2.1 Recommended Dosage

Apply one drop to the affected eye once daily beginning 1 day prior to cataract surgery, continued on the day of surgery, and through the first 14 days of the postoperative period.

2.2 Use with Other Topical Ophthalmic Medications

PROLENSA may be administered in conjunction with other topical ophthalmic medications such as alpha agonists, beta-blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics. Drops should be administered at least 5 minutes apart.

5.1 Sulfite Allergic Reactions

PROLENSA contains sodium sulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-asthmatic people.

5.2 Slow or Delayed Healing

All topical nonsteroidal anti-inflammatory drugs (NSAIDs), including bromfenac, 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.

5.3 Potential for Cross-Sensitivity

There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs, including bromfenac. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.

5.4 Increased Bleeding Time

With some NSAIDs, including bromfenac, there exists the potential for increased bleeding time due to interference with platelet aggregation. There have been reports that ocularly applied NSAIDs may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery.

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

5.5 Keratitis and Corneal Reactions

Use of topical NSAIDs, including bromfenac, 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, including bromfenac, 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 postsurgery may increase patient risk for the occurrence and severity of corneal adverse events.

5.6 Risk of Contamination

Do not touch dropper tip to the eye, eyelids, or to any surface, as this may contaminate the contents. Replace the bottle cap after using.

5.7 Contact Lens Wear

PROLENSA should not be instilled while wearing contact lenses. Remove contact lenses prior to instillation of PROLENSA. The preservative in PROLENSA, benzalkonium chloride, may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of PROLENSA.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most commonly reported adverse reactions following use of PROLENSA following cataract surgery include: anterior chamber inflammation, foreign body sensation, eye pain, photophobia, and vision blurred. These reactions were reported in 3% to 8% of patients.

8.1 Pregnancy

Risk Summary

There are no available data on PROLENSA use in pregnant women to evaluate a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

The systemic exposure to bromfenac following topical ocular administration is low [see Clinical Pharmacology ( 12.3)]. Consequently, the systemic exposure of a pregnant woman to bromfenac is expected to be minimal following topical ocular administration.

However, because of the known effects of prostaglandin biosynthesis-inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), the use of PROLENSA during late pregnancy should be avoided.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Premature closure of the ductus arteriosus in the fetus has occurred with third trimester use of oral and injectable NSAIDs. Measurable maternal and fetal plasma drug levels are available with oral and injectable routes of NSAID administration. The maternal plasma level of PROLENSA following ocular administration is unknown [see Clinical Pharmacology ( 12.3)] .

Data

Animal Data

Embryo-fetal lethality and maternal toxicity were produced in rats and rabbits treated with bromfenac during the period of organogenesis at oral doses up to 0.9 mg/kg/day and 7.5 mg/kg/day, respectively. These doses corresponded to a Cmax 90- and 150- times the predicted Cmax at the recommended human ophthalmic dose (RHOD), respectively. In rats, bromfenac treatment caused delayed parturition at 0.3 mg/kg/day (30 times the predicted human Cmax at the RHOD), and caused dystocia, increased neonatal mortality, and reduced postnatal growth at 0.9 mg/kg/day (90 times the predicted human Cmax at the RHOD).

8.2 Lactation

There are no data on the presence of bromfenac in human milk, the effects on the breastfed infant, or the effects on milk production.

The systemic exposure of a breastfeeding woman to bromfenac is expected to be minimal following topical ocular administration, however, the possibility of harm to the breastfed infant cannot be ruled out.

The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for PROLENSA, and any potential adverse effects on the breastfed infant from PROLENSA or from the underlying maternal conditions.

8.4 Pediatric Use

The safety and effectiveness of PROLENSA have not been established in pediatric patients.

8.5 Geriatric Use

No overall differences in safety or effectiveness of PROLENSA have been observed between patients 70 years of age and older and younger adult patients.

12.1 Mechanism of Action

Bromfenac is a nonsteroidal anti-inflammatory drug (NSAID) that has anti-inflammatory activity. The mechanism of its action is thought to be due to its ability to block prostaglandin synthesis by inhibiting cyclooxygenase (COX) 1 and 2. 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.

12.3 Pharmacokinetics

The plasma concentration of bromfenac following ocular administration of PROLENSA (bromfenac ophthalmic solution) 0.07% in humans is unknown. Based on the maximum proposed dose of one drop to each eye (0.035 mg) and PK information from other routes of administration, the systemic concentration of bromfenac is estimated to be below the limit of quantification (50 ng/mL) at steady-state in humans.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studies in rats and mice given oral doses of bromfenac up to 0.6 mg/kg/day (systemic exposure 30 times the systemic exposure predicted from RHOD assuming the human systemic concentration is at the limit of quantification) and 5 mg/kg/day (340 times the predicted human systemic exposure), respectively, revealed no significant increases in tumor incidence.

Mutagenesis

Bromfenac did not show mutagenic potential in various mutagenicity studies, including the reverse mutation, chromosomal aberration, and micronucleus tests.

Impairment of Fertility

Bromfenac did not impair fertility when administered orally to male and female rats at doses up to 0.9 mg/kg/day and 0.3 mg/kg/day, respectively (systemic exposure 90 and 30 times the predicted human exposure, respectively).

14.1 Ocular Inflammation and Pain

Bromfenac 0.07% QD for the treatment of postoperative inflammation and reduction of ocular pain was evaluated in two multi-center, randomized, double-masked, parallel-group, and placebo (vehicle)-controlled studies. Patients undergoing cataract surgery self-administered bromfenac 0.07% or vehicle once daily, beginning 1 day prior to surgery, continuing on the morning of surgery and for 14 days after surgery. Complete clearance of ocular inflammation (0 cell and no flare) was assessed on Days 1, 3, 8, and 15 postsurgery using slit lamp biomicroscopy. The pain score was self-reported. The primary efficacy endpoint was the proportion of subjects who had complete clearance of ocular inflammation by Day 15. In the intent-to-treat analyses from both assessments, complete clearance at Day 8 and Day 15, bromfenac 0.07% was superior to vehicle as shown in the following table.