NDA 20-037/S-014
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`VOLTAREN OPHTHALMIC®
`(diclofenac sodium ophthalmic solution) 0.1%
`
`Sterile Ophthalmic Solution
`
`Prescribing Information
`
`DESCRIPTION
`Voltaren Ophthalmic (diclofenac sodium ophthalmic solution) 0.1% solution is a sterile, topical,
`nonsteroidal, anti-inflammatory product for ophthalmic use. Diclofenac sodium is designated
`chemically as 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt, with an empirical
`formula of C14H10Cl2NO2Na. The structural formula of diclofenac sodium is:
`
`
`[Structural formula]
`
`Voltaren Ophthalmic is available as a sterile solution which contains diclofenac sodium 0.1%
`(1mg/mL).
`
`Inactive Ingredients: polyoxyl 35 castor oil, Boric acid, tromethamine, sorbic acid (2 mg/mL), edetate
`disodium (1 mg/mL), and purified water.
`
`Diclofenac sodium is a faintly yellow-white to light-beige, slightly hygroscopic crystalline powder. It
`is freely soluble in methanol, sparingly soluble in water, very slightly soluble in acetonitrile, and
`insoluble in chloroform and in 0.1N hydrochloric acid. Its molecular weight is 318.14. Voltaren
`Ophthalmic 0.1% is an iso-osmotic solution with an osmolality of about 300 mOsmol/1000 g, buffered
`at approximately pH 7.2. Voltaren Ophthalmic solution has a faint characteristic odor of castor oil.
`
`CLINICAL PHARMACOLOGY
`Pharmacodynamics
`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.
`
`Animal Studies
`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.
`
`Pharmacokinetics
`Results from a bioavailability study established that plasma levels of diclofenac following ocular
`instillation of two drops of Voltaren Ophthalmic 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
`Voltaren Ophthalmic.
`
`
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`SENJU EXHIBIT 2057
`LUPIN v SENJU
`IPR2015-01105
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`PAGE 1 OF 5
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`NDA 20-037/S-014
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`Clinical Trials
`Postoperative Anti-Inflammatory Effects:
`In two double-masked, controlled, efficacy studies of postoperative inflammation, a total of 206
`cataract patients were treated with Voltaren Ophthalmic and 103 patients were treated with vehicle
`placebo. Voltaren 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 Voltaren Ophthalmic and/or vehicle
`placebo. The efficacy of Voltaren 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 Voltaren Ophthalmic for
`up to three days after PRK.
`
`INDICATIONS AND USAGE
`Voltaren 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.
`
`CONTRAINDICATIONS
`Voltaren Ophthalmic is contraindicated in patients who are hypersensitive to any component of the
`medication.
`
`WARNINGS
`The refractive stability of patients undergoing corneal refractive procedures and treated with Voltaren
`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
`General
`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.
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`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 Voltaren 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.
`
`Results from clinical studies indicate that Voltaren Ophthalmic has no significant effect upon ocular
`pressure. However, elevations in intraocular pressure may occur following cataract surgery.
`
`Information for Patients
`Except for the use of a bandage hydrogel soft contact lens during the first 3 days following refractive
`surgery, Voltaren Ophthalmic should not be used by patients currently wearing soft contact lenses due
`to adverse events that have occurred in other circumstances.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Long-term carcinogenicity studies in rats given Voltaren in oral doses up to 2 mg/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 Voltaren up to 2
`mg/kg/day did not reveal any oncogenic potential. Voltaren did not show mutagenic potential in
`various mutagenicity studies including the Ames test. Voltaren administered to male and female rats at
`4 mg/kg/day (approximately 1000 times the human topical ophthalmic dose) did not affect fertility.
`
`Geriatric Use
`No overall differences in safety or effectiveness have been observed between elderly and younger adult
`patients.
`
`PREGNANCY
`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 Voltaren 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. Voltaren 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.
`
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`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 Voltaren Ophthalmic during late pregnancy should be
`avoided.
`
`Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
`
`ADVERSE REACTIONS
`Clinical Practice: The following events 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 events, 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,
`epithelial breakdown, and superficial punctate keratitis, (see PRECAUTIONS, General).
`
`Ocular: Transient burning and stinging were reported in approximately 15% of patients across studies
`with the use of Voltaren Ophthalmic. In cataract surgery studies, keratitis was reported in up to 28% of
`patients receiving Voltaren Ophthalmic, 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, injection, iritis, irritation, itching, lacrimation
`disorder and ocular allergy.
`
`Systemic: 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.
`
`OVERDOSAGE
`Overdosage will not ordinarily cause acute problems. If Voltaren Ophthalmic is accidentally ingested,
`fluids should be taken to dilute the medication.
`
`DOSAGE AND ADMINISTRATION
`Cataract Surgery: One drop of Voltaren 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 post
`operative period.
`
`Corneal Refractive Surgery: One or two drops of Voltaren 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.
`
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`NDA 20-037/S-014
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`HOW SUPPLIED
`Voltaren Ophthalmic 0.1% (1 mg/mL) Sterile Solution is supplied in a low density polyethylene
`(LDPE) white bottle with a LDPE Dropper Tip and Polypropylene grey closure. The 2.5 mL fill is
`supplied in a 7.5 mL size bottle. The 5.0 mL fill is supplied in a 10.0 mL size bottle.
`
`Bottles of 2.5 mL NDC 58768-100-02
`Bottles of 5 mL NDC 58768-100-05
`
`Store at 15°C to 25°C (59° to 77°F).
`Dispense in original, unopened container only.
`
`Printed in Canada
`Made in Canada. Manufactured for:
`Novartis Ophthalmics, Duluth, Georgia 30097
`
`CS 665635G
`Novartis ® September, 2003
`
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