XELPROS

1 INDICATIONS AND USAGE XELPROS (latanoprost ophthalmic emulsion) 0.005% is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. XELPROS is a prostaglandin F 2α analog indicated for reduction of elevated intraocular pressure in patients with open-angle glaucoma, or ocular hypertension. ( 1 )

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 XELPROS should not exceed once daily; the combined use of two or more prostaglandins, or prostaglandin analogs including XELPROS 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 intraocular pressure starts approximately 3 to 4 hours after administration and the maximum effect is reached after 8 to 12 hours. XELPROS may be 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. Contact lenses should be removed prior to the administration of XELPROS, and may be reinserted 15 minutes after administration. One drop in the affected eye(s) once daily in the evening. ( 2 )

4 CONTRAINDICATIONS Known hypersensitivity to latanoprost, or any other ingredients in this product. Known hypersensitivity to latanoprost or any other ingredients in this product. ( 4 )

5 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 ) 5.1 Pigmentation Topical latanoprost ophthalmic products, including XELPROS, have 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. The long-term effects of increased pigmentation are not known. 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 XELPROS can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly . 5.2 Eyelash Changes Latanoprost ophthalmic products, including XELPROS, 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. 5.3 Intraocular Inflammation XELPROS 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 latanoprost ophthalmic products, including XELPROS. XELPROS 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 latanoprost. XELPROS should be used with caution in patients with a history of herpetic keratitis. XELPROS 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 . 5.7 Contact Lens Use Contact lenses should be removed prior to the administration of XELPROS and may be reinserted 15 minutes after administration .

7 DRUG INTERACTIONS In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with XELPROS. 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 XELPROS 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. Thimerosal: Precipitation may occur if drugs containing thimerosal are used concomitantly with XELPROS. If such drugs are used, they should be administered at least five (5) minutes apart. ( 7 )

6 ADVERSE REACTIONS Most common ocular adverse reactions (incidence ≥5%) for XELPROS are: eye pain/stinging, ocular hyperemia, conjunctival hyperemia, eye discharge, growth of eyelashes, and eyelash thickening. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials 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 clinical practice. Across multiple clinical trials conducted with XELPROS (latanoprost ophthalmic emulsion) 0.005%, the most frequently reported ocular adverse reactions were eye pain/stinging upon instillation and ocular hyperemia, reported in 55% and 41% of XELPROS treated patients, respectively (Table 1). Less than 1% of patients discontinued therapy because of intolerance to the eye pain/stinging or to the ocular hyperemia. Table 1. Ocular Adverse Reactions Reported by ≥ 1% of Subjects Receiving XELPROS System Organ Class/ Preferred Term XELPROS (N = 448) Eye disorders 325 (73%) Eye pain / stinging 246 (55%) Ocular hyperemia 185 (41%) Conjunctival hyperemia 65 (15%) Eye discharge 53 (12%) Growth of eyelashes 47 (11%) Eyelash thickening 35 (8%) Ocular Itching 20 (5%) Visual acuity reduced 16 (4%) Dry eye 13 (3%) Erythema of eyelid 14 (3%) Foreign body sensation in eyes 9 (2%) Eyelid edema 7 (2%) Punctate keratitis 6 (1%) Eyelash discoloration 5 (1%) Conjunctival edema 5 (1%) 6.2 Postmarketing Experience The following reactions have been identified during postmarketing use of topical latanoprost products 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 latanoprost ophthalmic emulsion or a combination of these factors, include: Nervous System Disorders : Dizziness, headache, toxic epidermal necrolysis Eye Disorders : 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; localized skin reaction on the eyelids; conjunctivitis; pseudopemphigoid of the ocular conjunctiva Respiratory, Thoracic and Mediastinal Disorders : Asthma and exacerbation of asthma; dyspnea Gastrointestinal Disorders: Nausea; vomiting 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

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of XELPROS ophthalmic emulsion in pregnant women to inform drug-associated risks. In animal reproduction studies, intravenous (IV) administration of latanoprost to pregnant rabbits and rats throughout the period of organogenesis produced malformations, embryofetal lethality and spontaneous abortion at clinically relevant doses [see Data ] . The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20% of clinically recognized pregnancies. Data Animal Data Embryofetal studies were conducted in pregnant rabbits administered latanoprost daily by IV injection on gestation days 6 through 18, to target the period of organogenesis. A no observed adverse effect level (NOAEL) was not established for rabbit developmental toxicity. Post-implantation loss due to late resorption was shown as doses ≥ 0.2 mcg/kg/day (equivalent to 1.3 times the maximum recommended human ophthalmic dose [RHOD], on a mg/m 2 basis, assuming 100% absorption). Spina bifida and abortion occurred at 5 mcg/kg/day (equivalent to 32 times the maximum RHOD). Total litter loss due to early resorption was observed at doses ≥ 50 mcg/kg/day (324 times the maximum RHOD). Transient signs of maternal toxicity were observed after IV dosing (increased breathing, muscle tremors, slight motor incoordination) at 300 mcg/kg/day (1946 times the maximum RHOD). No maternal toxicity was observed at doses up to 50 mcg/kg/day. Embryofetal studies were conducted in pregnant rats administered latanoprost daily by IV injection on gestation days 6 through 15, to target the period of organogenesis. A NOAEL for rat developmental toxicity was not established. Cleft palate was observed at 1 mcg/kg (equivalent to 3.2 times the maximum RHOD, on a mg/m 2 basis, assuming 100% absorption). Brain porencephalic cyst(s) were observed ≥50 mcg/kg (162 times the maximum RHOD). Skeletal anomalies were observed at 250 mcg/kg (811 times the maximum RHOD). No maternal toxicity was detectable at 250 mcg/kg/day. Prenatal and postnatal development was assessed in rats. Pregnant rats were administered latanoprost daily by IV injection from gestation day 15, through delivery, until weaning (lactation Day 21). No adverse effects on rat offspring were observed at doses up to 10 mcg/kg/day (32 times the maximum RHOD, on a mg/m 2 basis, assuming 100% absorption). At 100 mcg/kg/day (324 times the maximum RHOD), maternal deaths and pup mortality occurred.