Tafluprost Ophthalmic

6 ADVERSE REACTIONS Most common ocular adverse reaction is conjunctival hyperemia (range 4% to 20%). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Thea Pharma Inc. at 1-833-838-4028 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.

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Tafluprost is a fluorinated analog of prostaglandin F2α. The chemical name for tafluprost is 1-methylethyl ( 5Z )-7-{( 1R , 2R , 3R , 5S )-2-[( 1E )-3,3-difluoro-4-phenoxy-1-butenyl}-3,5-dihydroxycyclopentyl]-5-heptenoate. The molecular formula of tafluprost is C 25 H 34 F 2 O 5 and its molecular weight is 452.53. Its structural formula is: Tafluprost is a colorless to light yellow viscous liquid that is practically insoluble in 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 mOsmo/kg. Tafluprost Ophthalmic Solution contains Active: tafluprost 0.015 mg/mL; Inactives: glycerol, sodium dihydrogen phosphate dihydrate, disodium edetate, polysorbate 80, hydrochloric acid and/or sodium hydroxide (to adjust pH) and Water for Injection. Tafluprost Ophthalmic Solution does not contain a preservative. Structural Formula

2 DOSAGE AND ADMINISTRATION The recommended dose is one drop of Tafluprost Ophthalmic Solution in the conjunctival sac of the affected eye(s) once daily in the evening. The dose should not exceed once daily since it has been shown that more frequent administration of prostaglandin analogs may lessen the intraocular pressure 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 intraocular pressure. If more than one topical ophthalmic product is being used, each one should be administered at least 5 minutes apart. 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 )

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 )

12 CLINICAL PHARMACOLOGY 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. 12.3 Pharmacokinetics Absorption Following instillation, tafluprost is absorbed through the cornea and is hydrolyzed to the biologically active acid metabolite, tafluprost acid. Following instillation of one drop of the 0.0015% solution once daily into each eye of healthy volunteers, the plasma concentrations of tafluprost acid peaked at a median time of 10 minutes on both Days 1 and 8. The mean plasma C max of tafluprost acid were 26 pg/mL and 27 pg/mL on Day 1, and Day 8, respectively. The mean plasma AUC estimates of tafluprost acid were 394 pg*min/mL and 432 pg*min/mL on Day 1 and 8, respectively. Metabolism Tafluprost, an ester prodrug, is hydrolyzed to its biologically active acid metabolite in the eye. The acid metabolite is further metabolized via fatty acid β-oxidation and phase II conjugation. Elimination Mean plasma tafluprost acid concentrations were below the limit of quantification of the bioanalytical assay (10 pg/mL) at 30 minutes following topical ocular administration of tafluprost 0.0015% ophthalmic solution.

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.

12.3 Pharmacokinetics Absorption Following instillation, tafluprost is absorbed through the cornea and is hydrolyzed to the biologically active acid metabolite, tafluprost acid. Following instillation of one drop of the 0.0015% solution once daily into each eye of healthy volunteers, the plasma concentrations of tafluprost acid peaked at a median time of 10 minutes on both Days 1 and 8. The mean plasma C max of tafluprost acid were 26 pg/mL and 27 pg/mL on Day 1, and Day 8, respectively. The mean plasma AUC estimates of tafluprost acid were 394 pg*min/mL and 432 pg*min/mL on Day 1 and 8, respectively. Metabolism Tafluprost, an ester prodrug, is hydrolyzed to its biologically active acid metabolite in the eye. The acid metabolite is further metabolized via fatty acid β-oxidation and phase II conjugation. Elimination Mean plasma tafluprost acid concentrations were below the limit of quantification of the bioanalytical assay (10 pg/mL) at 30 minutes following topical ocular administration of tafluprost 0.0015% ophthalmic solution.

20220601

1

3 DOSAGE FORMS AND STRENGTHS Ophthalmic solution containing tafluprost 0.015 mg/mL. Ophthalmic solution containing tafluprost 0.015 mg/mL. ( 3 )

Tafluprost Ophthalmic tafluprost Tafluprost Tafluprost Glycerin Sodium Phosphate, Monobasic, Dihydrate Edetate Disodium Polysorbate 80 Water Hydrochloric Acid Sodium Hydroxide

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Tafluprost was not carcinogenic when administered subcutaneously daily for 24 months at doses up to 30 mcg/kg/day in rats and for 18 months at doses up to 100 mcg/kg/day in mice (over 1600 and 1300 times, respectively, the maximum clinical exposure based on plasma AUC). Tafluprost was not mutagenic or clastogenic in a battery of genetic toxicology studies, including an in vitro microbial mutagenesis assay, an in vitro chromosomal aberration assay in Chinese hamster lung cells, and an in vivo mouse micronucleus assay in bone marrow. In rats, no adverse effects on mating performance or fertility were observed with intravenous dosing of tafluprost at a dose of 100 mcg/kg/day (over 14000 times the maximum clinical exposure based on plasma C max or over 3600 times based on plasma AUC).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Tafluprost was not carcinogenic when administered subcutaneously daily for 24 months at doses up to 30 mcg/kg/day in rats and for 18 months at doses up to 100 mcg/kg/day in mice (over 1600 and 1300 times, respectively, the maximum clinical exposure based on plasma AUC). Tafluprost was not mutagenic or clastogenic in a battery of genetic toxicology studies, including an in vitro microbial mutagenesis assay, an in vitro chromosomal aberration assay in Chinese hamster lung cells, and an in vivo mouse micronucleus assay in bone marrow. In rats, no adverse effects on mating performance or fertility were observed with intravenous dosing of tafluprost at a dose of 100 mcg/kg/day (over 14000 times the maximum clinical exposure based on plasma C max or over 3600 times based on plasma AUC).

NDA202514

Tafluprost Ophthalmic

tafluprost

66993-429

HUMAN PRESCRIPTION DRUG

OPHTHALMIC

Principal Display Panel Text for Container Label: Tafluprost Ophthalmic Solution 0.0015% Mfd. for: Prasco Laboratories Rx only Label

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling ( Patient Information ). 17.1 Nightly Application Advise patients to not exceed once daily dosing since more frequent administration may decrease the intraocular pressure lowering effect of Tafluprost Ophthalmic Solution. 17.2 Handling the Single-Use Container Advise patients that Tafluprost Ophthalmic Solution is a sterile solution that does not contain a preservative. 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. 17.3 Potential for Pigmentation Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Also inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of Tafluprost Ophthalmic Solution. 17.4 Potential for Eyelash Changes Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with Tafluprost Ophthalmic Solution. These changes may result in a 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. 17.5 When to Seek Physician Advice Advise patients that if they develop a new ocular condition (e.g., trauma or infection), experience a sudden decrease in visual acuity, have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of Tafluprost 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 between applications. 17.7 Storage Information Instruct patients on proper storage of cartons, unopened foil pouches, and opened foil pouches [see How Supplied/Storage and Handling ( 16 )] . Recommended storage for cartons and unopened foil pouches is to store refrigerated at 2° to 8°C (36° to 46°F). After the pouch is opened, the single-use 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. Manufactured for: Prasco Laboratories Mason, OH 45040 USA Made in France Rev. 06/22

Instructions for Use Read these Instructions for Use before using your Tafluprost Ophthalmic Solution and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment. Important: Tafluprost Ophthalmic Solution is for the eye only. Do not swallow Tafluprost Ophthalmic Solution . Tafluprost Ophthalmic Solution single-use containers are packaged in a foil pouch. Do not use the Tafluprost Ophthalmic Solution single-use containers if the foil pouch is opened. Write down the date you open the foil pouch in the space provided on the pouch. Every time you use Tafluprost Ophthalmic Solution: Step 1. Wash your hands. Step 2. Take the strip of single-use containers from the foil pouch. Step 3. Pull off one single-use container from the strip. Step 4. Put the remaining strip of single-use containers back in the foil pouch and fold the edge to close the pouch. Step 5. Hold the single-use container upright. Make sure that your Tafluprost Ophthalmic Solution medicine is in the bottom part of the single-use container. See Figure A. Figure A Step 6. Open the single-use container by twisting off the tab. See Figure B. Figure B Step 7. Tilt your head backwards. If you are unable to tilt your head, lie down. Figure C Step 8. Place the tip of the single-use container close to your eye. Be careful not to touch your eye with the tip of the single-use container. See Figure C. Step 9. Pull your lower eyelid downwards and look up. Figure D Step 10. Gently squeeze the container and let 1 drop of Tafluprost Ophthalmic Solution fall into the space between your lower eyelid and your eye. If a drop misses your eye, try again. See Figure D. If your doctor has told you to use Tafluprost Ophthalmic Solution drops in both eyes, repeat Steps 7 to 10 for your other eye. There is enough Tafluprost Ophthalmic Solution in one single-use container for both of your eyes. Throw away the opened single-use container with any remaining Tafluprost Ophthalmic Solution right away. This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration. Rx only Manufactured for: Prasco Laboratories Made in France Rev. 06/22 Figure A Figure B Figure C Figure D

14 CLINICAL STUDIES In clinical studies up to 24 months in duration, patients with open-angle glaucoma or ocular hypertension and baseline pressure of 23 to 26 mmHg who were treated with Tafluprost Ophthalmic Solution dosed once daily in the evening demonstrated reductions in intraocular pressure at 3 and 6 months of 6 to 8 mmHg and 5 to 8 mmHg, respectively.

8.5 Geriatric Use No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients.

8.3 Nursing Mothers A study in lactating rats demonstrated that radio-labeled tafluprost and/or its metabolites were excreted in milk. 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 Tafluprost Ophthalmic Solution is administered to a nursing woman.

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.

8.1 Pregnancy Pregnancy Category C. Teratogenic effects: In embryo-fetal development studies in rats and rabbits, tafluprost administered intravenously was teratogenic. Tafluprost caused increases in post-implantation losses in rats and rabbits and reductions in fetal body weights in rats. Tafluprost also increased the incidence of vertebral skeletal abnormalities in rats and the incidence of skull, brain and spine malformations in rabbits. 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 . In rabbits, effects were seen at a tafluprost dose of 0.03 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid during organogenesis that were approximately 5 times higher than the 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 in rats, increased mortality of newborns, decreased body weights and delayed pinna unfolding were observed 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. There are no adequate and well-controlled studies in pregnant woman. Although animal reproduction studies are not always predictive of human response, Tafluprost Ophthalmic Solution should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Women of childbearing age/potential should have adequate contraceptive measures in place.

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 Pregnancy Category C. Teratogenic effects: In embryo-fetal development studies in rats and rabbits, tafluprost administered intravenously was teratogenic. Tafluprost caused increases in post-implantation losses in rats and rabbits and reductions in fetal body weights in rats. Tafluprost also increased the incidence of vertebral skeletal abnormalities in rats and the incidence of skull, brain and spine malformations in rabbits. 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 . In rabbits, effects were seen at a tafluprost dose of 0.03 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid during organogenesis that were approximately 5 times higher than the 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 in rats, increased mortality of newborns, decreased body weights and delayed pinna unfolding were observed 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. There are no adequate and well-controlled studies in pregnant woman. Although animal reproduction studies are not always predictive of human response, Tafluprost Ophthalmic Solution should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Women of childbearing age/potential should have adequate contraceptive measures in place. 8.3 Nursing Mothers A study in lactating rats demonstrated that radio-labeled tafluprost and/or its metabolites were excreted in milk. 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 Tafluprost Ophthalmic Solution is administered to a nursing woman. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Tafluprost Ophthalmic Solution 0.0015% is supplied as a sterile solution in translucent low density polyethylene single-use containers packaged in foil pouches (10 single-use containers per pouch). Each single-use container has 0.3 mL solution corresponding to 0.0045 mg tafluprost. NDC 66993-429-30; Unit-of-Use Carton of 30. 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, the single-use 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 unused containers 30 days after first opening the pouch.

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, the single-use 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 unused containers 30 days after first opening the pouch.