DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with latanoprost. 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 latanoprost 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.. In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with Latanoprost. If such drugs are used, they should be administered at least minutes apart. 7).

DOSAGE & ADMINISTRATION SECTION.

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 latanoprost ophthalmic solution should not exceed once daily; the combined use of two or more prostaglandins, or prostaglandin analogs including latanoprost 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 to hours after administration and the maximum effect is reached after to 12 hours.Latanoprost ophthalmic solution 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 latanoprost ophthalmic solution, and may be reinserted 15 minutes after administration.. One drop in the affected eye(s) once daily in the evening. 2).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Elevated Baseline IOP. Patients with mean baseline IOP of 24-25 mmHg who were treated for months in multi-center, randomized, controlled trials demonstrated 6-8 mmHg reductions in IOP. This IOP reduction with latanoprost 0.005% dosed once daily was equivalent to the effect of timolol 0.5% dosed twice daily.. 14.2 Progression of Increased Iris Pigmentation. 3-year open-label, prospective safety study with 2-year extension phase was conducted to evaluate the progression of increased iris pigmentation with continuous use of latanoprost 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.

DESCRIPTION SECTION.

11 DESCRIPTION. Latanoprost is prostaglandin 2 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 26H 40O and its chemical structure is: Latanoprost is 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. Latanoprost ophthalmic solution 0.005% is supplied as sterile, isotonic, buffered aqueous solution of latanoprost with pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg. Each mL of Latanoprost ophthalmic solution contains 50 micrograms of latanoprost. Benzalkonium chloride, 0.02% is added as preservative. The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, and water for injection. One drop contains approximately 1.5 mcg of latanoprost.. Latanoprost chemical structure.

ADVERSE REACTIONS SECTION.

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) 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) . Iris pigmentation changes see Warnings and Precautions (5.1) . 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) . 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 epithelial keratopathy, and upper respiratory tract infection/cold/flu. 6). To report SUSPECTED ADVERSE REACTIONS, contact Bausch Lomb, division of Valeant Pharmaceuticals North America LLC at 1-800-321-4576 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, the adverse reaction rates observed in the clinical studies of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Latanoprost was studied in three multicenter, randomized, controlled clinical trials. Patients received 50 mcg/mL latanoprost once daily or mg/mL active-comparator (timolol) twice daily. The patient population studied had 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 LatanoprostSymptom/FindingAdverse Reactions (incidence (%))Latanoprost(n=460)Timolol(n=369)Foreign body sensation138Punctate epithelial keratopathy109Stinging912Conjunctival hyperemia83Blurred vision88Itching88Burning78Increased pigmentation of the iris70Less than 1% of the patients treated with latanoprost required discontinuation of therapy because of intolerance to conjunctival hyperemia.Table 2: Adverse Reactions that were reported in 1-5% of patients receiving LatanoprostAdverse Reactions (incidence (%))Latanoprost(n=460)Timolol(n=369)Ocular Events/Signs and Symptoms Excessive tearing46 Lid discomfort/pain42 Dry eye33 Eye pain33 Lid crusting33 Lid erythema32 Photophobia21 Lid edema13Systemic Events Upper respiratory tract infection/cold/flu33 Muscle/joint/back pain10.5 Rash/allergic skin reaction10.3. 6.2 Postmarketing Experience. The following reactions have been identified during postmarketing use of latanoprost in clinical practice. Because they are reported voluntarily from population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to latanoprost, or combination of these factors, include:Nervous System disorders: dizziness, headache, and toxic epidermal necrolysis Eye Disorders: eyelash and vellus hair changes (increased length, thickness, pigmentation, and number); keratitis; corneal edema and erosions; intraocular inflammation (iritis/uveitis); macular edema, including cystoid macular edema; misdirected eyelashes sometimes resulting in eye irritation; periorbital and lid changes resulting in deepening of the eyelid sulcus. Respiratory, Thoracic and Mediastinal Disorders: asthma and exacerbation of asthma; dyspnea Skin and Subcutaneous Tissue Disorders: eyelid skin darkening Infections and Infestations: Herpes keratitis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Latanoprost is 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 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. AbsorptionLatanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active.DistributionThe distribution volume in humans is 0.16 0.02 L/kg. The acid of latanoprost can be measured in aqueous humor during the first 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. MetabolismLatanoprost, 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 -oxidation.ExcretionThe elimination of the acid of latanoprost from human plasma is rapid (t 1/2 17 min) after both intravenous and topical administration. Systemic clearance is approximately mL/min/kg. Following hepatic -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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Latanoprost ophthalmic solution is clear, isotonic, buffered, preserved colorless solution of latanoprost 0.005% (50 mcg/mL). It is supplied as 2.5 mL solution in 4 mL clear low density polyethylene bottle with low density polyethylene dropper tip, and turquoise high density polypropylene screw cap, and clear PVC film with single perforation.2.5 mL fill, 0.005% (50 mcg/mL): Package of bottle:NDC 68071-4612-2Storage: Protect from light. Store unopened bottle(s) under refrigeration at to 8C (36 to 46F). During shipment to the patient, the bottle may be maintained at temperatures up to 40C (104F) for period not exceeding days. Once bottle is opened for use, it may be stored at room temperature up to 25C (77F) for weeks.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.1 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 Latanoprost ophthalmic solution see Warnings and Precautions (5.1) ]. 17.2 Potential for Eyelash Changes. Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with Latanoprost ophthalmic solution. These changes may result in 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.. 17.3 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) ]. 17.4 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 physicians advice concerning the continued use of the multiple-dose container.. 17.5 Use with Contact Lenses. Advise patients that Latanoprost ophthalmic solution 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 Latanoprost ophthalmic solution.. 17.6 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.Bausch Lomb, division ofValeant Pharmaceuticals North America LLCBridgewater, NJ 08807 USA(C)Bausch Lomb IncorporatedRevised: June 20169144707 (flat)9144807 (folded).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionLatanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active.DistributionThe distribution volume in humans is 0.16 0.02 L/kg. The acid of latanoprost can be measured in aqueous humor during the first 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. MetabolismLatanoprost, 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 -oxidation.ExcretionThe elimination of the acid of latanoprost from human plasma is rapid (t 1/2 17 min) after both intravenous and topical administration. Systemic clearance is approximately mL/min/kg. Following hepatic -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.

SPL UNCLASSIFIED SECTION.

5.1 Pigmentation. Latanoprost 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 years the effects of increased pigmentation are not known see Clinical Studies (14.2 )]. 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 latanoprost can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly see Patient Counseling Information (17.1) ].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Teratogenic Effects: Pregnancy Category C.Reproduction studies have been performed in rats and rabbits. In rabbits, an incidence of of 16 dams had no viable fetuses at 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. Latanoprost 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 latanoprost is administered to 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.

WARNINGS AND PRECAUTIONS SECTION.

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) 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. Latanoprost 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 years the effects of increased pigmentation are not known see Clinical Studies (14.2 )]. 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 latanoprost 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. Latanoprost 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. Latanoprost should be used with caution in patients with 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. Latanoprost ophthalmic solution should be used with caution in aphakic patients, in pseudophakic patients with 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 ophthalmic solution. Latanoprost should be used with caution in patients with history of herpetic keratitis. Latanoprost 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 concurrent corneal disease or 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 latanoprost ophthalmic solution, and may be reinserted 15 minutes after administration.