Lifitegrast

Lifitegrast ophthalmic solution 5% is indicated for the treatment of the signs and symptoms of dry eye disease (DED). 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).

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

Ophthalmic solution containing lifitegrast 50 mg/mL (5%). Ophthalmic solution containing lifitegrast 50 mg/mL (5%).

Lifitegrast 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.

The following serious adverse reactions are described elsewhere in the labeling:

• Hypersensitivity [see Contraindications (4) ] The most common adverse reactions (incidence 5% to 25%) following the use of lifitegrast were instillation-site irritation, dysgeusia and decreased visual acuity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc., at 1-866-850-2876 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% to 25% of patients were instillation-site irritation, dysgeusia, and reduced visual acuity. Other adverse reactions reported in 1% to 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 lifitegrast. 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) ].

8.1 Pregnancy Risk Summary There are no available data on lifitegrast 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 lifitegrast at the RHOD is low, the applicability of animal findings to the risk of lifitegrast 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 lifitegrast, 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 lifitegrast and any potential adverse effects on the breastfed child from lifitegrast.

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.

Risk Summary There are no available data on lifitegrast 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 lifitegrast at the RHOD is low, the applicability of animal findings to the risk of lifitegrast 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 lifitegrast, 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.

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

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

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 practically insoluble in water. 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 to 8.0 and an osmolality range of 200 to 330 mOsmol/kg. Lifitegrast ophthalmic solution contains Active: lifitegrast 50 mg/mL; Inactives: sodium chloride, dibasic sodium phosphate anhydrous, sodium thiosulfate pentahydrate, sodium hydroxide and/or hydrochloric acid (to adjust pH) and water for injection. Lifitegrast ophthalmic solution 5% figure1

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 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.

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.

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 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.

, 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.

17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Handling the Single-Dose Container Advise patients not to touch the tip of the single-dose 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 lifitegrast ophthalmic solution and can be reinserted 15 minutes after administration [see Dosage and Administration (2) ]. Administration Advise patients that the solution from one single-dose container is to be used immediately after opening. It can be used to dose both eyes. The single-dose container, including any remaining contents should be discarded immediately after administration [see Dosage and Administration (2) ]. Storage Information Instruct patients to store single-dose containers in the original foil pouch until ready to use [see How Supplied/Storage and Handling (16) ] . Dispense with Patient Information and Instructions for Use available at: https://www.aurobindousa.com/medication-guides/ Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Eugia Pharma Specialities Limited Hyderabad - 500032 India