HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`XALATAN safely and effectively. See full prescribing
`information for XALATAN.
`
`XALATAN® (latanoprost ophthalmic solution) 0.005%
`Initial U.S. Approval: 1996
`
`------------------------INDICATIONS AND USAGE--------------------­
`XALATAN is a prostaglandin F2α analogue indicated for the
`reduction of elevated intraocular pressure in patients with open-angle
`glaucoma or ocular hypertension. (1)
`
`-----------------------DOSAGE AND ADMINISTRATION------------­
`One drop in the affected eye(s) once daily in the evening. (2)
`
`----------------------DOSAGE FORMS AND STRENGTHS----------­
`Ophthalmic solution containing 50 mcg/mL latanoprost (0.005%). (3)
`
`-----------------------------CONTRAINDICATIONS--------------------­
`Known hypersensitivity to latanoprost, benzalkonium chloride or any
`other ingredients in this product. (4)
`
`--------------------WARNINGS AND PRECAUTIONS----------------­
` Pigmentation: pigmentation of the iris, periorbital tissue (eyelid)
`and eyelashes can occur. Iris pigmentation likely to be permanent.
`(5.1)
` Eyelash Changes: gradual change to eyelashes including increased
`length, thickness and number of lashes. Usually reversible. (5.2)
`
`-----------------------------ADVERSE REACTIONS---------------------­
`Most common adverse reactions (≥4%) from clinical trials are
`blurred vision, burning and stinging, conjunctival hyperemia, foreign
`body sensation, itching, increased pigmentation of the iris, punctate
`keratitis, and upper respiratory tract
`infection/nasopharyngitis/influenza. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Pfizer
`at 1-800-438-1985 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`----------------------------DRUG INTERACTIONS----------------------­
`In vitro studies have shown that precipitation occurs when eye drops
`containing thimerosal are mixed with XALATAN. If such drugs are
`used, they should be administered at least 5 minutes apart. (7)
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: M/YYYY
`
`________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`INDICATIONS AND USAGE
`1
`2 DOSAGE AND ADMINISTRATION
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pigmentation
`5.2 Eyelash Changes
`5.3 Intraocular Inflammation
`5.4 Macular Edema
`5.5 Herpetic Keratitis
`5.6 Bacterial Keratitis
`5.7 Use with Contact Lenses
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`6.2 Postmarketing Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`*Sections or subsections omitted from the full prescribing
`8.1 Pregnancy
`information are not listed
`________________________________________________________________________________________________________________________
`
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Elevated Baseline IOP
`14.2 Progression of Increased Iris Pigmentation
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`Reference ID: 4081740
`
`IPR Page 1/9
`
`Santen/Asahi Glass Exhibit 2037
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`
`XALATAN is indicated for the reduction of elevated intraocular pressure in patients with open-angle
`glaucoma or ocular hypertension.
`
`2 DOSAGE AND ADMINISTRATION
`
`The recommended dosage is one drop in the affected eye(s) once daily in the evening. If one dose is missed,
`treatment should continue with the next dose as normal.
`
`The dosage of XALATAN should not exceed once daily; the combined use of two or more prostaglandins,
`or prostaglandin analogs including XALATAN is not recommended. It has been shown that administration
`of these prostaglandin drug products more than once daily may decrease the intraocular pressure (IOP)
`lowering effect or cause paradoxical elevations in IOP.
`
`
`Reduction of the IOP starts approximately 3 to 4 hours after administration and the maximum effect is
`reached after 8 to 12 hours.
`
`
`XALATAN may be used concomitantly with other topical ophthalmic drug products to lower IOP. If more
`
`than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes
`apart. Contact lenses should be removed prior to the administration of XALATAN, and may be reinserted
`15 minutes after administration
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Sterile ophthalmic solution containing 50 mcg/mL latanoprost.
`
`4 CONTRAINDICATIONS
`
`Known hypersensitivity to latanoprost, benzalkonium chloride, or any other ingredients in this product.
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Pigmentation
`
`
`XALATAN has been reported to cause changes to pigmented tissues. The most frequently reported changes
`
`have been increased pigmentation of the iris, periorbital tissue (eyelid), and eyelashes. Pigmentation is
`expected to increase as long as latanoprost is administered.
`
`The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase
`in the number of melanocytes. After discontinuation of latanoprost, pigmentation of the iris is likely to be
`permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be
`reversible in some patients. Patients who receive treatment should be informed of the possibility of
`increased pigmentation. Beyond 5 years the effects of increased pigmentation are not known [see Clinical
`Studies (14.2)].
`
`Reference ID: 4081740
`
`IPR Page 2/9
`
`

`

`Iris color change 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. While
`treatment with XALATAN can be continued in patients who develop noticeably increased iris pigmentation,
`these patients should be examined regularly [see Patient Counseling Information (17.1)].
`
`5.2 Eyelash Changes
`
` XALATAN may gradually change eyelashes and vellus hair in the treated eye; these changes include
`
`increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of
`eyelashes. Eyelash changes are usually reversible upon discontinuation of treatment [see Patient Counseling
`Information (17.2)].
`
`5.3 Intraocular Inflammation
`
`
`XALATAN should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis)
`and should generally not be used in patients with active intraocular inflammation because inflammation may
`be exacerbated.
`
`5.4 Macular Edema
`
`Macular edema, including cystoid macular edema, has been reported during treatment with XALATAN.
`
`XALATAN 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.
`
`5.5 Herpetic Keratitis
`
`Reactivation of Herpes Simplex keratitis has been reported during treatment with XALATAN. XALATAN
`should be used with caution in patients with a history of herpetic keratitis. XALATAN should be avoided in
`cases of active herpes simplex keratitis because inflammation may be exacerbated.
`
`5.6 Bacterial Keratitis
`
`There have been reports of 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 Patient Counseling
`Information (17.3)].
`
`5.7 Use with Contact Lenses
`
`Contact lenses should be removed prior to the administration of XALATAN, and may be reinserted
`
`15 minutes after administration.
`
`
`6 ADVERSE REACTIONS
`
`The following adverse reactions were reported in postmarketing experience and are discussed in greater
`detail in other sections of the label:
`
`
`
`Iris pigmentation changes [see Warnings and Precautions (5.1)]
`
`
`Reference ID: 4081740
`
`IPR Page 3/9
`
`

`

` Eyelid skin darkening [see Warnings and Precautions (5.1)]
`
`
` Eyelash changes (increased length, thickness, pigmentation, and number of lashes) [see Warnings and
`
`
`Precautions (5.2)]
` Intraocular inflammation (iritis/uveitis) [see Warnings and Precautions (5.3)]
`
`
` Macular edema, including cystoid macular edema [see Warnings and Precautions (5.4)]
`
`
`6.1 Clinical Trials Experience
`
`Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in
`the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and
`
`may not reflect the rates observed in clinical practice.
`
`
`XALATAN was studied in three multicenter, randomized, controlled clinical trials. Patients received 50
`mcg/mL XALATAN once daily or 5 mg/mL active-comparator (timolol) twice daily. The patient population
`studied had a mean age of 65±10 years. Seven percent of patients withdrew before the 6-month endpoint.
`
`Table 1: Ocular Adverse Reactions and Ocular Signs/Symptoms Reported by 5-15% of Patients
`
`Receiving Latanoprost
`
`Symptom/Finding
`Foreign body sensation
`Punctate keratitis
`Stinging
`Conjunctival hyperemia
`Blurred vision
`
` Itching
`Burning
`Increased pigmentation of the Iris
`
`Adverse Reactions (incidence (%))
`Latanoprost
`Timolol
`(n=460)
`(n=369)
`13
`8
`10
`9
`9
`12
`8
`3
`8
`8
`8
`8
`7
`8
`7
`0
`
`Less than 1% of the patients treated with XALATAN required discontinuation of therapy because of
`intolerance to conjunctival hyperemia.
`
`Table 2: Adverse Reactions That Were Reported in 1-5% of Patients Receiving Latanoprost
`Adverse Reactions (incidence (%))
`Latanoprost
`Timolol
`(n=460)
`(n=369)
`
` Ocular Events/Signs and Symptoms
`
`Excessive tearing
`Eyelid discomfort/pain
`Dry eye
`Eye pain
`Eyelid margin crusting
`Erythema of the eyelid
`Photophobia
`Eyelid edema
`Systemic Events
`Upper respiratory tract
`
`Reference ID: 4081740
`
`4
`4
`3
`3
`3
`3
`2
`1
`
`3
`
`6
`2
`3
`3
`3
`2
`1
`3
`
`3
`
`IPR Page 4/9
`
`

`

`infection/nasopharyngitis/influenza
`Myalgia/arthralgia/back pain
`Rash/allergic skin reaction
`
`1
`1
`
`0.5
`0.3
`
`The ocular event/signs and symptoms of blepharitis have been identified as “commonly observed” through
`analysis of clinical trial data.
`
`6.2 Postmarketing Experience
`
`The following reactions have been identified during postmarketing use of XALATAN in clinical practice.
`Because they are reported voluntarily from a population of unknown size, it is not always possible to
`reliably estimate their frequency or establish a causal relationship to drug exposure. The reactions, which
`have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal
`connection to XALATAN, or a combination of these factors, include:
`
`Nervous System disorders: Dizziness; headache; toxic epidermal necrolysis
`
`Eye Disorders: Eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation, and
`number of eyelashes); keratitis; corneal edema and erosions; intraocular inflammation (iritis/uveitis);
`macular edema, including cystoid macular edema; trichiasis; periorbital and lid changes resulting in
`deepening of the eyelid sulcus; iris cyst; eyelid skin darkening; localised skin reaction on the eyelids;
`conjunctivitis; pseudopemphigoid of the ocular conjunctiva
`
`Respiratory, Thoracic and Mediastinal Disorders: Asthma and exacerbation of asthma; dyspnea
`
`Skin and Subcutaneous Tissue Disorders: Pruritus
`
`
`Infections and Infestations: Herpes keratitis
`
`Cardiac Disorders: Angina; palpitations; angina unstable
`
`General Disorders and Administration Site Conditions: Chest pain
`
`7 DRUG INTERACTIONS
`
`In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with
`
`XALATAN. If such drugs are used, they should be administered at least five (5) minutes apart.
`
`The combined use of two or more prostaglandins, or prostaglandin analogs including XALATAN is not
`recommended. It has been shown that administration of these prostaglandin drug products more than once
`daily may decrease the IOP lowering effect or cause paradoxical elevations in IOP.
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Teratogenic Effects: Pregnancy Category C.
`
`Reference ID: 4081740
`
`IPR Page 5/9
`
`

`

`
`
` Reproduction studies have been performed in rats and rabbits. In rabbits, an incidence of 4 of 16 dams had
`
` no viable fetuses at a dose that was approximately 80 times the maximum human dose, 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. XALATAN should be used during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
`
`8.3 Nursing Mothers
`
`It is not known whether this drug or its metabolites are excreted in human milk. Because many drugs are
`excreted in human milk, caution should be exercised when XALATAN 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 younger patients.
`
`10 OVERDOSAGE
`
`Intravenous infusion of up to 3 mcg/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 mcg/kg caused abdominal pain, dizziness, fatigue, hot flushes, nausea, and sweating.
`
`
`If overdosage with XALATAN occurs, treatment should be symptomatic.
`
`
`11 DESCRIPTION
`
`Latanoprost is a prostaglandin F2α analogue. Its chemical name is isopropyl-(Z)-7[(1R,2R,3R,5S)3,5­
`
`dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate. Its molecular formula is C26H40O5
`and its chemical structure is:
`
`Latanoprost is a colorless to slightly yellow oil that is very soluble in acetonitrile and freely soluble in
`acetone, ethanol, ethyl acetate, isopropanol, methanol, and octanol. It is practically insoluble in water.
`
`XALATAN (latanoprost ophthalmic solution) 0.005% is supplied as a sterile, isotonic, buffered aqueous
`
`solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg.
`Each mL of XALATAN contains 50 mcg of latanoprost. Benzalkonium chloride, 0.02% is added as a
`preservative. The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate,
`
`Reference ID: 4081740
`
`IPR Page 6/9
`
`

`

`disodium hydrogen phosphate anhydrous, and water for injection. One drop contains approximately 1.5 mcg
`of latanoprost.
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`Latanoprost is a prostanoid selective FP receptor agonist that is believed to reduce the intraocular pressure
`(IOP) by increasing the outflow of aqueous humor. Studies in animals and man suggest that the main
`mechanism of action is increased uveoscleral outflow. Elevated IOP represents a major risk factor for
`glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and
`visual field loss.
`
`12.2 Pharmacodynamics
`
`Reduction of the IOP in man starts about 3-4 hours after administration and maximum effect is reached after
`8-12 hours. IOP reduction is present for at least 24 hours.
`
`12.3 Pharmacokinetics
`
`Absorption
`
`Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form
`to become biologically active.
`
`Distribution
`
`The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can be measured in aqueous
`humor during the first 4 hours, and in plasma only during the first hour after local administration. Studies in
`man indicate that the peak concentration in the aqueous humor is reached about two hours after topical
`administration.
`
`Metabolism
`
`
`Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the biologically active
`acid. The active acid of latanoprost reaching the systemic circulation is primarily metabolized by the liver to
`the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid β-oxidation.
`
`Excretion
`
`
`
` The elimination of the acid of latanoprost from human plasma is rapid (t1/2 = 17 min) after both intravenous
`and topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepatic β-
`oxidation, the metabolites are mainly eliminated via the kidneys. Approximately 88% and 98% of the
`administered dose are recovered in the urine after topical and intravenous dosing, respectively.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Reference ID: 4081740
`
`IPR Page 7/9
`
`

`

`Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to
`170 mcg/kg/day (approximately 2800 times the recommended maximum human dose) for up to 20 and 24
`months, respectively.
`
`Latanoprost was not mutagenic in bacteria, in mouse lymphoma, or in mouse micronucleus tests.
`Chromosome aberrations were observed in vitro with human lymphocytes. 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.
`
`14 CLINICAL STUDIES
`
`14.1 Elevated Baseline IOP
`
`Patients with mean baseline IOP of 24 – 25 mmHg who were treated for 6 months in multi-center,
`randomized, controlled trials demonstrated 6 – 8 mmHg reductions in IOP. This IOP reduction with
`
`XALATAN 0.005% dosed once daily was equivalent to the effect of timolol 0.5% dosed twice daily.
`
`14.2 Progression of Increased Iris Pigmentation
`
`A 3-year open-label, prospective safety study with a 2-year extension phase was conducted to evaluate the
`
`progression of increased iris pigmentation with continuous use of XALATAN once-daily as adjunctive
`
`therapy in 519 patients with open-angle glaucoma. The analysis was based on observed-cases population of
`the 380 patients who continued in the extension phase.
`
`Results showed that the onset of noticeable increased iris pigmentation occurred within the first year of
`treatment for the majority of the patients who developed noticeable increased iris pigmentation. Patients
`continued to show signs of increasing iris pigmentation throughout the five years of the study. Observation
`of increased iris pigmentation did not affect the incidence, nature, or severity of adverse events (other than
`increased iris pigmentation) recorded in the study. IOP reduction was similar regardless of the development
`of increased iris pigmentation during the study.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`XALATAN is a clear, isotonic, buffered, preserved colorless solution of latanoprost 0.005% (50 mcg/mL).
`
`It is supplied as a 2.5 mL solution in a 5 mL clear low density polyethylene bottle with a clear polyethylene
`dropper tip, a turquoise high density polyethylene screw cap, and a tamper-evident clear low density
`polyethylene overcap.
`
`2.5 mL fill, 0.005% (50 mcg/mL): Package of 1 bottle: NDC 0013-8303-04
`2.5 mL fill, 0.005% (50 mcg/mL): Multi-pack of 3 bottles: NDC 0013-8303-01
`
`Storage: Protect from light. Store unopened bottle(s) under refrigeration at 2° to 8°C (36° to 46°F). During
`
`shipment to the patient, the bottle may be maintained at temperatures up to 40°C (104°F) for a period not
`exceeding 8 days. Once a bottle is opened for use, it may be stored at room temperature up to 25°C (77°F)
`for 6 weeks.
`
`17 PATIENT COUNSELING INFORMATION
`
`Reference ID: 4081740
`
`IPR Page 8/9
`
`

`

`Potential for Pigmentation
`
`Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent.
`Inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation
`of XALATAN [see Warnings and Precautions (5.1)].
`
`
`Potential for Eyelash Changes
`
`Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with
`
` XALATAN. These changes may result in a disparity between eyes in length, thickness, pigmentation,
`number of eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually
`reversible upon discontinuation of treatment.
`
`Handling the Container
`
`Instruct patients to avoid allowing the tip of the dispensing container to contact the eye or surrounding
`structures because this could cause the tip to become contaminated by common bacteria known to cause
`ocular infections. Serious damage to the eye and subsequent loss of vision may result from using
`contaminated solutions [see Warnings and Precautions (5.6)].
`
`When to Seek Physician Advice
`
`Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection) or have
`ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should
`immediately seek their physician’s advice concerning the continued use of the multiple-dose container.
`
`Use with Contact Lenses
`
`Advise patients that XALATAN contains benzalkonium chloride, which may be absorbed by contact lenses.
`Contact lenses should be removed prior to administration of the solution. Lenses may be reinserted 15
`
`minutes following administration of XALATAN.
`
`Use with Other Ophthalmic Drugs
`
`
`If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5)
`
`minutes apart.
`
`Pfizer Manufacturing Belgium NV
`Puurs, Belgium
`
`LAB-0135-11.2
`
`Reference ID: 4081740
`
`IPR Page 9/9
`
`