latanoprost 0.05 MG/ML Ophthalmic Suspension

INDICATIONS AND USAGE Latanoprost ophthalmic solution is indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Latanoprost ophthalmic solution is a prostaglandin F 2α analogue indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. ( 1 )

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 IYUZEH should not exceed once daily; the combined use of two or more prostaglandins, or prostaglandin analogs including IYUZEH 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. Reduction of the IOP starts approximately 3 to 4 hours after administration and the maximum effect is reached after 8 to 12 hours. IYUZEH may be used concomitantly with other topical ophthalmic drug products to lower IOP. In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with the preserved 0.005% latanoprost reference product. 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 IYUZEH and may be reinserted 15 minutes after administration. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded immediately after administration. One drop in the affected eye(s) once daily in the evening. ( 2 )

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 Latanoprost ophthalmic solution 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 )] . 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 ophthalmic solution can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. 5.2 Eyelash Changes Latanoprost ophthalmic solution 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 Latanoprost ophthalmic solution 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 solution. Latanoprost ophthalmic solution 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 ophthalmic solution. Latanoprost ophthalmic solution should be used with caution in patients with a history of herpetic keratitis. Latanoprost ophthalmic solution 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 Latanoprost ophthalmic solution contains benzalkonium chloride, which may be absorbed by contact lenses. Contact lenses should be removed prior to the administration of latanoprost ophthalmic solution, and may be reinserted 15 minutes after administration.

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

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Latanoprost is a prostaglandin F2α analogue that is believed to reduce the 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. Elimination 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 IV 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 IV dosing, respectively.