Profenal® 1%
`(Suprofen)
`Sterile Ophthalmic Solution
`
`DESCRIPTION
`PROFENAL® (suprofen) 1% ophthalmic solution is a topical nonsteroidal anti-inflammatory product for
`ophthalmic use. Suprofen chemically is α -methyl-4-(2-thienylcarbonyl)benzeneacetic acid, with an empirical
`formula of C H O S, and a molecular weight of 260.3. The chemical structure of suprofen is:
`14 12 3
`
`PROFENAL Sterile Ophthalmic Solution contains suprofen 1.0% (10 mg/mL), thimerosal 0.005% (0.05
`mg/mL), caffeine 2% (20 mg/mL), edetate disodium, dibasic sodium phosphate, monobasic sodium phosphate,
`sodium chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH to 7.4) and purified water.
`DM-00
`
`CLINICAL PHARMACOLOGY
`Suprofen 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 cyclooxygenase 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 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, PROFENAL has been shown to
`inhibit the miosis induced during the course of cataract surgery. PROFENAL could possibly interfere with the
`miotic effect of intraoperatively administered acetylcholine chloride.
`Results from clinical studies indicate that PROFENAL Ophthalmic Solution has no significant effect on
`intraocular pressure.
`There are no data available on the systemic absorption of ocularly applied suprofen. The oral dose of suprofen
`is 200 mg every four to six hours. If PROFENAL 1% Ophthalmic Solution is applied as two drops (1 mg
`suprofen) to one eye five times on the day prior to surgery and three times on the day of surgery, the total
`applied dose over the two days would be about 25 times less than a single 200 mg oral dose.
`
`INDICATIONS AND USAGE
`PROFENAL Ophthalmic Solution is indicated for inhibition of intraoperative miosis.
`
`CONTRAINDICATIONS
`
`Page 1 of 4
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`SENJU EXHIBIT 2056
`LUPIN v. SENJU
`IPR2015-01099
`
`

`
`PROFENAL is contraindicated in epithelial herpes simplex keratitis (dendritic keratitis) and in individuals
`hypersensitive to any component of the medication.
`
`WARNINGS
`The potential exists 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.
`With nonsteroidal anti-inflammatory drugs, the potential exists 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 tendency of ocular tissues in conjunction with ocular surgery.
`
`PRECAUTIONS
`
`General
`Use of oral suprofen has been associated with a syndrome of acute flank pain and generally reversible renal
`insufficiency, which may present as acute uric acid nephropathy. This syndrome occurs in approximately 1 in
`3500 patients and has been reported with as few as one to two doses of a 200 mg capsule. If PROFENAL 1%
`Ophthalmic Solution is applied as two drops (1 mg suprofen) to one eye five times on the day prior to surgery
`and three times on the day of surgery, the total applied dose over the two days would be about 25 times less
`than a single 200 mg oral dose. Do not touch dropper tip to any surface, as this may contaminate the solution.
`
`Ocular
`Patients with histories of herpes simplex keratitis should be monitored closely. PROFENAL is contraindicated
`in patients with active herpes simplex keratitis.
`The possibility of increased ocular bleeding during surgery associated with nonsteroidal anti-inflammatory
`drugs should be considered.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`In an 18-month study in mice, an increased incidence of benign hepatomas occurred in females at a dose of 40
`mg/kg/day. Male mice, treated at doses of 2, 5, 10 and 40 mg/kg/day, also had an increased incidence of
`hepatomas when compared to control animals. No evidence of carcinogenicity was found in long term studies in
`doses as high as 40 mg/kg/day in the rat and mouse. Based on a battery of mutagenicity tests (Ames,
`micronucleus, and dominant lethal), suprofen does not appear to have mutagenic potential. Reproductive studies
`in rats at a dose of up to 40 mg/kg/day revealed no impairment of fertility and only slight reductions of fertility
`at doses of 80 mg/kg/day. However, testicular atrophy/hypoplasia was observed in a six-month dog study (at 80
`mg/kg/day) and a 12-month rat study (at 40 mg/kg/day).
`
`Pregnancy Category C
`Reproductive studies have been performed in rabbits at doses up to 200 mg/kg/day and in rats at doses up to 80
`mg/kg/day. In rats, doses of 40 mg/kg/day and above, and in rabbits, doses of 80 mg/kg/day and above, resulted
`in an increased incidence of fetal resorption associated with maternal toxicity. There was an increase in
`stillbirths and a decrease in postnatal survival in pregnant rats treated with suprofen at 2.5 mg/kg/day and
`above. An increased incidence of delayed parturition occurred in rats. As there are no adequate and well-
`controlled studies in pregnant women, this drug should be used during pregnancy only if the potential benefit
`justifies the potential risk to the fetus. Because of the known effect of nonsteroidal anti-inflammatory drugs on
`the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.
`
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`

`
`Nursing Mothers
`Suprofen is excreted in human milk after a single oral dose. Based on measurements of plasma and milk levels
`in women taking oral suprofen, the milk concentration is about 1% of the plasma level. Because systemic
`absorption may occur from topical ocular administration, a decision should be considered to discontinue nursing
`while receiving PROFENAL®, since the safety of suprofen in human neonates has not been established.
`
`Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
`
`Drug Interactions
`Clinical studies with acetylcholine chloride revealed no interference, and there is no known pharmacological
`basis for such an interaction. However, with other topical nonsteroidal anti-inflammatory products, there have
`been reports that acetylcholine chloride and carbachol have been ineffective when used in patients treated with
`these agents.
`Interaction of PROFENAL with other topical ophthalmic medications has not been fully investigated.
`
`ADVERSE REACTIONS
`
`Ocular
`The most frequent adverse reactions reported are burning and stinging of short duration. Instances of
`discomfort, itching and redness have been reported. Other reactions occurring in less than 0.5% of patients
`include allergy, iritis, pain, chemosis, photophobia, irritation, and punctate epithelial staining.
`
`Systemic
`Systemic reactions related to therapy were not reported in the clinical studies. It is known that some systemic
`absorption does occur with ocularly applied drugs, and that nonsteroidal anti-inflammatory drugs have been
`shown to increase bleeding time by interference with thrombocyte aggregation. It is recommended that
`PROFENAL be used with caution in patients with bleeding tendencies and those taking anticoagulants.
`
`OVERDOSAGE
`Overdosage will not ordinarily cause acute problems. If accidentally ingested, drink fluids to dilute.
`
`DOSAGE AND ADMINISTRATION
`On the day of surgery, instill two drops into the conjunctival sac at three, two and one hour prior to surgery.
`Two drops may be instilled into the conjunctival sac every four hours, while awake, the day preceding surgery.
`
`HOW SUPPLIED
`Sterile ophthalmic solution, 2.5 mL in plastic DROP-TAINER® dispensers.
`2.5 mL NDC 0065-0348-25
`STORAGE: Store at room temperature.
`Rx Only
`U.S. Patents Nos. 4,035,376; 4,559,343
`
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`

`
`Alcon Laboratories, Inc.
`Fort Worth, Texas 76134 USA
`Printed in USA
`343005-0798 Revised: July 1998
`
`PROFENAL
`suprofen solution
`
`Product Information
`Product Type
`
`HUMAN PRESCRIPTION DRUG
`
`Item Code (Source)
`
`NDC:0065-0348
`
`Route of Administration
`
`OPHTHALMIC
`
`DEA Schedule
`
`Active Ingredient/Active Moiety
`Ingredient Name
`suprofen (UNII: 988GU2F9PE) (suprofen - UNII:988GU2F9PE)
`
`Inactive Ingredients
`
`Ingredient Name
`
`thimerosal (UNII: 2225PI3MOV)
`caffeine (UNII: 3G6A5W338E)
`edetate disodium (UNII: 7FLD91C86K)
`dibasic sodium phosphate (UNII: GR686LBA74)
`monobasic sodium phosphate (UNII: 3980JIH2SW)
`sodium chloride (UNII: 451W47IQ8X)
`sodium hydroxide and/or hydrochloric acid ()
`water (UNII: 059QF0KO0R)
`
`Packaging
`#
`Item Code
`1 NDC:0065-0348-25
`
`Package Description
`2.5 mL in 1 BOTTLE, PLASTIC
`
`Labeler - Alcon Laboratories, Inc.
`
`Revised: 2/2006
`
`Basis of Strength
`
`Strength
`10 mg in 1 mL
`
`Strength
`0.05 mg in 1 mL
`20 mg in 1 mL
`
`Marketing Start Date
`
`Marketing End Date
`
`Alcon Laboratories, Inc.
`
`Page 4 of 4