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:oIris pigmentation changes [see Warnings and Precautions (5.1)]oEyelid skin darkening [see Warnings and Precautions (5.1)]oEyelash changes (increased length, thickness, pigmentation, and number of lashes) [see Warnings and Precautions (5.2)]oIntraocular inflammation (iritis/uveitis) [see Warnings and Precautions (5.3)]oMacular edema, including cystoid macular edema [see Warnings and Precautions (5.4)]. oIris pigmentation changes [see Warnings and Precautions (5.1)]. oEyelid skin darkening [see Warnings and Precautions (5.1)]. oEyelash changes (increased length, thickness, pigmentation, and number of lashes) [see Warnings and Precautions (5.2)]. oIntraocular inflammation (iritis/uveitis) [see Warnings and Precautions (5.3)]. oMacular edema, including cystoid macular edema [see Warnings and Precautions (5.4)]. Most common adverse reactions (5-15%) from clinical trials are blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the iris, and punctate keratitis. (6)To report SUSPECTED ADVERSE REACTIONS, contact Bausch Lomb Incorporated 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 Ophthalmic Solution was studied in three multicenter, randomized, controlled clinical trials. Patients received 50 mcg/mL Latanoprost Ophthalmic Solution 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 keratitis109Stinging912Conjunctival hyperemia83Blurred vision88Itching88Burning78Increased pigmentation of the iris70Less than 1% of the patients treated with Latanoprost Ophthalmic Solution 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(n=460)Timolol(n=369)Ocular Events/Signs and SymptomsExcessive tearing46Eyelid discomfort/pain42Dry eye33Eye pain33Eyelid margin crusting33Erythema of the eyelid32Photophobia21Eyelid edema13Blepharitis13Systemic EventsUpper respiratory tract infection/nasopharyngitis/influenza33Myalgia/arthralgia/back pain10.5Rash/allergic skin reaction10.3. 6.2 Postmarketing Experience The following reactions have been identified during postmarketing use of Latanoprost Ophthalmic Solution in clinical practice. Because they are reported voluntarily from population of unknown size, it is not always possible to reliably estimate their frequency or establish 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 Solution, or combination of these factors, include:Nervous System Disorders: Dizziness; headache; toxic epidermal necrolysisEye 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; localized 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 keratitisCardiac Disorders: Angina; palpitations; angina unstableGeneral Disorders and Administration Site Conditions: Chest pain.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisLatanoprost 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.MutagenesisLatanoprost 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.Impairment of FertilityLatanoprost has not been found to have any effect on male or female fertility in rat studies at IV doses up to 250 mcg/kg/day (811 times the maximum RHOD, on mg/m2 basis, assuming 100% absorption).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Latanoprost is prostaglandin F2 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 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.EliminationMetabolismLatanoprost, 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 (t1/2 17 min) after both IV 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 IV dosing, respectively.

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 - mmHg reductions in IOP. This IOP reduction with Latanoprost Ophthalmic Solution 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 2-year extension phase was conducted to evaluate the progression of increased iris pigmentation with continuous use of Latanoprost Ophthalmic Solution 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 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 F2 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 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 mcg 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.

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 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. In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are mixed with latanoprost. 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Potential for PigmentationAdvise 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)].Potential for Eyelash ChangesInform 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.Handling the ContainerInstruct 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 AdviceAdvise 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.Contact Lens UseAdvise 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.Use with Other Ophthalmic DrugsAdvise patients that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart.If Dose is MissedAdvise patients that if one dose is missed, treatment should continue with the next dose as normal.Distributed by:Bausch Lomb, division ofBausch Health US, LLCBridgewater, NJ 08807 USA(C) 2021 Bausch Lomb Incorporated or its affiliates 9144711 (folded)9144811 (flat).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisLatanoprost 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.MutagenesisLatanoprost 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.Impairment of FertilityLatanoprost has not been found to have any effect on male or female fertility in rat studies at IV doses up to 250 mcg/kg/day (811 times the maximum RHOD, on mg/m2 basis, assuming 100% absorption).

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.EliminationMetabolismLatanoprost, 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 (t1/2 17 min) after both IV 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 IV dosing, respectively.

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryThere are no adequate and well-controlled studies of Latanoprost Ophthalmic Solution administration 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 to 4%, and of miscarriage is 15 to 20% of clinically recognized pregnancies.DataAnimal DataEmbryofetal studies were conducted in pregnant rabbits administered latanoprost daily by IV injection on gestation Days through 18, to target the period of organogenesis. no observed adverse effect level (NOAEL) was not established for rabbit developmental toxicity. Post-implantation loss due to late resorption was shown at doses >=0.2 mcg/kg/day (equivalent to 1.3 times the maximum recommended human ophthalmic dose [RHOD], on mg/m2 basis, assuming 100% absorption). Spina bifida and abortion occurred at 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 (1,946 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 through 15, to target the period of organogenesis. NOAEL for rat developmental toxicity was not established. Cleft palate was observed at mcg/kg (equivalent to 3.2 times the maximum RHOD, on mg/m2 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 mg/m2 basis, assuming 100% absorption). At 100 mcg/kg/day (324 times the maximum RHOD), maternal deaths and pup mortality occurred.

SPL UNCLASSIFIED SECTION.

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 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk SummaryThere are no adequate and well-controlled studies of Latanoprost Ophthalmic Solution administration 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 to 4%, and of miscarriage is 15 to 20% of clinically recognized pregnancies.DataAnimal DataEmbryofetal studies were conducted in pregnant rabbits administered latanoprost daily by IV injection on gestation Days through 18, to target the period of organogenesis. no observed adverse effect level (NOAEL) was not established for rabbit developmental toxicity. Post-implantation loss due to late resorption was shown at doses >=0.2 mcg/kg/day (equivalent to 1.3 times the maximum recommended human ophthalmic dose [RHOD], on mg/m2 basis, assuming 100% absorption). Spina bifida and abortion occurred at 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 (1,946 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 through 15, to target the period of organogenesis. NOAEL for rat developmental toxicity was not established. Cleft palate was observed at mcg/kg (equivalent to 3.2 times the maximum RHOD, on mg/m2 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 mg/m2 basis, assuming 100% absorption). At 100 mcg/kg/day (324 times the maximum RHOD), maternal deaths and pup mortality occurred.. 8.2 Lactation Risk SummaryIt 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 Ophthalmic Solution is administered to nursing woman. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Latanoprost Ophthalmic Solution and any potential adverse effects on the breastfed child from Latanoprost Ophthalmic Solution.. 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 oPigmentation: Pigmentation of the iris, periorbital tissue (eyelid) and eyelashes can occur. Iris pigmentation likely to be permanent. (5.1)oEyelash Changes: Gradual change to eyelashes including increased length, thickness, and number of lashes. Usually reversible. (5.2). oPigmentation: Pigmentation of the iris, periorbital tissue (eyelid) and eyelashes can occur. Iris pigmentation likely to be permanent. (5.1). oEyelash 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 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 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 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 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 concurrent corneal disease or 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.