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`Santen/Asahi Glass Exhibit 2060
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
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`NDA20-597/S-023
`Page 4
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`Excretion: The elimination of the acid of latanoprost from human plasma wasrapid (ty,=17 min)after
`both intravenous andtopical administration. Systemic clearance is approximately
`7 mL/min/kg. Following hepatic B-oxidation, the metabolites are mainly eliminated via the kidneys.
`Approximately 88% and 98% of the administered dose is recovered in the urine after topical and
`intravenousdosing, respectively.
`
`AnimalStudies
`In monkeys, latanoprost has been shownto induce increased pigmentation ofthe iris. The results from
`the preclinical program demonstrated that the increased pigmentation is unlikely to be associated with
`proliferation of melanocytes. It appears that the mechanism of increased pigmentation is stimulation of
`melanin production in melanocytesofthe iris stroma.
`
`In ocular toxicity studies, administration of latanoprost at a dose of 6ug/eye/day (4 times the daily
`human dose) to cynomolgus monkeyshas also been shownto induce increased palpebralfissure. This
`effect is reversible and occurs at doses above the standard clinical doselevel.
`
`INDICATIONS AND USAGE
`XALATANSterile Ophthalmic Solution is indicated for the reduction of elevated intraocular pressure
`in patients with open-angle glaucomaand ocular hypertension whoare intolerant of other intraocular
`pressure lowering medicationsor insufficiently responsive (failed to achieve target IOP determined after
`multiple measurements over time) to another intraocular pressure lowering medication.
`
`CLINICAL STUDIES
`Patients with mean baseline intraocular pressure of 24-25 mmHg whoweretreated for 6 months in
`multi-center, randomized, controlled trials demonstrated 6-8 mmHg reductions in intraocular pressure.
`This IOP reduction with XALATANSterile Ophthalmic Solution 0.005% dosed once daily was
`equivalent to the effect of timolol 0.5% dosed twice daily.
`
`CONTRAINDICATIONS
`Knownhypersensitivity to latanoprost, benzalkonium chloride or any other ingredients in this product.
`
`WARNINGS
`XALATAN hasbeenreported to cause changesto pigmentedtissues. The most frequently
`reported changes have been increased pigmentation of the iris and periorbital tissue (eyelid) and
`increased pigmentation and growth of eyelashes. These changes may be permanent.
`
`XALATANSterile Ophthalmic Solution may gradually change eye color, increasing the amount of
`brown pigmentin the iris by increasing the number of melanosomes(pigment granules) in melanocytes.
`The long term effects on the melanocytes and the consequencesof potential injury to the melanocytes
`and/or deposition of pigment granules to other areas of the eye are currently unknown. The change in
`iris color occurs slowly and maynotbe noticeable for several months to years. Patients should be
`informed ofthe possibility of iris color change.
`
`Eyelid skin darkening hasalso been reported in association with the use of XALATAN.
`
`XALATANmaygradually change eyelashes and vellus hair; these changes include increased length,
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`NDA20-597/S-023
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`thickness, pigmentation, and numberoflashes orhairs, and misdirected growth of eyelashes.
`
`Patients who are expectedto receive treatment in only one eye should be informed aboutthe potential
`for increased brown pigmentation ofthe iris, periorbital tissue, and eyelashes in the treated eye and thus,
`heterochromia between the eyes. They should also be advised ofthe potential for a disparity between
`the eyes in length, thickness, and/or numberof eyelashes. These changes in pigmentation and lash
`growth may be permanent.
`
`PRECAUTIONS
`General: Latanoprost is hydrolyzed in the cornea. The effect of continued administration of
`XALATANSterile Ophthalmic Solution on the corneal endothelium has not been fully evaluated.
`
`There have been reportsof bacterial keratitis associated with the use of multiple-dose containers of
`topical ophthalmic products. These containers had been inadvertently contaminated by patients who,in
`most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface (See
`Information for Patients).
`
`Patients may slowly develop increased brown pigmentation ofthe iris. This change may not be
`noticeable for several months to years (see WARNINGS). Typically the brown pigmentation around
`the pupil spreads concentrically towards the periphery in affected eyes, but the entireiris or parts ofit
`may also become more brownish. Until more information about increased brown pigmentationis
`available, patients should be examined regularly and, depending on the clinical situation, treatment may
`be stoppedif increased pigmentation ensues. During clinical trials, the increase in browniris pigment
`has not been shown toprogress further upon discontinuation oftreatment, but the resultant color change
`may be permanent. Neither nevi nor freckles of the iris have been affected by treatment.
`
`XALATANshould be used with caution in patients with active intraocular inflammation(iritis/uveitis).
`
`Macular edema,including cystoid macular edema,has been reported during treatment with XALATAN.
`These reports have mainly occurred in aphakic patients, in pseudophakic patients with a torn posterior
`lens capsule, or in patients with knownrisk factors for macular edema. XALATANshould be used with
`caution in these patients.
`
`Thereis limited experience with XALATANinthe treatmentof angle closure, inflammatory or
`neovascular glaucoma.
`
`XALATANhasnotbeenstudied in patients with renal or hepatic impairment and should therefore be
`used with caution in such patients.
`
`XALATANshould not be administered while wearing contact lenses.
`
`Informationfor Patients (see WARNINGS): Patients should be informed aboutthe possibility ofiris
`color change dueto anincrease of the brown pigmentand resultant cosmetically different eye coloration
`that may occur whenonly oneeyeis treated.
`Iris pigmentation changes may be morenoticeable in
`patients with green-brown, blue/gray-brown or yellow-brownirides.
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`NDA20-597/S-023
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`Patients should also be informed ofthe possibility of eyelash and vellus hair changesin the treated eye,
`which mayresult in a disparity between eyes in length, thickness, pigmentation, number of eyelashes or
`vellus hairs, and/or direction of eyelash growth.
`
`Patients should also be informed aboutthe possibility of eyelid skin darkening.
`
`The increased pigmentation to the iris and eyelid, as well as the changes to the eyelashes, may be
`permanent.
`
`Patients should be instructed to avoid allowingthe tip of the dispensing container to contact the eye or
`surrounding structures becausethis could cause the tip to become contaminated by commonbacteria
`knownto cause ocular infections. Serious damage to the eye and subsequentloss of vision may result
`from using contaminatedsolutions.
`
`Patients also should be advised that if they develop an intercurrent ocular condition (e.g., trauma or
`infection) or have ocular surgery, they should immediately seek their physician's advice concerning the
`continued use of the multidose container.
`
`Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis andlid
`reactions, they should immediately seek their physician’s advice.
`
`Patients should also be advised that XALATANcontains benzalkonium chloride which may be
`absorbed bysoft contact lenses. Contact lenses should be removedprior to administration of the
`solution. Lenses may bereinserted 15 minutes following administration of XALATAN.
`
`If more than one topical ophthalmic drug is being used, the drugs should be administered at least five
`(5) minutes apart.
`
`Drug Interactions: In vitro studies have shownthat precipitation occurs when eye drops containing
`thimerosal are mixed with XALATAN. If such drugs are used they should be administered with an
`interval of at least five (5) minutes between applications.
`
`Carcinogenesis, Mutagenesis, ImpairmentofFertility:
`Latanoprost was not mutagenic in bacteria, in mouse lymphomaor in mouse micronucleustests.
`
`Chromosome aberrations were observed in vitro with human lymphocytes.
`
`Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up
`to 170 uwg/kg/day (approximately 2,800 times the recommended maximum humandose) for up to 20
`and 24 months, respectively.
`
`Additional in vitro and in vivo studies on unscheduled DNA synthesis in rats were negative.
`Latanoprost has not been found to have any effect on male or female fertility in animal studies.
`
`Pregnancy: Teratogenic Effects: Pregnancy Category C.
`Reproduction studies have been performedin rats and rabbits. In rabbits an incidence of 4 of 16 dams
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`NDA 20-597/S-023
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`had no viable fetuses at a dose that was approximately 80 times the maximum humandose, and the
`highest nonembryocidal dose in rabbits was approximately 15 times the maximum human dose. There
`are no adequate and well-controlled studies in pregnant women. XALATANshould be used during
`pregnancyonly if the potential benefit justifies the potential risk to the fetus.
`
`It is not known whetherthis drug or its metabolites are excreted in human milk.
`Nursing Mothers:
`Because many drugsare excreted in human milk, caution should be exercised when XALATANis
`administered to a nursing woman.
`
`Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
`
`Geriatric Use: No overall differences in safety or effectiveness have been observed betweenelderly
`and youngerpatients.
`
`ADVERSE REACTIONS
`Adverse events referred to in other sections of this insert:
`Eyelash changes(increased length, thickness, pigmentation, and numberoflashes); eyelid skin
`darkening;intraocular inflammation(iritis/uveitis); iris pigmentation changes; and macular edema,
`including cystoid macular edema (See WARNINGSand PRECAUTIONS).
`
`Controlled Clinical Trials:
`The ocular adverse events and ocular signs and symptoms reported in 5 to 15% of the patients on
`XALATANSterile Ophthalmic Solution in the 6-month, multi-center, double-masked, active-controlled
`trials were blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation,
`itching, increased pigmentation ofthe iris, and punctate epithelial keratopathy.
`
`Local conjunctival hyperemia was observed; however, less than 1% of the patients treated with
`XALATANrequired discontinuation of therapy because of intolerance to conjunctival hyperemia.
`
`In addition to the abovelisted ocular events/signs and symptoms,the following were reported in | to
`4% of the patients: dry eye, excessive tearing, eye pain, lid crusting, lid discomfort/pain, lid edema, lid
`erythema, and photophobia.
`
`The following events were reported in less than 1% ofthe patients: conjunctivitis, diplopia and
`discharge from the eye.
`
`Duringclinical studies, there were extremely rare reports of the following:retinal artery embolus,
`retinal detachment, and vitreous hemorrhage from diabetic retinopathy.
`
`The most commonsystemic adverse events seen with XALATANwereupperrespiratory tract
`infection/cold/flu which occurred at a rate of approximately 4%. Chest pain/angina pectoris,
`muscle/joint/back pain, and rash/allergic skin reaction each occurredata rate of 1 to 2%.
`
`Clinical Practice: The following events have been identified during postmarketing use of XALATAN
`in clinical practice. Because they are reported voluntarily from a population of unknownsize, estimates
`of frequency cannot be made. The events, which have been chosenfor inclusion dueto either their
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`NDA 20-597/S-023
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`seriousness, frequency of reporting, possible causal connection to XALATAN, or a combination of
`these factors, include: asthma and exacerbation of asthma; corneal edema and erosions; dyspnea;
`eyelash and vellus hair changes (increased length, thickness, pigmentation, and number); eyelid skin
`darkening; herpeskeratitis; intraocular inflammation(iritis/uveitis); keratitis; macular edema, including
`cystoid macular edema; misdirected eyelashes sometimesresulting in eyeirritation; and toxic epidermal
`necrolysis.
`
`OVERDOSAGE
`Apart from ocularirritation and conjunctival or episcleral hyperemia, the ocular effects of latanoprost
`administered at high doses are not known. Intravenous administration of large doses of latanoprost in
`monkeyshas been associated with transient bronchoconstriction; however, in 11 patients with bronchial
`asthma treated with latanoprost, bronchoconstriction was not induced.
`Intravenousinfusion of up to 3
`“g/kg in healthy volunteers produced mean plasma concentrations 200 times higher than during clinical
`treatment and no adverse reactions were observed. Intravenous dosages of 5.5 to 10 g/kg caused
`abdominalpain, dizziness, fatigue, hot flushes, nausea and sweating.
`
`If overdosage with XALATANSterile Ophthalmic Solution occurs, treatment should be symptomatic.
`
`DOSAGE AND ADMINISTRATION
`The recommended dosageis one drop (1.5 g) in the affected eye(s) once daily in the evening.
`
`The dosage of XALATANSterile Ophthalmic Solution should not exceed once daily since it has been
`shownthat more frequent administration may decrease the intraocular pressure lowering effect.
`
`Reduction ofthe intraocular pressure starts approximately 3 to 4 hours after administration and the
`maximum effect is reached after 8 to 12 hours.
`
`XALATANmaybe used concomitantly with other topical ophthalmic drug products to lower
`intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be
`administered at least five (5) minutes apart.
`
`HOW SUPPLIED
`XALATANSterile Ophthalmic Solution is a clear, isotonic, buffered, preserved colorless solution of
`latanoprost 0.005% (50 wg/mL).
`It is supplied as a 2.5 mL solution in a 5 mL clear low density
`polyethylene bottle with a clear low density polyethylene droppertip, a turquoise high density
`polyethylene screw cap, and a tamper-evident clear low density polyethylene overcap.
`
`NDC 0013-8303-04
`2.5 mL fill, 0.005% (50 g/mL).
`
`Storage: Store between 2° to 25°C (36° to 77°F). Protect from light.
`Discard the container 6 weeksafter opening.
`
`Rx only.
`U.S. Patent Nos. 4,599,353; 5,296,504 and 5,422,368.
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`NDA20-597/S-023
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`Manufactured for:
`Pharmacia & Upjohn Company
`A subsidiary of Pharmacia Corporation
`Kalamazoo, MI 49001, USA
`By:
`Automatic Liquid Packaging, Inc.
`Woodstock, IL 60098, USA
`
`Revised
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`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Linda Ng
`11/26/01 12:40:39 PM
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