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)].

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.

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.

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.