Ophthalmic – Nonsteroidal Anti-inflammatories

• Ophthalmic anesthetics
• Ophthalmic Antibacterials and combination products
• Ophthalmic Anti-allergy agents
• Ophthalmic Antivirals
• Ophthalmic Corticosteroids
• Ophthalmic - Dry eye disease (DED)
• Ophthalmic - Glaucoma
• Ophthalmic Mydriatics
• Ophthalmic NSAIDs
• Fortified Ophthalmic Preparations

• Bromfenac (Prolensa® -0.07%, Bromsite®-0.075%, generic 0.09%)
• Diclofenac 0.1% (Voltaren ®)
• Flurbiprofen 0. 03% (Ocufen ®)
• Ketorolac (Acular LS®-0.4%, Acuvail®-0.45%, Acular-0.5%)
• Ketorolac/phenylephrine 0.3%/1% (Omidria®)
• Nepafenac - 0.1% (Nevanac®), 0.3% (Ilevro®)

Indications: 
PROLENSA (bromfenac ophthalmic solution) 0.07% is indicated for the treatment of postoperative inflammation and reduction of ocular pain in patients who have undergone cataract surgery.

Dosing:
RECOMMENDED DOSING
One drop of PROLENSA ophthalmic solution should be applied 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.

Precautions/Warnings:
• Sulfite Allergic Reactions (5.1)
• Slow or Delayed Healing (5.2)
• Potential for Cross-Sensitivity (5.3)
• Increased Bleeding Time (5.4)
• Keratitis and Corneal Reactions (5.5)
• Contact Lens Wear (5.6)

Supplied:
Topical ophthalmic solution: bromfenac 0.07%
PROLENSA (bromfenac ophthalmic solution) 0.07% is supplied in a white LDPE plastic squeeze bottle with a 15 mm LDPE white dropper tip and 15 mm polypropylene gray cap as follows:

• 3 mL in a 7.5 mL container (NDC 24208-602-03)

Storage: Store at 15º to 25ºC (59º to 77ºF).

Efficacy:
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.

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.

Bromfenac 0.075% (Bromsite ®) 

Indications: 
Diclofenac Sodium Ophthalmic is indicated for the treatment of postoperative inflammation in patients who have undergone cataract extraction and for the temporary relief of pain and photophobia in patients undergoing corneal refractive surgery.

Dosing:

Cataract Surgery

One drop of Diclofenac Sodium Ophthalmic should be applied to the affected eye, 4 times daily beginning 24 hours after cataract surgery and continuing throughout the first 2 weeks of the postoperative period.

Corneal Refractive Surgery

One or two drops of Diclofenac Sodium Ophthalmic 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.

Precautions/Warnings:
WARNINGS
The refractive stability of patients undergoing corneal refractive procedures and treated with Diclofenac Sodium has not been established. Patients should be monitored for a year following use in this setting. 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.

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.

PRECAUTIONS
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 post surgery may increase patient risk for occurrence and severity of corneal adverse events.

It is recommended that Diclofenac Sodium Ophthalmic, like other NSAIDs, be used with caution in patients with known bleeding tendencies or who are receiving other medications, which may prolong bleeding time. Use of the same bottle for both eyes is not recommended with topical eye drops that are used in association with surgery.

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

Supplied:
Diclofenac Sodium Ophthalmic 0.1% (1 mg/mL) Sterile Solution is supplied in a low-density polyethylene (LDPE) white bottle with a LDPE Dropper Tip and a gray cap. The 2.5 mL fill and the 5 mL fill are supplied in a 7.5 mL size bottle.
2.5 mL NDC 24208-457-25
5 mL NDC 24208-457-05

Efficacy:

Diclofenac Sodium Ophthalmic Solution, 0.1% is a sterile, topical, nonsteroidal, anti-inflammatory product for ophthalmic use.

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 and 103 patients were treated with vehicle placebo. Diclofenac Sodium Ophthalmic 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 and/or vehicle placebo. The efficacy of Diclofenac Sodium Ophthalmic 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 for up to three days after PRK.

Indications: 
Flurbiprofen Sodium Ophthalmic Solution is indicated for the inhibition of intraoperative miosis.

Dosing:
DOSAGE AND ADMINISTRATION
A total of four (4) drops of Flurbiprofen Sodium Ophthalmic Solution should be administered by instilling one (1) drop approximately every 1/2 hour beginning 2 hours before surgery.

Precautions/Warnings:
WARNINGS
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 Flurbiprofen Sodium Ophthalmic Solution may cause increased bleeding of ocular tissues (including hyphemas) in conjunction with ocular surgery.

There is the potential for cross-sensitivity to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs. Therefore, caution should be used when treating individuals who have previously exhibited sensitivities to these drugs.

PRECAUTIONS
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.

It is recommended that Flurbiprofen Sodium Ophthalmic Solution be used with caution in surgical patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time.

Supplied:
Flurbiprofen Sodium Ophthalmic Solution, USP 0.03% is supplied in a plastic bottle with a controlled drop tip in the following size:

2.5 mL - NDC 69292-722-25

Efficacy:
Flurbiprofen Sodium Ophthalmic Solution, USP 0.03% is a sterile topical nonsteroidal anti-inflammatory product for ophthalmic use.
Flurbiprofen sodium is one of a series of phenylalkanoic acids that have shown analgesic, antipyretic, and anti-inflammatory activity in animal inflammatory diseases. Its mechanism of action is believed to be through inhibition of the cyclo-oxygenase enzyme that 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 on animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilatation, 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. In clinical studies, Flurbiprofen Sodium Ophthalmic Solution has been shown to inhibit the miosis induced during the course of cataract surgery.

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

Dosing:
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.

Precautions/Warnings:
Delayed healing (5.1)
Cross-sensitivity or hypersensitivity (5.2)
Increased bleeding time due to interference with thrombocyte aggregation (5.3)
Corneal effects including keratitis (5.4)

Supplied:
ACULAR LS ® (ketorolac tromethamine ophthalmic solution) 0.4% is supplied sterile, in white opaque plastic LDPE bottles with white droppers, with a gray high impact polystyrene (HIPS) caps as follows:

5 mL in 10 mL bottle NDC 0023-9277-05

Storage: Store at 15o-25oC (59o-77oF). Protect from light.

Efficacy:
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.

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

ACULAR ® 0.5% (ketorolac tromethamine ophthalmic soln)

[Package insert]

Indications: 
ACULAR ® ophthalmic solution is indicated for the temporary relief of ocular itching due to seasonal allergic conjunctivitis. ACULAR ® ophthalmic solution is also indicated for the treatment of postoperative inflammation in patients who have undergone cataract extraction.

Dosing:
The recommended dose of ACULAR ® 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 ACULAR ® 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.

ACULAR ® ophthalmic solution has been safely administered in conjunction with other ophthalmic medications such as antibiotics, beta blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics.

Precautions/Warnings:
WARNINGS
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.

PRECAUTIONS
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.

Supplied:
HOW SUPPLIED
ACULAR ® (ketorolac tromethamine ophthalmic solution) is supplied sterile in opaque white LDPE plastic bottles with white droppers with gray high impact polystyrene (HIPS) caps as follows:

5 mL in 10 mL bottle - NDC 16590-002-05
Store at 15°C - 25°C (59°F- 77°F) with protection from light.

ACUVAIL ® ophthalmic solution 0.45% 

[Package insert]

Indications: 
ACUVAIL ® ophthalmic solution is indicated for the treatment of pain and inflammation following cataract surgery.

Dosing:
One drop of ACUVAIL should be applied to the affected eye twice daily beginning 1 day prior to cataract surgery, continued on the day of surgery, and through the first 2 weeks of the postoperative period.

USE WITH OTHER TOPICAL OPHTHALMIC MEDICATIONS
ACUVAIL ophthalmic solution 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.

Precautions/Warnings:
Delayed healing (5.1)
Cross-sensitivity or hypersensitivity (5.2)
Increased bleeding time due to interference with thrombocyte aggregation (5.3)
Corneal effects including keratitis (5.4)

Supplied:
ACUVAIL (ketorolac tromethamine ophthalmic solution) 0.45% is available as a sterile solution supplied in clear, LDPE, single-use vials packaged in 3 foil pouches, 10 vials per pouch:

30 Single-Use Vials 0.4 mL each: NDC 0023-3507-31

Storage : Store at 15o-30º C (59o-86º F). Store the vials in the pouch, protected from light. Fold pouch ends closed.

Indications:: 
Omidria® is added to an ocular irrigating solution used during cataract surgery or intraocular lens replacement and is indicated for maintaining pupil size by preventing intraoperative miosis and reducing postoperative ocular pain.

Dosing::
Omidria must be diluted prior to intraocular use. For administration to patients undergoing cataract surgery or intraocular lens replacement, 4 mL of Omidria is diluted in 500 mL of ocular irrigating solution. Irrigation solution is to be used as needed for the surgical procedure for a single patient.

The storage period for the diluted product is not more than 4 hours at room temperature or 24 hours under refrigerated conditions.

Do not use if the solution is cloudy or if it contains particulate matter.

Precautions/Warnings::
Systemic exposure to phenylephrine may cause elevations in blood pressure. (5.1)

Supplied:

Omidria® (phenylephrine and ketorolac intraocular solution) 1%/0.3% is supplied in a clear, 5-mL glass, single-patient-use vial containing 4 mL of sterile solution, for addition to ocular irrigating solution.

Omidria is supplied in a multi-pack containing:

4 vials : NDC 62225-600-04 or

10 vials: NDC 62225-600-10

Efficacy:
Omidria is a sterile aqueous solution, containing the α1-adrenergic receptor agonist phenylephrine HCl and the nonsteroidal anti-inflammatory ketorolac tromethamine, for addition to ocular irrigating solution.

Phenylephrine is an α1-adrenergic receptor agonist and, in the eye, acts as a mydriatic agent by contracting the radial muscle of the iris. Ketorolac is a nonsteroidal anti-inflammatory that inhibits both cyclooxygenase enzymes (COX-1 and COX-2), resulting in a decrease in tissue concentrations of prostaglandins to reduce pain due to surgical trauma. Ketorolac, by inhibiting prostaglandin synthesis secondary to ocular surgical insult or direct mechanical stimulation of the iris, also prevents surgically induced miosis.

Indications: 
NEVANAC 0.1% is indicated for the treatment of pain and inflammation associated with cataract surgery.

Dosing:
One drop of NEVANAC 0.1% should be applied to the affected eye three times daily beginning 1 day prior to cataract surgery, continued on the day of surgery and through the first 2 weeks of the postoperative period. Shake the container well prior to dosing.

Precautions/Warnings:
WARNINGS AND PRECAUTIONS
Increased bleeding time due to interference with thrombocyte aggregation (5.1)
Delayed healing (5.2)
Corneal effects including keratitis (5.3)

Supplied:
 HOW SUPPLIED/STORAGE AND HANDLING
NEVANAC 0.1% is supplied in a white, oval, low density polyethylene DROP-TAINER® dispenser with a natural low density polyethylene dispensing plug and gray polypropylene cap. The 1.7 mL fill is presented in an overwrap, which provides tamper evidence to the package. Tamper evidence for the 3 mL fill is provided with a shrink band around the closure and neck area of the package.

3 mL in a 4 mL………………………..NDC 0065-0002-03

Storage: Store at 2°C to 25°C (36°F-77°F).

Efficacy:

 In two double-masked, randomized clinical trials in which patients were dosed 3 times-daily beginning 1 day prior to cataract surgery, continued on the day of surgery and for the first 2 weeks of the postoperative period, NEVANAC 0.1% demonstrated superior clinical efficacy compared to its vehicle in treating postoperative pain and inflammation.

Patients treated with NEVANAC* 0.1% were less likely to have ocular pain and measurable signs of inflammation (cells and flare) in the early postoperative period through the end of treatment than those treated with its vehicle.

For ocular pain in both studies, a significantly higher percentage of patients (approximately 80%) in the nepafenac group reported no ocular pain on the day following cataract surgery (Day 1) compared to those in the vehicle group (approximately 50%).

Results from clinical studies indicated that NEVANAC 0.1% has no significant effect upon IOP; however, changes in IOP may occur following cataract surgery.