Xiidra

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Hypersensitivity [see Contraindications (4)] The most common adverse reactions (incidence 5%-25%) following the use of Xiidra were instillation-site irritation, dysgeusia, and decreased visual acuity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 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. In five clinical trials of DED conducted with lifitegrast ophthalmic solution, 1401 patients received at least one dose of lifitegrast (1287 of which received lifitegrast 5%). The majority of patients (84%) had less than or equal to 3 months of treatment exposure. One hundred-seventy patients were exposed to lifitegrast for approximately 12 months. The majority of the treated patients were female (77%). The most common adverse reactions reported in 5%-25% of patients were instillation-site irritation, dysgeusia, and reduced visual acuity. Other adverse reactions reported in 1%-5% of the patients were blurred vision, conjunctival hyperemia, eye irritation, headache, increased lacrimation, eye discharge, eye discomfort, eye pruritus, and sinusitis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Xiidra. Because these 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. Rare serious cases of hypersensitivity, including anaphylactic reaction, bronchospasm, respiratory distress, pharyngeal edema, swollen tongue, urticaria, allergic conjunctivitis, dyspnea, angioedema, and allergic dermatitis have been reported. Eye swelling and rash have also been reported [see Contraindications (4)] .

4 CONTRAINDICATIONS Xiidra is contraindicated in patients with known hypersensitivity to lifitegrast or to any of the other ingredients in the formulation [see Adverse Reactions (6.2)] . Hypersensitivity. ( 4 )

11 DESCRIPTION The chemical name for lifitegrast is (S)-2-(2-(benzofuran-6-carbonyl)-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)-3-(3-(methylsulfonyl)phenyl)propanoic acid. The molecular formula of lifitegrast is C 29 H 24 Cl 2 N 2 O 7 S and its molecular weight is 615.5 g/mol. The structural formula of lifitegrast is: *Chiral center Lifitegrast is a white to off-white powder, which is soluble in water. Xiidra (lifitegrast ophthalmic solution) 5% is a lymphocyte function-associated antigen-1 (LFA-1) antagonist supplied as a sterile, clear, colorless to slightly brownish-yellow colored, isotonic solution of lifitegrast with a pH of 7.0-8.0, and an osmolality range of 200-330 mOsmol/kg. Xiidra contains Active: lifitegrast 50 mg/mL; Inactives : sodium chloride, sodium phosphate dibasic anhydrous, sodium thiosulfate pentahydrate, and water for injection. Sodium hydroxide and/or hydrochloric acid (to adjust pH). Chemical Structure

2 DOSAGE AND ADMINISTRATION Instill one drop of Xiidra twice daily (approximately 12 hours apart) into each eye using a single-use container. Discard the single-use container immediately after using in each eye. Contact lenses should be removed prior to the administration of Xiidra and may be reinserted 15 minutes following administration. One drop twice daily in each eye (approximately 12 hours apart). ( 2 )

1 INDICATIONS AND USAGE Xiidra ® (lifitegrast ophthalmic solution) 5% is indicated for the treatment of the signs and symptoms of dry eye disease (DED). Xiidra (lifitegrast ophthalmic solution) 5% is a lymphocyte function-associated antigen-1 (LFA-1) antagonist indicated for the treatment of the signs and symptoms of dry eye disease (DED). ( 1 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lifitegrast binds to the integrin LFA-1, a cell surface protein found on leukocytes and blocks the interaction of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressed in corneal and conjunctival tissues in DED. LFA-1/ICAM-1 interaction can contribute to the formation of an immunological synapse resulting in T-cell activation and migration to target tissues. In vitro studies demonstrated that lifitegrast may inhibit T-cell adhesion to ICAM-1 in a human T-cell line and may inhibit secretion of inflammatory cytokines in human peripheral blood mononuclear cells. The exact mechanism of action of lifitegrast in DED is not known. 12.3 Pharmacokinetics In a subset of DED patients (n = 47) enrolled in a Phase 3 trial, the pre-dose (trough) plasma concentrations of lifitegrast were measured after 180 and 360 days of topical ocular dosing (one drop twice daily) with Xiidra (lifitegrast ophthalmic solution) 5%. A total of nine of the 47 patients (19%) had plasma lifitegrast trough concentrations above 0.5 ng/mL (the lower limit of assay quantitation). Trough plasma concentrations that could be quantitated ranged from 0.55 ng/mL to 3.74 ng/mL.

12.1 Mechanism of Action Lifitegrast binds to the integrin LFA-1, a cell surface protein found on leukocytes and blocks the interaction of LFA-1 with its cognate ligand intercellular adhesion molecule-1 (ICAM-1). ICAM-1 may be overexpressed in corneal and conjunctival tissues in DED. LFA-1/ICAM-1 interaction can contribute to the formation of an immunological synapse resulting in T-cell activation and migration to target tissues. In vitro studies demonstrated that lifitegrast may inhibit T-cell adhesion to ICAM-1 in a human T-cell line and may inhibit secretion of inflammatory cytokines in human peripheral blood mononuclear cells. The exact mechanism of action of lifitegrast in DED is not known.

12.3 Pharmacokinetics In a subset of DED patients (n = 47) enrolled in a Phase 3 trial, the pre-dose (trough) plasma concentrations of lifitegrast were measured after 180 and 360 days of topical ocular dosing (one drop twice daily) with Xiidra (lifitegrast ophthalmic solution) 5%. A total of nine of the 47 patients (19%) had plasma lifitegrast trough concentrations above 0.5 ng/mL (the lower limit of assay quantitation). Trough plasma concentrations that could be quantitated ranged from 0.55 ng/mL to 3.74 ng/mL.

20230802

5

3 DOSAGE FORMS AND STRENGTHS Ophthalmic solution containing lifitegrast 50 mg/mL (5%). Ophthalmic solution containing lifitegrast 50 mg/mL (5%). ( 3 )

Xiidra Lifitegrast LIFITEGRAST LIFITEGRAST SODIUM CHLORIDE SODIUM PHOSPHATE, DIBASIC, ANHYDROUS SODIUM THIOSULFATE SODIUM HYDROXIDE HYDROCHLORIC ACID WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies have not been conducted to determine the carcinogenic potential of lifitegrast. Mutagenesis Lifitegrast was not mutagenic in the in vitro Ames assay. Lifitegrast was not clastogenic in the in vivo mouse micronucleus assay. In an in vitro chromosomal aberration assay using mammalian cells (Chinese hamster ovary cells), lifitegrast was positive at the highest concentration tested, without metabolic activation. Impairment of Fertility Lifitegrast administered at IV doses of up to 30 mg/kg/day (5400-fold the human plasma exposure at the RHOD of lifitegrast ophthalmic solution, 5%) had no effect on fertility and reproductive performance in male and female-treated rats.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal studies have not been conducted to determine the carcinogenic potential of lifitegrast. Mutagenesis Lifitegrast was not mutagenic in the in vitro Ames assay. Lifitegrast was not clastogenic in the in vivo mouse micronucleus assay. In an in vitro chromosomal aberration assay using mammalian cells (Chinese hamster ovary cells), lifitegrast was positive at the highest concentration tested, without metabolic activation. Impairment of Fertility Lifitegrast administered at IV doses of up to 30 mg/kg/day (5400-fold the human plasma exposure at the RHOD of lifitegrast ophthalmic solution, 5%) had no effect on fertility and reproductive performance in male and female-treated rats.

NDA208073

Xiidra

Lifitegrast

0078-0911

HUMAN PRESCRIPTION DRUG

OPHTHALMIC

PRINCIPAL DISPLAY PANEL NDC 0078-0911-12 Rx Only 60 Single-Use Containers: 12 pouches x 5 single-use containers (0.2 mL each) xiidra ® (lifitegrast ophthalmic solution) 5% NOVARTIS Principal Display Panel NDC 0078-0911-12 xiidra®

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Handling the Single-use Container Advise patients not to touch the tip of the single-use container to their eye or to any surface, in order to avoid eye injury or contamination of the solution. Use With Contact Lenses Advise patients that contact lenses should be removed prior to administration of Xiidra and can be reinserted 15 minutes after administration [see Dosage and Administration (2)] . Administration Advise patients that the solution from one single-use container is to be used immediately after opening. It can be used to dose both eyes. The single-use container, including any remaining contents should be discarded immediately after administration [see Dosage and Administration (2)] . Storage Information Instruct patients to store single-use containers in the original foil pouch until ready to use [see How Supplied/Storage and Handling (16)] . Distributed by: Novartis Pharmaceuticals Corporation One Health Plaza East Hanover, NJ 07936 T2020-87

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Revised: June 2020 INSTRUCTIONS FOR USE XIIDRA ® [ZYE-druh] (lifitegrast ophthalmic solution) 5% for topical ophthalmic use Read this Instructions for Use before you start using Xiidra and each time you get a refill. There may be new information. This leaflet does not take the place of talking to your doctor about your medical condition or your treatment. Important Information You Need to Know Before Using Xiidra: Xiidra is for use in the eye. Wash your hands before each use to make sure you do not infect your eyes while using Xiidra. If you wear contact lenses, remove them before using Xiidra. Xiidra single-use containers are packaged in a foil pouch. Do not remove from the foil pouch until you are ready to use Xiidra. Do not let the tip of the Xiidra single-use container touch your eye or any other surfaces. Use one drop of Xiidra in each eye two times each day (one drop in the morning and one drop in the evening, approximately 12 hours apart). Each single-use container of Xiidra will give you enough medicine to treat both of your eyes, one time. There is some extra Xiidra in each single-use container in case you miss getting a drop into your eye. After you have applied the drops, throw away the single-use container and any unused Xiidra. Do not save any unused Xiidra. Follow Steps 1 to 9 each time you use Xiidra. Step 1. Take a foil pouch out of the Xiidra box. Open the pouch and remove the strip of single-use containers (see Figure A ). Figure A Pull off one single-use container from the strip (see Figure B ). Figure B Step 2. Put the remaining strip of single-use containers back in the pouch (see Figure C ). Figure C Fold the edge to close the pouch (see Figure D ). Figure D Step 3. Hold the Xiidra container upright (see Figure E ). Figure E Tap the top of the container until all of the solution is in the bottom part of the container (see Figure F ). Figure F Step 4. Open the Xiidra single-use container by twisting off the tab. Make sure that the tip of the single-use container does not touch anything, to avoid contamination (see Figure G ). Figure G Step 5. Tilt your head backwards. If you are not able to tilt your head, lie down. Step 6. Gently pull your lower eyelid downwards and look up. Step 7. Place the tip of the Xiidra single-use container close to your eye, but be careful not to touch your eye with it. Step 8. Gently squeeze the single-use container and let one drop of Xiidra fall into the space between your lower eyelid and your eye. If a drop misses your eye, try again (see Figure H ). Figure H Step 9. Repeat Steps 5 to 8 for your other eye. There is enough Xiidra in one single-use container for both eyes. Once you have applied a drop to both eyes, throw away the opened single-use container with any remaining solution. If you use contact lenses, wait for at least 15 minutes before placing them back in your eyes. Distributed by: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936 T2020-89 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H

14 CLINICAL STUDIES The safety and efficacy of lifitegrast for the treatment of DED were assessed in a total of 1181 patients (1067 of which received lifitegrast 5%) in four 12-week, randomized, multi-center, double-masked, vehicle-controlled studies. Patients were randomized to Xiidra or vehicle (placebo) in a 1:1 ratio and dosed twice a day. Use of artificial tears was not allowed during the studies. The mean age was 59 years (range, 19-97 years). The majority of patients were female (76%). Enrollment criteria included minimal signs (i.e., Corneal Fluorescein Staining and non-anesthetized Schirmer Tear Test) and symptoms (i.e., Eye Dryness Score (EDS) and Ocular Discomfort Score) severity scores at baseline. Effects on Symptoms of Dry Eye Disease Eye dryness score was rated by patients using a visual analogue scale (0 = no discomfort, 100 = maximal discomfort) at each study visit. The average baseline EDS was between 40 and 70. A larger reduction in EDS favoring Xiidra was observed in all studies at Day 42 and Day 84 (see Figure 1). Figure 1: Mean Change (SD) From Baseline and Treatment Difference (Xiidra – Vehicle) in Eye Dryness Score in 12-Week Studies in Patients With Dry Eye Disease [1] Based on analysis of covariance (ANCOVA) model adjusted for baseline value in Study 1, and ANCOVA model adjusted for baseline value and randomization stratification factors in Studies 2-4. All randomized and treated patients were included in the analysis and missing data were imputed using last-available data. In Study 1, one Xiidra-treated subject who did not have a baseline value was excluded from analysis. Effects on Signs of Dry Eye Disease Inferior fluorescein corneal staining score (ICSS) (0 = no staining, 1 = few/rare punctate lesions, 2 = discrete and countable lesions, 3 = lesions too numerous to count but not coalescent, 4 = coalescent) was recorded at each study visit. The average baseline ICSS was approximately 1.8 in Studies 1 and 2, and 2.4 in Studies 3 and 4. At Day 84, a larger reduction in ICSS favoring Xiidra was observed in three of the four studies (see Figure 2). Figure 2: Mean Change (SD) From Baseline and Treatment Difference (Xiidra – Vehicle) in Inferior Corneal Staining Score in 12-Week Studies in Patients With Dry Eye Disease [1] Based on ANCOVA model adjusted for baseline value in Study 1, and ANCOVA model adjusted for baseline value and randomization stratification factors in Studies 2-4. All randomized and treated patients were included in the analysis and missing data were imputed using last-available data. In Study 2, one vehicle-treated subject who did not have a study eye designated was excluded from analysis. Figure 1 Figure 2

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

8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 17 years have not been established.

8.1 Pregnancy Risk Summary There are no available data on Xiidra use in pregnant women to inform any drug-associated risks. Intravenous (IV) administration of lifitegrast to pregnant rats, from premating through gestation day 17, did not produce teratogenicity at clinically relevant systemic exposures. Intravenous administration of lifitegrast to pregnant rabbits during organogenesis produced an increased incidence of omphalocele at the lowest dose tested, 3 mg/kg/day (400-fold the human plasma exposure at the recommended human ophthalmic dose [RHOD], based on the area under the curve [AUC] level). Since human systemic exposure to lifitegrast following ocular administration of Xiidra at the RHOD is low, the applicability of animal findings to the risk of Xiidra use in humans during pregnancy is unclear [see Clinical Pharmacology (12.3)] . Data Animal Data Lifitegrast administered daily by IV injection to rats, from premating through gestation day 17, caused an increase in mean pre-implantation loss and an increased incidence of several minor skeletal anomalies at 30 mg/kg/day, representing 5,400-fold the human plasma exposure at the RHOD of Xiidra, based on AUC. No teratogenicity was observed in the rat at 10 mg/kg/day (460-fold the human plasma exposure at the RHOD, based on AUC). In the rabbit, an increased incidence of omphalocele was observed at the lowest dose tested, 3 mg/kg/day (400-fold the human plasma exposure at the RHOD, based on AUC), when administered by IV injection daily from gestation days 7 through 19. A fetal no observed adverse effect level (NOAEL) was not identified in the rabbit.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on Xiidra use in pregnant women to inform any drug-associated risks. Intravenous (IV) administration of lifitegrast to pregnant rats, from premating through gestation day 17, did not produce teratogenicity at clinically relevant systemic exposures. Intravenous administration of lifitegrast to pregnant rabbits during organogenesis produced an increased incidence of omphalocele at the lowest dose tested, 3 mg/kg/day (400-fold the human plasma exposure at the recommended human ophthalmic dose [RHOD], based on the area under the curve [AUC] level). Since human systemic exposure to lifitegrast following ocular administration of Xiidra at the RHOD is low, the applicability of animal findings to the risk of Xiidra use in humans during pregnancy is unclear [see Clinical Pharmacology (12.3)] . Data Animal Data Lifitegrast administered daily by IV injection to rats, from premating through gestation day 17, caused an increase in mean pre-implantation loss and an increased incidence of several minor skeletal anomalies at 30 mg/kg/day, representing 5,400-fold the human plasma exposure at the RHOD of Xiidra, based on AUC. No teratogenicity was observed in the rat at 10 mg/kg/day (460-fold the human plasma exposure at the RHOD, based on AUC). In the rabbit, an increased incidence of omphalocele was observed at the lowest dose tested, 3 mg/kg/day (400-fold the human plasma exposure at the RHOD, based on AUC), when administered by IV injection daily from gestation days 7 through 19. A fetal no observed adverse effect level (NOAEL) was not identified in the rabbit. 8.2 Lactation Risk Summary There are no data on the presence of lifitegrast in human milk, the effects on the breastfed infant, or the effects on milk production. However, systemic exposure to lifitegrast from ocular administration is low [see Clinical Pharmacology (12.3)] . The developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for Xiidra and any potential adverse effects on the breastfed child from Xiidra. 8.4 Pediatric Use Safety and efficacy in pediatric patients below the age of 17 years have not been established. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger adult patients.

16 HOW SUPPLIED/STORAGE AND HANDLING Xiidra (lifitegrast ophthalmic solution) 5% (50 mg/mL) is supplied in a foil pouch containing 5 low-density polyethylene 0.2 mL single-use containers. Carton of 60 single-use containers NDC 0078-0911-12 Storage: Store at 20°C to 25°C (68°F to 77°F). Store single-use containers in the original foil pouch.