Tafluprost

1 INDICATIONS AND USAGE Tafluprost ophthalmic solution, 0.0015% is indicated for reducing elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Tafluprost ophthalmic solution, 0.0015% is a prostaglandin analog indicated for reducing elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. ( 1 )

2 DOSAGE AND ADMINISTRATION Apply one drop in the affected eye(s) once daily in the evening. ( 2 ) 2.1 Recommended Dosage The recommended dosage is one drop in the conjunctival sac of the affected eye(s) once daily in the evening. 2.2 Administration Instructions Tafluprost ophthalmic solution should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs may lessen the intraocular pressure (IOP) lowering effect. Reduction of the intraocular pressure starts approximately 2 to 4 hours after the first administration with the maximum effect reached after 12 hours. Tafluprost ophthalmic solution may be used concomitantly with other topical ophthalmic drug products to lower IOP. If more than one topical ophthalmic product is being used, each one should be administered at least 5 minutes apart. The solution from one single-dose container is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the single-dose container is opened, discard the open single-dose container and the remaining contents immediately after administration.

3 DOSAGE FORMS AND STRENGTHS Ophthalmic solution: 0.0015% tafluprost in a single-dose container. Ophthalmic solution: 0.0015% tafluprost in a single-dose container. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS Most common ocular adverse reaction is conjunctival hyperemia (range 4% – 20%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Because clinical studies 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 practice. Preservative-containing or preservative-free tafluprost 0.0015% was evaluated in 905 patients in five controlled clinical studies of up to 24-months duration. The most common adverse reaction observed in patients treated with tafluprost was conjunctival hyperemia which was reported in a range of 4% to 20% of patients. Approximately 1% of patients discontinued therapy due to ocular adverse reactions. Ocular adverse reactions reported at an incidence of ≥ 2% in these clinical studies included ocular stinging/irritation (7%), ocular pruritus including allergic conjunctivitis (5%), cataract (3%), dry eye (3%), ocular pain (3%), eyelash darkening (2%), growth of eyelashes (2%) and vision blurred (2%). Nonocular adverse reactions reported at an incidence of 2% to 6% in these clinical studies in patients treated with tafluprost 0.0015% were headache (6%), common cold (4%), cough (3%) and urinary tract infection (2%). 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of tafluprost. Because postapproval adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory disorders : exacerbation of asthma, dyspnea Eye disorders : iritis/uveitis In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid sulcus have been observed.

8 USE IN SPECIFIC POPULATIONS Use in pediatric patients is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use. ( 8.4 ) 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of tafluprost ophthalmic solution administration in pregnant women to inform of drug-associated risks. In animal reproduction studies, intravenous administration of tafluprost to pregnant rabbits and rats throughout organogenesis resulted in embryofetal toxicities at exposures ≥5-times the human dose in rabbit and ≥2362-times the human dose in rat. (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In embryo-fetal development studies, intravenous administration of tafluprost to pregnant rats and rabbits during organogenesis caused increases in post-implantation losses in both species and reductions in fetal body weights in rats (≥0.03 mcg/kg/day in rabbits, 5-times the maximum clinical exposure based on C max ; ≥10 mcg/kg/day in rats, 2362-times the maximum clinical exposure based on C max ). Tafluprost also increased the incidence of vertebral skeletal abnormalities in rats and the incidence of skull, brain and spine malformations in rabbits at these same doses. In rats, there were no adverse effects on embryo-fetal development at a dose of 3 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid that were 343 times the maximum clinical exposure based on C max . At the no-effect dose in rabbits (0.01 mcg/kg/day), maternal plasma levels of tafluprost acid were below the lower level of quantification (20 pg/mL). In a pre- and postnatal development study, intravenous administration of tafluprost to pregnant rats during organogenesis and through birth and lactation, caused increased mortality of newborns, decreased body weights and delayed pinna unfolding in offsprings. The no observed adverse effect level was at a tafluprost intravenous dose of 0.3 mcg/kg/day which is greater than 3 times the maximum recommended clinical dose based on body surface area comparison. 8.2 Lactation Risk Summary There are no data on the presence of tafluprost or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production following topical ocular administration. Tafluprost and/or its metabolites are present in rat milk following ocular administration. When a drug is present in animal milk, it is likely that the drug will be present in human milk. 8.4 Pediatric Use Use in pediatric patients 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 other adult patients.

12.1 Mechanism of Action Tafluprost acid, a prostaglandin analog, is a selective FP prostanoid receptor agonist which is believed to reduce intraocular pressure by increasing uveoscleral outflow. The exact mechanism of action is unknown at this time.

11 DESCRIPTION Tafluprost is a fluorinated analog of prostaglandin F2α. The chemical name for tafluprost is Propan-2-yl (5 Z )-7-{(1 R ,2 R ,3 R ,5 S )-2-[(1 E )-3,3 difluoro-4-phenoxybut-1-enyl]-3,5-dihydroxycyclopentyl}hept-5-enoate. The molecular formula of tafluprost is C 25 H 34 F 2 O 5 and its molecular weight is 452.5. Its structural formula is: Tafluprost is a colorless to yellowish hygroscopic oil that is very soluble in acetone, acetonitrile, dichloromethane, diethylether, ethanol, methanol and tert -butyl(methyl)ether and practically insoluble in n -heptane and water. Tafluprost ophthalmic solution, 0.0015% is supplied as a sterile solution of tafluprost with a pH range of 5.5 to 6.7 and an Osmolality range of 260 to 300 mOsmol/kg. Tafluprost ophthalmic solution contains Active: tafluprost 0.015 mg/mL; Inactives: glycerin, monobasic sodium phosphate dihydrate, edetate disodium dihydrate, polysorbate 80, hydrochloric acid and/or sodium hydroxide (to adjust pH) and Water for Injection. Tafluprost ophthalmic solution does not contain a preservative. Image

16 HOW SUPPLIED/STORAGE AND HANDLING Tafluprost ophthalmic solution 0.0015% is supplied as 0.3 mL a sterile solution in translucent low density polyethylene single-dose containers packaged in foil pouches (15 single-dose containers per pouch). Each single-dose container has 0.3 mL solution corresponding to 0.0045 mg tafluprost. Unit-of-Use Carton of 15 NDC 42571-264-26 Unit-of-Use Carton of 30 NDC 42571-264-73 Unit-of-Use Carton of 90 NDC 42571-264-74 Storage: Store refrigerated at 2° to 8°C (36° to 46°F). During shipment tafluprost ophthalmic solution may be maintained at temperatures up to 40°C (104°F) for a period not exceeding 2 days. Mail-order prescriptions received after two days of the dispensing date noted in the prescribing label should not be used. Store in the original pouch. After the pouch is opened, unopened single-dose containers may be stored in the opened foil pouch for up to 30 days at room temperature 20° to 25°C (68° to 77°F). Protect from moisture. Write down the date you open the foil pouch in the space provided on the pouch. Discard any unopened containers 30 days after first opening the pouch.