Summary Basis of Decision for Xiidra
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Xiidra is located below.
Recent Activity for Xiidra
The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.
Post-Authorization Activity Table (PAAT) for Xiidra
Updated: 2025-07-24
The following table describes post-authorization activity for Xiidra, a product which contains the medicinal ingredient lifitegrast. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).
For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.
Drug Identification Number (DIN):
DIN 02471027 - 5 % (w/v), lifitegrast, solution, ophthalmic administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
NDS # 288415 |
2024-07-09 |
Issued NOC 2024-08-20 |
Submission filed to transfer ownership of the drug product from Novartis Pharmaceuticals Canada Inc. to Bausch & Lomb Inc. An NOC was issued and the DIN was retained. |
|
SNDS # 281129 |
2023-11-15 |
Issued NOC 2024-06-28 |
Submission filed as a Level I – Supplement for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 270465 |
2022-12-07 |
Issued NOC 2023-07-27 |
Submission filed as a Level I – Supplement for a change in the specification for the drug product tests and acceptance criteria. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 274073 |
2023-04-06 |
Cancellation Letter Received 2023-05-24 |
Submission filed as a Level I – Supplement for the addition of a drug substance manufacturing site. Additional information was to be incorporated so the submission was cancelled administratively by the sponsor. |
|
Drug product (DIN 02471027) market notification |
Not applicable |
Date of first sale 2021-04-22 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
SNDS # 224297 |
2019-01-31 |
Issued NOC 2020-02-13 |
Submission filed as a Level I – Supplement to update the PM. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Action and Clinical Pharmacology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued. |
|
NDS # 232457 |
2019-10-17 |
Issued NOC 2019-11-22 |
Submission filed to transfer ownership of the product (that is [i.e.] drug sponsor name) from Shire Pharma Canada ULC to Novartis Pharmaceuticals Canada Inc. An NOC was issued. |
|
NC # 218601 |
2018-07-25 |
Issued NOL 2018-09-21 |
Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions section of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
Drug product (DIN 02471027) market notification |
Not applicable |
Date of first sale: 2018-02-12 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NDS # 199810 |
2016-10-28 |
Issued NOC 2017-12-22 |
Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Xiidra
Date SBD issued: 2018-02-20
The following information relates to the New Drug Submission for Xiidra.
Lifitegrast
5% (w/v), solution, ophthalmic
Drug Identification Number (DIN):
- 02471027
Shire Pharma Canada ULC
New Drug Submission Control Number: 199810
On December 22, 2017, Health Canada issued a Notice of Compliance to Shire Pharma Canada ULC for the drug product Xiidra.
The market authorization was based on quality (chemistry and manufacturing), non clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-risk profile of Xiidra is favourable for the treatment of the signs and symptoms of dry eye disease.
1 What was approved?
Xiidra, a lymphocyte function associated antigen-1 (LFA-1) antagonist, was authorized for the treatment of the signs and symptoms of dry eye disease.
No overall differences in safety or effectiveness have been observed between elderly (>65 years of age) and younger patients.
The safety and efficacy of Xiidra have not been established in pediatric patients (<18 years of age).
Xiidra is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.
Xiidra was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Xiidra (lifitegrast 5%) is presented as an ophthalmic solution. In addition to the medicinal ingredient, the solution contains sodium chloride, sodium phosphate dibasic anhydrous, sodium hydroxide and/or hydrochloric acid (to adjust pH), sodium thiosulfate pentahydrate and water for injection.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Xiidra Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Xiidra approved?
Health Canada considers that the benefit-risk profile of Xiidra (lifitegrast) is favourable for the treatment of the signs and symptoms of dry eye disease (DED).
Dry eye disease is a common and challenging problem for both clinicians and patients. It is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Subjective symptoms are the most striking feature of the disease and often times the only factor upon which the diagnosis is based.
Xiidra has been shown to be efficacious in patients with DED. The market authorization was based on four 12-week, randomized, multicentre, double masked, placebo controlled studies. A total of 2,247 patients with DED were evaluated. In addition, the long-term safety of Xiidra was evaluated in a 12-month placebo-controlled study. In all efficacy studies, patients were randomized to Xiidra or placebo in a 1:1 ratio.
In the 12-week studies, evidence of improvement in symptoms of DED was observed in all four studies and an improvement in signs was observed in three of the four studies. Eye Dryness Score (EDS, a measure of symptoms) 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 favouring Xiidra was observed at Day 42 and Day 84. Inferior fluorescein corneal staining score (ICSS, a measure of DED signs; 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 between 1.8 and 2.4. At Day 84, a larger reduction in ICSS favouring Xiidra was observed in three studies.
The safety of Xiidra was assessed in 1,287 patients exposed to Xiidra; a total of 170 patients were exposed to Xiidra for at least 12 months. Adverse reactions related to Xiidra included dysgeusia, reduced visual acuity, and instillation site reactions (itching, redness, pain, and irritation). The treatment duration (12 weeks versus 1 year) did not affect the safety profile.
Clinical and non-clinical pharmacology studies showed minimal systemic absorption of lifitegrast following topical ocular application. The results of the non-clinical safety studies showed no significant adverse ocular or systemic toxicological findings in the central nervous, cardiovascular or pulmonary functions, or evidence of genotoxicity.
A Risk Management Plan (RMP) for Xiidra was submitted by Shire Pharma Canada ULC to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Xiidra Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look alike Sound alike brand name assessment was performed and the proposed name Xiidra was accepted.
Based on the data reviewed, the benefit-risk assessment for Xiidra used in the treatment of the signs and symptoms of DED is considered to be positive. Xiidra is efficacious in the treatment of DED based on the clinical studies and has an acceptable safety profile based on the non-clinical data and clinical studies. Appropriate warnings and precautions are in place in the Xiidra Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Xiidra?
Submission Milestones: Xiidra
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2016-08-09 |
| Submission filed: | 2016-10-28 |
| Screening | |
| Screening Acceptance Letter issued: | 2016-12-19 |
| Review | |
| Biostatistics Evaluation complete: | 2017-05-28 |
| Review of Risk Management Plan complete: | 2017-08-09 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2017-12-15 |
| Quality Evaluation complete: | 2017-12-20 |
| Clinical Evaluation complete: | 2017-12-21 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2017-12-22 |
The Canadian regulatory decision on the quality and non-clinical review of Xiidra was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the United States Food and Drug Administration (FDA) were used as an added reference for the non-clinical review.
For the clinical review, the Canadian regulatory decision was based on an assessment of the foreign review conducted by the FDA, in accordance with Method 1 as stated in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
The clinical pharmacology data support the use of Xiidra for the treatment of the signs and symptoms of dry eye disease (DED).
In accordance with the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, and Method 1 for the use of foreign reviews, the Canadian regulatory decision making process included an assessment of the clinical pharmacology review conducted by the United States Food and Drug Administration (FDA).
The FDA review reports adequately characterized the pharmacology of the drug product for the same indication.
The clinical pharmacology program of Xiidra (lifitegrast 5% solution) included human pharmacokinetic (PK) studies of plasma PK and tear fluid PK in healthy subjects, and limited plasma PK and pharmacodynamic (PD) data (lymphocyte counts) from a subset of DED patients enrolled in a Phase III study (SONATA). In vitro data on the metabolism of lifitegrast in human hepatocytes, protein binding, and cytochrome P450 (CYP) 2C9 inhibitory potential, as well as in vitro primary PD and cardiovascular safety pharmacology were also included.
The medicinal ingredient of Xiidra, lifitegrast, binds to the integrin lymphocyte function associated antigen 1 (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). In DED, ICAM-1 may be overexpressed in corneal and conjunctival tissues and the LFA-1/ICAM-1 interactions support T-cell migration and activation, which promotes the release of cytokines that sustain inflammation. In vitro studies demonstrated that lifitegrast may inhibit T-cell adhesion to ICAM-1 and may inhibit the secretion of key inflammatory cytokines in human peripheral blood mononuclear cells. The exact mechanism of action of lifitegrast in DED is not known.
The clinical PK studies conducted in healthy volunteers and in DED patients demonstrated minimal systemic availability and no systemic accumulation of lifitegrast. Electrocardiogram assessments from the Phase I dose escalation study (single and multiple dosing) demonstrated no effect and no dose related trends on heart rate, PR interval, QRS duration and QT/QTcB/QTcF. Given the lack of any non-clinical or clinical signals to indicate a cardiovascular safety risk, the minimal system absorption, and that the International Council for Harmonization (ICH) guideline ICH E14 is generally applicable to drugs having systemic bioavailability, a thorough QT study was not conducted for Xiidra. Overall, the pharmacological data support the use of Xiidra for the recommended indication. The data from the submitted clinical pharmacology studies are considered sufficient and there are no major concerns to prevent the market authorization of Xiidra for the treatment of the signs and symptoms of DED.
For further details, please refer to the Xiidra Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy data support the use of Xiidra (lifitegrast 5% solution) for the treatment of the signs and symptoms of DED.
In accordance with the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, and Method 1 for the use of foreign reviews, the Canadian regulatory decision making process was based on an assessment of the clinical review conducted by the FDA.
The FDA review reports adequately supported the clinical use of this drug product for the same indication filed to Health Canada.
The clinical efficacy of Xiidra treatment on the signs and symptoms of DED was assessed in a total of 2,247 patients in four 12 week, randomized, multicentre, double masked, placebo controlled studies. There was one Phase II study KCS 100 and three Phase III studies OPUS 1, OPUS 2, and OPUS 3. In all studies, patients were randomized to Xiidra or placebo in 1:1 ratio. The majority of patients were 55 years of age and older (68%), white (85%) and female (76%). In all studies, patients reported a history of DED in both eyes at study entry. Use of artificial tears was prohibited during the 12-week study period. Treatment in each study was administered as a single drop twice daily (AM and PM) in each eye for 12 weeks.
Eye dryness Score (EDS) was rated by patients 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.
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.
Overall, the submitted studies support Xiidra for the treatment of the signs and symptoms of DED. The recommended indication is the same as the indication filed with the submission.
For more information, refer to the Xiidra Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety data support the use of Xiidra (lifitegrast 5%) for the treatment of the signs and symptoms of DED.
In accordance with the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, and Method 1 for the use of foreign reviews, the Canadian regulatory decision making process was based on an assessment of the clinical review conducted by the FDA.
The FDA review reports adequately supported the clinical use of this drug product for the same indication filed to Health Canada.
In five clinical studies of patients with DED, 1,287 patients were exposed to Xiidra. The most common ocular adverse reactions were eye irritation (18%), eye pain (13%) and instillation site reactions (12%). The majority of these adverse reactions were mild and transient in nature. The most common non-ocular adverse reaction was dysgeusia (14%).
In the longer-term randomized placebo controlled safety study conducted over the course of 12 months in in which 262 patients with DED completed the study, the observed safety profile was similar to that seen in the 12-week studies. In the longer-term study, patients were allowed to use artificial tears concomitantly.
Appropriate warnings and precautions are in place in the approved Xiidra Product Monograph to address the identified safety concerns.
For more information, refer to the Xiidra Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical program was designed to characterize both in vitro and in vivo, the pharmacology, pharmacokinetics, and toxicology of lifitegrast, the medicinal ingredient of Xiidra, to support the proposed clinical dose of lifitegrast 5.0% ophthalmic solution (approximately 2.5 mg, 50 µL) applied to each eye 2 times per day for a total of 10 mg per day.
All pivotal toxicology studies were performed under Good Laboratory Practice (GLP) conditions and according to the recommendations laid out in the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidance documents where appropriate.
Lifitegrast demonstrated potent dose-dependent inhibition of T-cell adhesion to immobilized ICAM-1. Topical ocular administration of ≥0.1% lifitegrast, prior to corneal abrasion and/or bacterial challenge, significantly inhibited recruitment/ infiltration of neutrophils into the corneal tissue, inhibiting inflammatory cell recruitment to the cornea.
In dogs with kerato-conjunctivitis sicca, lifitegrast treatment (1% three times a day for 12 weeks) significantly improved Schirmer Tear Test scores by an average of 2.4 mm over baseline values, indicative of increased tear production.
The PK studies showed that the topical ocular instillation of lifitegrast resulted in the adequate distribution to the anterior ocular tissues known to be chronically inflamed in DED. Lifitegrast is absorbed into the eye with the highest exposure in the anterior ocular tissues (bulbar and palpebral conjunctiva, cornea, and iris/ciliary body), the site of action. Concentrations in the posterior tissues were low. Systemic exposure was limited, if any. The lack of hepatic metabolism and primary elimination as an intact drug suggests that lifitegrast is anticipated to have a low risk of CYP or transporter mediated drug drug interactions.
The results of the non-clinical safety studies showed no significant adverse ocular or systemic toxicological findings, no adverse effects on the central nervous, cardiovascular or pulmonary functions, or evidence of genotoxicity. Given the lack of in vitro and in vivo mutagenic effects and the low systemic exposure following topical ocular administration in the rat and dog, carcinogenicity studies were not conducted.
The most notable non-adverse finding following ocular instillation was mild ocular irritation. No other adverse findings were reported in the ocular toxicity studies; representing adequate safety margins to clinical exposures. The lifitegrast non clinical review adequately supports the clinical administration of a 5.0% solution (2.5 mg, 50 µL) administered twice a day for the treatment of the signs and symptoms of DED.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Xiidra Product Monograph.
For more information, refer to the Xiidra Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Xiidra has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is acceptable when the drug product is stored at room temperature (15° to 30°C) in the original foil pouch to protect from light.
Proposed limits of drug-related impurities are considered adequately qualified; i.e., within ICH limits and/or qualified from toxicological studies.
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
Neither the drug substance nor the reagents are obtained from sources that are at risk of transmitting bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE).
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| XIIDRA | 02471027 | BAUSCH & LOMB INC | LIFITEGRAST 5 % / W/V |