` NDA 21-214/S-006
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` NDA 21-214/S-007
`Page 5
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`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`RESCULA safely and effectively. See full prescribing information
`
`for RESCULA.
`
`Rescula (unoprostone isopropyl ophthalmic solution) 0.15%
`
`Initial U.S. Approval: 2000
`
`
`------------------------ INDICATIONS AND USAGE -----------------------
`
`• Rescula (unoprostone isopropyl ophthalmic solution) 0.15% is
`
`indicated for the lowering of intraocular pressure in patients with
`open-angle glaucoma or ocular hypertension. (1)
`
`
`------------------- DOSAGE AND ADMINISTRATION ------------------
`
`• One drop in the affected eye(s) twice daily (2)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact
`
`
`Sucampo Pharma Americas at 1-855-RESCULA (1-855-737-2852)
`
`------------------ DOSAGE FORMS AND STRENGTHS -----------------
`
`or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`• Unoprostone isopropyl ophthalmic solution, 1.5 mg/mL (3)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`-------------------------- CONTRAINDICATIONS --------------------------
`
`
`• Hypersensitivity to unoprostone isopropyl or any of the excipients (4)
`
`Revised: 11/2012
`__________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`
`-------------------- WARNINGS AND PRECAUTIONS -------------------
`• Rescula has been reported to increase pigmentation of the iris (5.1)
`
`
`• Rescula has been reported to increase pigmentation of the periorbital
`
`tissues and eyelashes (5.2)
`• Rescula should be used with caution in patients with active
`
`intraocular inflammation because the inflammation may be
`exacerbated (5.3)
`
`
`--------------------------- ADVERSE REACTIONS --------------------------
`
`• Most common adverse reactions (incidence 10–25%) are
`
`burning/stinging, burning/stinging upon drug instillation, dry eyes,
`itching, increased length of eyelashes and injection (6.1)
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`INDICATIONS AND USAGE
`1
`
`DOSAGE AND ADMINISTRATION
`2
`
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1
`Iris Pigmentation
`5.2
`Lid Pigmentation
`Intraocular Inflammation
`5.3
`
`Macular Edema
`5.4
`5.5
`Contamination of Tip and Solution
`5.6
`Use with Contact Lenses
`ADVERSE REACTIONS
`6.1
`Clinical Studies Experience
`6.2
`Postmarketing Experience
`USE IN SPECIFIC POPULATIONS
`Pregnancy
`8.1
`
`Nursing Mothers
`8.3
`
`8
`
`6
`
`Pediatric Use
`8.4
`Geriatric Use
`8.5
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`17.1 Handling the Bottle
`
`17.2
`Potential for Iris Darkening
`17.3
`Potential for Eyelid Skin Darkening
`17.4 Use with Contact Lenses
`
`17.5 Multiple Therapies
`
`
`
`*Sections or subsections omitted from the full prescribing
`
`information are not listed
`
`___________________________________________________________________________________________________________
`
`
`
`Reference ID: 3227684
`
`IPR Page 1/7
`
`Santen/Asahi Glass Exhibit 2042
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`

`

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` NDA 21-214/S-006
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` NDA 21-214/S-007
`Page 6
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`
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`Rescula (unoprostone isopropyl ophthalmic solution) 0.15% is indicated for the lowering of
`intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
`
`
`2
`
`
`3
`
`
`4
`
`
`5
`
`DOSAGE AND ADMINISTRATION
`The recommended dosage is one drop in the affected eye(s) twice daily.
`
`Rescula may be used concomitantly with other topical ophthalmic drug products to lower
`intraocular pressure. If two drugs are used, they should be administered at least five (5)
`minutes apart [see Patient Counseling Information (17.5)].
`
`DOSAGE FORMS AND STRENGTHS
`Unoprostone isopropyl ophthalmic solution 1.5 mg/mL.
`
`CONTRAINDICATIONS
`Rescula is contraindicated in patients with hypersensitivity to unoprostone isopropyl or any
`other ingredient in this product.
`
`WARNINGS AND PRECAUTIONS
`
`
`5.1 Iris Pigmentation
`Unoprostone isopropyl ophthalmic solution may gradually increase the pigmentation of the
`iris. The pigmentation change is believed to be due to increased melanin content in the
`
`melanocytes rather than to an increase in the number of melanocytes. The long term effects
`of increased pigmentation are not known. Iris color changes seen with administration of
`unoprostone isopropyl ophthalmic solution may not be noticeable for several months to
`years. Typically, the brown pigmentation around the pupil spreads concentrically towards the
`periphery of the iris and the entire iris or parts of the iris become more brownish. Neither
`
`nevi nor freckles of the iris appear to be affected by treatment. Treatment with Rescula
`solution can be continued in patients who develop noticeably increased iris pigmentation.
`
` Patients who receive treatment with Rescula should be informed of the possibility of
`
`
` increased pigmentation [see Patient Counseling Information (17.2)].
`
`
`
`
`5.2 Lid Pigmentation
`Unoprostone isopropyl has been reported to cause pigment changes (darkening) to periorbital
`pigmented tissues and eyelashes. The pigmentation is expected to increase as long as
`
`unoprostone isopropyl is administered, but has been reported to be reversible upon
`discontinuation of unoprostone isopropyl ophthalmic solution in most patients.
`
`5.3 Intraocular Inflammation
`Rescula should be used with caution in patients with active intraocular inflammation (e.g.,
`uveitis) because the inflammation may be exacerbated.
`
`
`
`
`Reference ID: 3227684
`
`IPR Page 2/7
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`

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`5.4 Macular Edema
`
`Macular edema, including cystoid macular edema, has been reported. Rescula should be used
`with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule,
`or in patients with known risk factors for macular edema.
`
`6
`
`5.5 Contamination of Tip And Solution
`To minimize contaminating the dropper tip and solution, care should be taken not to touch
`the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed
`when not in use. There have been reports of bacterial keratitis associated with the use of
`
`multiple-dose containers of topical ophthalmic products [see Patient Counseling Information
`(17.1)].
`
`5.6 Use with Contact Lenses
`Rescula contains benzalkonium chloride, which may be absorbed by soft contact lenses.
`Contact lenses should be removed prior to application of solution and may be reinserted 15
`minutes following its administration [see Patient Counseling Information (17.4)].
`
`
`ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`Because clinical studies are conducted under widely varying conditions, adverse reaction
`rates observed in the clinical studies of a drug cannot be directly compared to rates in the
`clinical studies of another drug and may not reflect the rates observed in practice.
`
`
`In clinical studies, the most common ocular adverse reactions with use of Rescula were
`burning/stinging, burning/stinging upon drug instillation, dry eyes, itching, increased length
`of eyelashes, and injection. These were reported in approximately 10–25% of patients.
`Approximately 10–14% of patients were observed to have an increase in the length of
`eyelashes (≥ 1 mm) at 12 months, while 7% of patients were observed to have a decrease in
`the length of eyelashes.
`
`Ocular adverse reactions occurring in approximately 5–10% of patients were abnormal
`vision, eyelid disorder, foreign body sensation, and lacrimation disorder.
`
`
`Ocular adverse reactions occurring in approximately 1–5% of patients were blepharitis,
`cataract, conjunctivitis, corneal lesion, discharge from the eye, eye hemorrhage, eye pain,
`keratitis, irritation, photophobia, and vitreous disorder.
`
`Other ocular adverse reactions reported in less than 1% of patients were acute elevated
`intraocular pressure, color blindness, corneal deposits, corneal edema, corneal opacity,
`
`diplopia, hyperpigmentation of the eyelid, increased number of eyelashes, iris
`hyperpigmentation, iritis, optic atrophy, ptosis, retinal hemorrhage, and visual field defect.
`
`The most frequently reported nonocular adverse reaction associated with the use of Rescula
`in the clinical trials was flu-like syndrome that was observed in approximately 6% of
`patients. Nonocular adverse reactions reported in the 1–5% of patients were accidental injury,
`
`
`
`Reference ID: 3227684
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`IPR Page 3/7
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`8
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`allergic reaction, back pain, bronchitis, increased cough, diabetes mellitus, dizziness,
`
`headache, hypertension, insomnia, pharyngitis, pain, rhinitis, and sinusitis.
`
`
`6.2 Postmarketing Experience
`
`The following adverse reactions have been identified during post-approval use of Rescula.
`Because these reactions are reported voluntarily from a population of uncertain size, it is not
`always possible to reliably estimate their frequency or establish a causal relationship to drug
`exposure.
`
`Voluntary reports of adverse reactions occurring with the use of Rescula include corneal
`erosion.
`
`There have been rare spontaneous reports with a different formulation of unoprostone
`isopropyl (0.12%) of chemosis, dry mouth, nausea, vomiting and palpitations.
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Pregnancy Category C
`Teratogenic effects: There were no teratogenic effects observed in rats and rabbits up to 5
`and 0.3 mg/kg/day (approximately 1,000 and 60 fold the recommended human dose of 0.005
`mg/kg/day in the rat and rabbit, respectively). There was an increase in the incidence of
`miscarriages and a decrease in live birth index in rats administered unoprostone isopropyl
`during organogenesis at subcutaneous doses of 5 mg/kg. There was an increase in incidence
`of miscarriages and resorptions and a decrease in the number of live fetuses in rabbits
`administered unoprostone isopropyl during organogenesis at subcutaneous doses of 0.3
`mg/kg. The no observable adverse effect level (NOAEL) for embryofetal toxicity in rats and
`rabbits was 2 and 0.1 mg/kg (approximately 400 and 20 fold the recommended human dose
`of 0.005 mg/kg/day in the rat and rabbit, respectively).
`
`There was an increase in incidence of premature delivery, a decrease in live birth index, and
`a decrease in weight at birth and through postpartum Day 7 in rats administered unoprostone
`isopropyl during late gestation through postpartum Day 21 at subcutaneous doses of 1.25
`mg/kg. In addition, pups from rats administered 1.25 mg/kg subcutaneously exhibited
`delayed growth and development characterized by delayed incisor eruption and eye opening.
`There was an increase in the number of stillborn pups and a decrease in perinatal survival in
`rats administered unoprostone isopropyl during late gestation through weaning at
`subcutaneous doses of ≥ 0.5 mg/kg. The NOAEL for pre- and postnatal toxicity in rats was
`0.2 mg/kg (approximately 40 fold the recommended human dose of 0.005 mg/kg/day).
`
`
`There are no adequate and well-controlled studies in pregnant women. Because animal
`studies are not always predictive of human response, Rescula should be used during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`
`
`Reference ID: 3227684
`
`IPR Page 4/7
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`8.3 Nursing Mothers
`It is not known whether Rescula is excreted in human milk. Because many drugs are
`
`excreted in human milk, caution should be exercised when Rescula is administered to a
`nursing woman.
`
`8.4 Pediatric Use
`Safety and effectiveness in pediatric patients have not been established.
`
`8.5 Geriatric Use
`No overall differences in safety or effectiveness have been observed between elderly and
`other adult patients.
`
`
`
`DESCRIPTION
`Rescula (unoprostone isopropyl ophthalmic solution) 0.15% is a synthetic docosanoid.
`Unoprostone isopropyl has the chemical name isopropyl (+)-(Z)-7-[(1R,2R,3R,5S)-3,5-
`dihydroxy-2-(3-oxodecyl)cyclopentyl]-5-heptenoate. Its molecular formula is C25H44O5 and
`its chemical structure is:
`
`
`
`
`
`
`Unoprostone isopropyl is a clear, colorless, viscous liquid that is very soluble in acetonitrile,
`ethanol, ethyl acetate, isopropanol, dioxane, ether, and hexane. It is practically insoluble in
`water. Rescula (unoprostone isopropyl ophthalmic solution) 0.15% is supplied as a sterile,
`isotonic, buffered, aqueous solution of unoprostone isopropyl with a pH of 5.0–6.5 and an
`osmolality of 235–300 mOsmol/kg.
`
`Each mL of Rescula contains 1.5 mg of unoprostone isopropyl. Benzalkonium chloride
`0.015% is added as a preservative. Inactive ingredients are mannitol, polysorbate 80, edetate
`disodium, sodium hydroxide or hydrochloric acid (to adjust pH), and water for injection.
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`Rescula is believed to reduce elevated intraocular pressure (IOP) by increasing the outflow of
`aqueous humor through the trabecular meshwork. Unoprostone isopropyl (UI) may have a
`local effect on BK (Big Potassium) channels and ClC-2 chloride channels, but the exact
`mechanism is unknown at this time.
`
`
`11
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`12
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`Reference ID: 3227684
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`IPR Page 5/7
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`12.3 Pharmacokinetics
`
`Absorption
`
`After application to the eye, unoprostone isopropyl is absorbed through the cornea and
`conjunctival epithelium where it is hydrolyzed by esterases to unoprostone free acid.
`
`
`A study conducted with 18 healthy volunteers dosed bilaterally with unoprostone isopropyl
`ophthalmic solution twice daily for 14 days demonstrated little systemic absorption of
`unoprostone isopropyl. The systemic exposure of its metabolite unoprostone free acid was
`minimal following the ocular administration. Mean peak unoprostone free acid concentration
`was less than 1.5 ng/mL. Little or no accumulation of unoprostone free acid was observed.
`
`Metabolism
`Following ocular application, unoprostone isopropyl is hydrolyzed by esterases in the cornea
`to its biological active metabolite, unoprostone free acid. Unoprostone free acid is further
`metabolized to several inactive metabolites with lower molecular weight and increased
`
`polarity via ω- or β-oxidation. No secondary conjugation is found and no significant effect on
`hepatic microsomal enzyme activity has been observed.
`
`Elimination
`
`Elimination of unoprostone free acid from human plasma is rapid, with a half-life of 14
`
`minutes. Plasma levels of unoprostone free acid dropped below the lower limit of
`quantitation (< 0.25 ng/mL) 1 hour following ocular instillation. The metabolites are excreted
`predominately in urine.
`
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Unoprostone isopropyl was not carcinogenic in rats administered oral doses up to 12
`mg/kg/day for up to 2 years (approximately 580 and 240 fold the recommended human dose
`of 0.005 mg/kg/day based on AUC0–24 in male and female rats, respectively).
`Under the conditions tested, unoprostone isopropyl and unoprostone free acid were neither
`mutagenic in an Ames assay nor clastogenic in a chromosome aberration assay in Chinese
`hamster lung–derived fibroblast cells. Under the conditions tested, unoprostone isopropyl
`was not genotoxic in a mouse lymphoma mutation assay or clastogenic in an in vivo
`
`
`chromosomal aberration test in mouse bone marrow.
`Unoprostone isopropyl did not impair male or female fertility in rats at subcutaneous doses
`up to 50 mg/kg (approximately 10,000 fold the recommended human dose of 0.005
`mg/kg/day).
`
`
`CLINICAL STUDIES
`
`In six (6) month randomized controlled clinical studies in patients with a mean baseline
`intraocular pressure of 23 mmHg, Rescula lowered intraocular pressure by approximately 3–
`4 mmHg throughout the day. Rescula appeared to lower intraocular pressure without
`affecting cardiovascular or pulmonary function.
`
`
`13
`
`
`14
`
`
`
`Reference ID: 3227684
`
`IPR Page 6/7
`
`

`

`HOW SUPPLIED/STORAGE AND HANDLING
`Rescula (unoprostone isopropyl ophthalmic solution) 0.15% is supplied sterile in a low-
`density polyethylene bottle with a low-density polyethylene dropper tip, a turquoise
`polypropylene closure, and a clear tamper-evident shrinkband.
`
`5 mL in a 7.5 mL bottle NDC 17350-015-05
`
`Storage: Store between 2° - 25°C (36° - 77°F).
`
`PATIENT COUNSELING INFORMATION
`
`17.1 Handling the Bottle
`Patients should be instructed that the Rescula bottle must be maintained intact and to avoid
`allowing the tip of the bottle to contact surrounding structures, fingers, or any other
`unintended surface in order to avoid contamination of the bottle or applicator by common
`bacteria known to cause ocular infections. Serious infections may result from using
`contaminated solutions.
`
`17.2 Potential for Iris Darkening
`Patients should be advised about the potential for increased brown iris pigmentation
`which is likely to be permanent.
`
`
`17.3 Potential For Eyelid Skin Darkening
`Patients should be informed about the possibility of eyelid skin darkening, which may be
`reversible after discontinuation of Rescula.
`
`17.4 Use with Contact Lenses
`Patients should be advised that Rescula contains benzalkonium chloride, which may be
`absorbed by soft contact lenses. Contact lenses should be removed prior to application of
`
`Rescula and may be reinserted 15 minutes following its administration.
`
`
`17.5 Multiple Therapies
`If more than one topical ophthalmic therapy is being used patients should be instructed to
`administer the drugs at least 5 minutes apart.
`
`
`Marketed by:
`Sucampo Pharma Americas, LLC
`Bethesda, MD 20814
`
`
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`17
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`Reference ID: 3227684
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`IPR Page 7/7
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