Latanoprostene Bunod Ophthalmic Solution, 0.024%

1 INDICATIONS AND USAGE Latanoprostene bunod ophthalmic solution, 0.024% is indicated for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Latanoprostene bunod ophthalmic solution is a prostaglandin analog indicated for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

2 DOSAGE AND ADMINISTRATION The recommended dosage is one drop in the conjunctival sac of the affected eye(s) once daily in the evening. Do not administer latanoprostene bunod ophthalmic solution, 0.024% more than once daily since it has been shown that more frequent administration of prostaglandin analogs may lessen the intraocular pressure lowering effect. If latanoprostene bunod ophthalmic solution is to be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure, administer each drug product at least five (5) minutes apart. One drop in the affected eye(s) once daily in the evening.

3 DOSAGE FORMS AND STRENGTHS Latanoprostene bunod ophthalmic solution is a topical ophthalmic solution containing latanoprostene bunod, 0.24 mg/mL. Topical ophthalmic solution: 0.24 mg/mL latanoprostene bunod (0.024%)

4 CONTRAINDICATIONS None. None.

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: • Pigmentation [ see Warnings and Precautions (5.1) ] • Eyelash Changes [ see Warnings and Precautions (5.2) ] • Intraocular Inflammation [ see Warnings and Precautions (5.3) ] • Macular Edema [ see Warnings and Precautions (5.4) ] • Bacterial Keratitis [ see Warnings and Precautions (5.5) ] • Use with Contact Lens [ see Warnings and Precautions (5.6 )] Most common ocular adverse reactions with incidence ≥ 2% are conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), and instillation site pain (2%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gland Pharma at (609) 250-7990 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 trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Latanoprostene bunod ophthalmic solution was evaluated in 811 patients in 2 controlled clinical trials of up to 12 months duration. The most common ocular adverse reactions observed in patients treated with latanoprostene bunod were: conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), and instillation site pain (2%). Approximately 0.6% of patients discontinued therapy due to ocular adverse reactions including ocular hyperemia, conjunctival irritation, eye irritation, eye pain, conjunctival edema, vision blurred, punctate keratitis and foreign body sensation.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available human data for the use of Latanoprostene bunod ophthalmic solution during pregnancy to inform any drug associated risks. Latanoprostene bunod has caused miscarriages, abortion, and fetal harm in rabbits. Latanoprostene bunod was shown to be abortifacient and teratogenic when administered intravenously (IV) to pregnant rabbits at exposures ≥ 0.28 times the clinical dose. Doses ≥ 20 mcg/kg/day (23 times the clinical dose) produced 100% embryofetal lethality. Structural abnormalities observed in rabbit fetuses included anomalies of the great vessels and aortic arch vessels, domed head, sternebral and vertebral skeletal anomalies, limb hyperextension and malrotation, abdominal distension and edema. Latanoprostene bunod was not teratogenic in the rat when administered IV at 150 mcg/kg/day (87 times the clinical dose) [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 latanoprostene bunod daily by intravenous injection on gestation days 7 through 19, to target the period of organogenesis. The doses administered ranged from 0.24 to 80 mcg/kg/day. Abortion occurred at doses ≥ 0.24 mcg/kg/day latanoprostene bunod (0.28 times the clinical dose, on a body surface area basis, assuming 100% absorption). Embryofetal lethality (resorption) was increased in latanoprostene bunod treatment groups, as evidenced by increases in early resorptions at doses ≥ 0.24 mcg/kg/day and late resorptions at doses ≥ 6 mcg/kg/day (approximately 7 times the clinical dose). No fetuses survived in any rabbit pregnancy at doses of 20 mcg/kg/day (23 times the clinical dose) or greater. Latanoprostene bunod produced structural abnormalities at doses ≥ 0.24 mcg/kg/day (0.28 times the clinical dose). Malformations included anomalies of sternum, coarctation of the aorta with pulmonary trunk dilation, retroesophageal subclavian artery with absent brachiocephalic artery, domed head, forepaw hyperextension and hindlimb malrotation, abdominal distention/edema, and missing/fused caudal vertebrae. An embryofetal study was conducted in pregnant rats administered latanoprostene bunod daily by intravenous injection on gestation days 7 through 17, to target the period of organogenesis. The doses administered ranged from 150 to 1500 mcg/kg/day. Maternal toxicity was produced at 1500 mcg/kg/day (870 times the clinical dose, on a body surface area basis, assuming 100% absorption), as evidenced by reduced maternal weight gain. Embryofetal lethality (resorption and fetal death) and structural anomalies were produced at doses ≥ 300 mcg/kg/day (174 times the clinical dose). Malformations included anomalies of the sternum, domed head, forepaw hyperextension and hindlimb malrotation, vertebral anomalies and delayed ossification of distal limb bones. A no observed adverse effect level (NOAEL) was established at 150 mcg/kg/day (87 times the clinical dose) in this study. 8.2 Lactation Risk Summary There are no data on the presence of latanoprostene bunod in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for latanoprostene bunod ophthalmic solution and any potential adverse effects on the breastfed infant from latanoprostene bunod ophthalmic solution. 8.4 Pediatric Use Use in pediatric patients aged 16 years and younger is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use. 8.5 Geriatric Use No overall clinical differences in safety or effectiveness have been observed between elderly and ot …

12.1 Mechanism of Action Latanoprostene bunod is thought to lower intraocular pressure by increasing outflow of aqueous humor through both the trabecular meshwork and uveoscleral routes. Intraocular pressure is a major modifiable risk factor for glaucoma progression. Reduction of intraocular pressure reduces risk of glaucomatous visual field loss.

11 DESCRIPTION Latanoprostene bunod ophthalmic solution, 0.024% is a prostaglandin analog formulated as a sterile topical ophthalmic solution. Latanoprostene bunod ophthalmic solution contains the active ingredient latanoprostene bunod 0.24 mg/mL, the preservative benzalkonium chloride 0.2 mg/mL, and the following inactive ingredients: polysorbate 80, glycerin, EDTA, and water. The formulation is buffered to pH 5.5 with citric acid/sodium citrate. Its chemical name is 4-(Nitrooxy)butyl (5Z)-7-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl}hept-5-enoate. Its molecular formula is C 27 H 41 NO 8 . Molecular weight: 507.62. Its chemical structure is Latanoprostene bunod is a colorless to pale yellow viscous oil. latanoprostene-bunod-spl-structure

16 HOW SUPPLIED/STORAGE AND HANDLING Latanoprostene bunod ophthalmic solution, 0.024% is supplied in low density polyethylene bottles with dropper tips and turquoise caps in the following sizes: 2.5 mL fill in a 4 mL white container - NDC 68083-563-01 5 mL fill in a 7 mL Natural container - NDC 68083-564-01 Storage: Unopened bottle should be stored refrigerated at 2o to 8oC (36o to 46oF). Once a bottle is opened it may be stored at 2o to 25oC (36o to 77oF) for 8 weeks. During shipment, bottles may be maintained at temperatures up to 40°C (104°F) for a period not exceeding 14 days. Protect from light. Protect from freezing.