUTIONS, General).

Transient burning and stinging were reported in approximately 15% of patients across studies with the use of diclofenac sodium ophthalmic solution, 0.1% in clinical practice. In cataract surgery studies, keratitis was reported in up to 28% of patients receiving diclofenac sodium ophthalmic solution although in many of these cases keratitis was initially noted prior to the initiation of treatment. Elevated intraocular pressure following cataract surgery was reported in approximately 15% of patients undergoing cataract surgery. Lacrimation complaints were reported in approximately 30% of case studies undergoing incisional refractive surgery.

The following adverse reactions were reported in approximately 5% or less of the patients: abnormal vision, acute elevated IOP, blurred vision, conjunctivitis, corneal deposits, corneal edema, corneal opacity, corneal lesions, discharge, eyelid swelling, eye pain, injection, iritis, irritation, itching, lacrimation disorder, and ocular allergy.

The following adverse reactions were reported in 3% or less of the patients: abdominal pain, asthenia, chills, dizziness, facial edema, fever, headache, insomnia, nausea, pain, rhinitis, viral infection and vomiting.

To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharmaceuticals, Inc., at 1-866-562-4597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

One drop of diclofenac sodium ophthalmic solution should be applied to the affected eye, 4 times daily beginning 24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative period.

One or two drops of diclofenac sodium ophthalmic solution should be applied to the operative eye within the hour prior to corneal refractive surgery. Within 15 minutes after surgery, one or two drops should be applied to the operative eye and continued 4 times daily for up to 3 days.