Treatment of signs and symptoms of dry eye disease (DED) in adults.

Posology

Adults and elderly

Instill one drop of XIIDRA twice a day into each eye.

The efficacy and safety of XIIDRA has been established in 12 week double-masked, vehicle- controlled studies. In addition, the safety of XIIDRA has been established in a 12 month double- masked, vehicle-controlled study.

Paediatric population

There is no relevant use of XIIDRA in children and adolescents aged below 18 in the treatment of dry eye disease.

Method of administration Ocular use.

Contact lenses should be removed prior to the administration of XIIDRA and may be reinserted 15 minutes following administration.

The single-dose container should be discarded immediately after use.

Despite topical administration to the eye, Lifitegrast eye drops are absorbed and are systemically available. Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with post marketing reports for Xiidra. If allergic-type hypersensitivity reactions occur, immediately discontinue administration of Xiidra and initiate appropriate treatment.

No interaction studies have been performed.

Pregnancy

There are no or limited amount of data from the use of Lifitegrast in pregnant women. It is not known if Lifitegrast will harm your unborn baby.

Studies in animals following systemic administration of Lifitegrast, at exposures in excess of maximum human exposures, have shown no evidence of reproductive toxicity (see section 5.3).

The use of XIIDRA may be considered during pregnancy, if necessary. Breast-feeding

It is unknown whether Lifitegrast/metabolites are excreted in human milk. Because many drugs are

excreted in human milk, caution should be exercised when XIIDRA is administered to a breast- feeding woman.

Fertility

No human data on the effect of Lifitegrast on fertility are available. In rats, systemic administration of Lifitegrast resulted in no effects on fertility or reproductive performance with Lifitegrast (see section 5.3).

XIIDRA has minor influence on the ability to drive and use machines.

XIIDRA may cause some temporary blurring of vision when drops are administered.

Summary of the safety profile

In clinical studies of dry eye disease, 1401 subjects received at least 1 dose of Lifitegrast (1287 of which received Lifitegrast 50 mg/ml). The majority of subjects (84%) had £3 months of treatment exposure. However, 177 subjects were exposed to Lifitegrast for >6 months and 170 subjects were exposed to Lifitegrast for 1 year (defined as ³355 days).

The incidence rates of adverse reactions listed in the following table were derived from vehicle- controlled trials of up to one year duration in patients receiving XIIDRA. The most common ocular adverse reactions were eye irritation (18%), eye pain (12%) and instillation site reactions (12%); the majority of ocular adverse reactions were mild and transient in nature. The most common non-ocular adverse reaction was dysgeusia (14%).

Tabulated list of adverse reactions

The following adverse reactions listed below were observed in clinical studies with XIIDRA. They are ranked according to system organ class and classified according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), not known (cannot be estimated from the available data).

Description of selected adverse reactions

Hypersensitivity

Hypersensitivity adverse reactions have been reported post-marketing, including anaphylactic reaction/anaphylaxis, type IV hypersensitivity with respiratory distress, swollen tongue and asthma (see section 4.3).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed below:

To report any side effect(s):

·         Saudi Arabia:

·         Other GCC States:

There is no information regarding overdose in patients taking Lifitegrast.

Mechanism of action

Lifitegrast targets the interaction between lymphocyte function-associated antigen-1 (LFA-1), a cell surface protein found on leukocytes, and intercellular adhesion molecule-1 (ICAM-1), its cognate ligand. LFA-1 is a heterodimer integrin protein that mediates cell-to-cell interactions essential to immune and inflammatory response mechanisms. Its expression is restricted to leukocytes (neutrophil, eosinophil, basophil, monocyte, T and B lymphocyte), where it functions both as a key adhesion receptor and as a signal-transducing molecule. ICAM-1 is a member of the immunoglobulin superfamily and is normally expressed in low levels on leukocytes, endothelium and epithelium. Its expression level can greatly increase in response to the presence of inflammatory cytokines. Among the ICAMs, ICAM-1 is the principle ligand for LFA-1. Notably, conjunctival biopsies from patients with dry eye disease (DED) exhibit significant expression of ICAM-1 compared with normal controls.

Studies indicate that T-cells play a critical role in the development of DED. ICAM-1 has been shown to facilitate many T-cell dependent immune functions through its interaction with LFA-1; including adhesion of T-cells to endothelial and epithelial cells, T-cell recruitment and trafficking, proliferation, and the release of inflammatory cytokines. ICAM-1/LFA-1 interaction supports the formation of an immunological synapse between T-cells and antigen presenting cells (APC), such as dendritic cells; inducing T-cell activation and the release of cytokines that promote ocular inflammation, a substantial component of DED pathophysiology.

Studies performed in vitro using a human T-cell line have demonstrated that through its interaction with LFA-1,  Lifitegrast inhibits T-cell adhesion to ICAM-1, and inhibits the secretion of key inflammatory cytokines, including T-cell regulating cytokines IL-2 and IL-4 and several cytokines associated with the clinical severity of dry eye (IL-1α, IL 1β, IL-6, IL-10, IFN-γ, MIP-1α). Lifitegrast’s mechanism of binding to LFA-1 also targets T-cell binding to antigen presenting cells at the LFA-1/ICAM-1 immunological synapse and demonstrates significant and concentration-dependent blocking of immunological synapse formation, disruption of existing immunological synapse and function, as well as interruption of downstream T-cell cytokine release. Topical ocular administration of Lifitegrast (≥ 0.1%) has also been shown to reduce neutrophil infiltration to the corneal stroma in a model of corneal inflammation. These data suggest that by targeting the LFA-1/ICAM-1 interaction, Lifitegrast reduces elevations in cytokines that have been correlated with the development and perpetuation of DED.

Pharmacodynamic effects

No studies of pharmacodynamic effects have been performed in humans.

Clinical efficacy and safety

The effects of Lifitegrast treatment on the signs and/or symptoms of dry eye were assessed in a total of 2247 subjects in four 12-week, randomised, multi-centre, double-masked, vehicle-controlled studies. In all studies, subjects were randomised to XIIDRA 5% or vehicle in 1:1 ratio; Study 1: n=58, 58; Study 2: n=293, 295; Study 3: n=358, 360; and Study 4: n=355, 356. Study 1 also included 2 lower strengths of Lifitegrast; subjects were randomised to the four groups in equal ratio. In these studies, the use of concomitant topical ophthalmic medicinal products including artificial tears, steroids and antihistamines were not permitted.

The majority of subjects were 55 years of age and older (68%), white (85%) and female (76%). Although the number of subjects in subgroup categories was low, there were no apparent differences in age, gender or race in response to treatment with XIIDRA.

In all studies, subjects reported a history of dry eye in both eyes at study entry and all subjects in Studies 3 and 4 had a history of artificial tear use. In Studies 1 and 2 only, subjects were selected for enrolment after exposure to a controlled adverse environment.

Enrolment criteria included minimal signs (i.e. Corneal Fluorescein Staining (CFS) and non- anaesthetised Schirmer Tear Test (STT)) and symptoms (i.e. Eye Dryness Score (EDS) and Ocular Discomfort Score (ODS)) severity scores at baseline.

Effects on symptoms of DED

Eye dryness Score (EDS) was rated by subjects using a visual analogue scale (VAS)

(0 = no discomfort, 100 = maximal discomfort) at each study visit. The average baseline EDS was between 40 and 70. A larger reduction in EDS favouring XIIDRA was observed in all studies at Day 42 and Day 84; and an improvement was apparent at Day 14 in a majority of subjects studied (see Figure 1).Figure 1: Mean change (SD) from baseline and treatment difference (XIIDRA – Vehicle) in Eye Dryness Score in 12-week studies in subjects with dry eye disease

Study 1

Study 2

Study 3

Study 4

[1] Based on ANCOVA model adjusted for baseline value in Study 1, and ANCOVA model adjusted for baseline value and randomisation stratification factors in Studies 2-4. All randomised 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 DED

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 favouring 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.

Study 1

Study 2

Study 3

[1] Based on ANCOVA model adjusted for baseline value in Study 1, and ANCOVA model adjusted for baseline value and randomisation stratification factors in Studies 2-4. All randomised 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.

Safetystudy

The safety of XIIDRA, administered twice daily, was studied in a randomised, double-masked, vehicle-controlled study in 332 subjects with dry eye disease for one year (defined as ³355 days). Subjects were randomised to Lifitegrast 5% or vehicle in a 2:1 ratio (Lifitegrast n=221; vehicle n=111). After Day 14, subjects were allowed to use artificial tears, topical ophthalmic/nasal antihistamines, steroids and mast cell stabilisers. The safety profile of Lifitegrast 5% over the one year period was similar to that seen in the 12-week dry eye disease studies.

Among the subjects in the one year study who responded to a question on artificial tear use, a lower proportion of subjects in the Lifitegrast group used artificial tears at any time during the study: 64 out of 195 (32.8%) Lifitegrast subjects compared with 43 out of 98 (43.9%) vehicle subjects.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with XIIDRA in all subsets of the paediatric population for dry eye disease (see section 4.2 for information on paediatric use).

Absorption

Tear

When administered twice daily for 10 days, tear pharmacokinetic parameters for Lifitegrast 5% were: Cmax = 91413 ±43308 ng/ml, AUC0-8hours = 127697 ±66418 ng·h/ml and Tmax 0.44 ±0.22 hours. There was no accumulation of Lifitegrast in tears during twice daily and 3 times daily administration of Lifitegrast.

Plasma

Lifitegrast 5% solution is rapidly absorbed into the plasma with a mean Tmax of 0.09 ±0.01 hours (approximately 5.4 minutes) when administered twice daily for 10 days. Lifitegrast is also rapidly eliminated from plasma with Lifitegrast concentrations typically being measureable for only up to 30 minutes after administration. Systemic exposure to Lifitegrast is extremely low with

Cmax=1.70 ±1.36 ng/ml and AUC0-8hours = 0.69 ±0.47 ng·h/ml when administered twice daily for 10 days; therefore Lifitegrast disposition half-life (t½) cannot be determined accurately. The overall plasma pharmacokinetic profile demonstrated no systemic accumulation of Lifitegrast when administered twice daily over 10 days.

Distribution

Lifitegrast is highly bound to human serum albumin (mean of 94.8 to 97.6%). In vitro study results suggest that Lifitegrast is a substrate for OATP1 and OATP4 uptake transporters. The clinical relevance of these findings is unknown given that systemic exposure to Lifitegrast via the topical ocular route of administration is very low.

Biotransformation

An in vitro 14C-Lifitegrast metabolic study in rat, dog, monkey and human hepatocytes indicated that Lifitegrast is metabolised by CYP-mediated hepatic metabolism.

Elimination

In nonclinical studies, the majority of the drug is excreted unchanged via the fecal route. The main route of excretion following ocular administration was the feces, accounting for approximately 60% of the administered radioactivity up to 168 hours post-dose. Urinary excretion accounted for up to 2% of the administered radioactivity.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, phototoxicity, repeated dose toxicity (both via topical ocular and systemic/intravenous administration), genotoxicity, and toxicity to reproduction and development.

Sodium chloride

Sodium phosphate dibasic anhydrous Sodium thiosulfate pentahydrate Sodium hydroxide solution

Diluted Hydrochloric acid solution Water for injection

Not applicable.

Store below 30°C.

After opening, store single-dose containers in the original aluminium pouch in order to protect from light.

XIIDRA is supplied in 0.2 ml single-dose, low-density polyethylene (LDPE) containers packaged in sealed laminate aluminium pouches.

Each pouch contains a strip of five single-dose containers Pack sizes: 60 single dose containers.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.