Summary Basis of Decision for Lixiana

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Lixiana is located below.

Recent Activity for Lixiana

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 Lixiana

Updated: 2024-06-19

The following table describes post-authorization activity for Lixiana, a product which contains the medicinal ingredient edoxaban (supplied as édoxaban tosylate). 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 Numbers (DINs):

  • DIN 02458640 - 15 mg, édoxaban , tablet, oral administration
  • DIN 02458659 - 30 mg, édoxaban , tablet, oral administration
  • DIN 02458667 - 60 mg, édoxaban , tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

New safety and effectiveness review

Not applicable

Started between 2024-02-01 to 2024-02-29

Health Canada started a new safety and effectiveness review for direct oral anticoagulants and warfarin-containing products related to Splenic rupture (tear in the spleen’s surface).

SNDS # 278099

2023-08-04

Issued NOC 2024-01-05

Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; and Drug Interactions sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 257921

2021-10-26

Issued NOC 2023-02-02

Submission filed as a Level I – Supplement to update the PM with new information pertaining to pharmacokinetics and route of administration. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Drug Interactions; Dosage and Administration; and Clinical Pharmacology sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

SNDS # 261122

2022-02-01

Issued NOC 2022-08-30

Submission filed as a Level I – Supplement to add an alternate manufacturing site for the production of the drug substance. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 244386

2020-09-25

Issued NOC 2021-12-01

Submission filed as a Level I – Supplement to update the PM with new safety and efficacy information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; Drug Interactions; Dosage and Administration; Action and Clinical Pharmacology; and Clinical Trials sections of the PM. Corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 233505

2019-11-14

Issued NOL 2020-02-14

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 Adverse Reactions section of the PM. Corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 229632

2019-07-12

Issued NOL 2019-10-18

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; Adverse Reactions; and Drug Interactions sections of the PM. Corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 205240

2017-05-03

Issued NOL 2017-07-31

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to fulfill the commitment to correct the PM in accordance with suggested changes made to the Summary Basis of Decision document. As a result of the NC, modifications were made to the Adverse Reactions and Drug Interactions sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DINs 02458640, 02458659, 02458667) market notification

Not applicable

Date of first sale: 2017-04-25

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 200126

2016-11-15

Issued NOC 2017-01-17

Submission filed to transfer ownership of the product from Daiichi-Sankyo Inc. to Servier Canada Inc. An NOC was issued.

NDS # 187363

2015-09-03

Issued NOC 2016-11-04

Notice of Compliance issued for New Drug Submission.
 
Summary Basis of Decision (SBD) for Lixiana

Date SBD issued: 2016-12-21

The following information relates to the New Drug Submission for Lixiana.

edoxaban, 15 mg, 30 mg, and 60 mg tablets, oral

Drug Identification Number (DIN):

  • 02458640 - 15 mg tablet
  • 02458659 - 30 mg tablet
  • 02458667 - 60 mg tablet

Daiichi Sankyo, Inc.

New Drug Submission Control Number: 187363

 

On November 4, 2016, Health Canada issued a Notice of Compliance to Daiichi Sankyo, Inc. for the drug product Lixiana.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Lixiana is favourable for:

  • Prevention of stroke and systemic embolic events in patients with atrial fibrillation, in whom anticoagulation is appropriate.
  • Treatment of venous thromboembolism (VTE) (deep vein thrombosis [DVT], pulmonary embolism [PE]) and the prevention of recurrent DVT and PE.

 

1 What was approved?

 

Lixiana, an anticoagulant, was authorized for:

  • Prevention of stroke and systemic embolic events in patients with atrial fibrillation, in whom anticoagulation is appropriate.
  • Treatment of venous thromboembolism (VTE) (deep vein thrombosis [DVT], pulmonary embolism [PE]) and the prevention of recurrent DVT and PE.

Clinical studies in stroke prevention in patients with atrial fibrillation (SPAF), treatment of VTE and prevention of recurrent DVT and PE, included patients ≥65 years of age.

The safety and efficacy of Lixiana in children under the age of 18 years have not yet been established. Therefore, use of Lixiana is not recommended in these patients.

Lixiana is contraindicated for:

  • Clinically significant active bleeding, including gastrointestinal bleeding.
  • Lesions or conditions at increased risk of clinically significant bleeding, for example (e.g.), recent cerebral infarction (hemorrhagic or ischemic), active peptic ulcer disease with recent bleeding, patients with spontaneous or acquired impairment of hemostasis.
  • Hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
  • Concomitant treatment with any other anticoagulant, including
    • unfractionated heparin (UFH), except at doses used to maintain a patent central venous or arterial catheter.
    • low molecular weight heparins (LMWH), such as enoxaparin and dalteparin.
    • heparin derivatives, such as fondaparinux.
    • oral anticoagulants, such as warfarin, dabigatran, apixaban, rivaroxaban except under circumstances of switching therapy to or from Lixiana.
  • Pregnancy.
  • Nursing women.
  • Hypersensitivity to edoxaban or to any ingredients of the formulation.

Lixiana was approved for use under the conditions stated in the Lixiana Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Lixiana (15 mg, 30 mg, and 60 mg edoxaban, as edoxaban tosylate monohydrate) is presented as a film-coated tablet. In addition to the medicinal ingredient, the tablet contains carnauba wax, crospovidone, hydroxypropyl cellulose, hypromellose, iron oxide red (30 mg tablets and 15 mg tablets), iron oxide yellow (60 mg tablets and 15 mg tablets), magnesium stearate, mannitol, polyethylene glycol 8000, pregelatinized starch, talc, and titanium dioxide.

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 Lixiana Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Lixiana approved?

 

Health Canada considers that the benefit/risk profile of Lixiana is favourable for:

  • Prevention of stroke and systemic embolic events in patients with atrial fibrillation, in whom anticoagulation is appropriate.
  • Treatment of venous thromboembolism (VTE) (deep vein thrombosis [DVT], pulmonary embolism [PE]) and the prevention of recurrent DVT and PE.

Atrial fibrillation (AF) is a condition in which the heartbeat is rapid and irregular, and can potentially lead to a stroke. It is a common condition, affecting approximately 2.3% to 3.4% of people in developed countries and its prevalence increases with older age; 1% in those >60 years and >8% in those >80 years. Compared to those without AF, people with arrhythmia have a 3-5 times higher risk of stroke. Atrial fibrillation can be classified as valvular, pertaining mainly to patients with mitral stenosis or mechanical prosthetic heart valves, or non-valvular, which encompasses the remaining vast majority of patients with atrial fibrillation. The risk of arterial thromboembolism can be significantly reduced by anticoagulant therapy.

Acute VTE, that is (i.e.), DVT or PE, is a common disorder with an annual incidence rate of approximately 1-2 per 1,000 inhabitants. Deep-vein thrombosis is a blood clot found anywhere in the deep veins of the legs, while PE occurs when part of a clot detaches and lodges in the pulmonary arteries. Novel oral anticoagulant therapy is the cornerstone of stroke prevention in patients with AF and, overlapped with parenteral heparin, for the treatment and prevention of VTE.

Lixiana has been shown to be efficacious in the prevention of stroke and systemic embolism in patients with atrial fibrillation, and efficacious in the treatment of patients with VTE to prevent reoccurrence of DVT and PE. The market authorization was based on two pivotal Phase III studies: the ENGAGE AF-TIMI 48 study and the HOKUSAI-VTE study.

The indication for atrial fibrillation (AF) was supported by a Phase III multicentre, randomized, double-blind, double-dummy, parallel-group, active-controlled study (ENGAGE AF-TIMI 48) conducted in 21,105 patients with AF who were at medium to high risk of stroke and systemic embolism. The patients were randomized to receive either Lixiana 30 mg (15 mg dose-reduced) once daily, Lixiana 60 mg (30 mg dose-reduced) once daily or warfarin titrated to a target international normalized ratio (INR) of 2.0 to 3.0. Patients in both Lixiana groups had their dose reduced, if one or more of the following clinical factors were present: moderate renal impairment, low body weight, or concomitant use of specific P-glycoprotein inhibitors. The median study drug exposure for both Lixiana groups was 2.5 years.

The Lixiana 60 mg (30 mg dose reduced) once-daily dosing regimen was non-inferior to warfarin for the primary efficacy endpoint of stroke and systemic embolism (SEE) (Lixiana 60/30 mg, 1.18% per year; warfarin 1.5% per year; hazard ratio [HR] 0.79; 97.5% confidence interval [CI]: 0.63-0.98; p<0.0001 for non-inferiority). The Lixiana 60 mg (30 mg dose reduced) regimen also significantly reduced the Major Adverse Cardiovascular Events (MACE) (HR 0.89, 95% CI: 0.81-0.97), compared with warfarin. Significant reduction of cardiovascular mortality (HR 0.87, 95% CI: 0.79-0.97) and fewer all-cause deaths were also observed with Lixiana compared to warfarin. The positive benefit-risk profile of Lixiana was also illustrated by the significant reduction in the important bleeding risks such as the hemorrhagic strokes, major bleeds and fatal bleeds compared to warfarin. The dosing regimen of Lixiana 30 mg (15 mg dose reduced) was numerically less effective than warfarin for the primary efficacy endpoint (Lixiana 30/15 mg, 1.61% per year; warfarin 1.5% per year; HR = 1.07; 97.5% CI: 0.87-1.31; p = 0.005 for non-inferiority) and was also markedly inferior in reducing the rate of ischemic stroke. Therefore, only the Lixiana 60 mg (30 mg dose reduced) regimen was recommended to be approved for this indication.

The indication for venous thromboembolism (VTE) was supported by a Phase III randomized, double-blind, matching placebo, parallel-group, active-controlled study (HOKUSAI-VTE) conducted in 8,292 patients with acute, symptomatic pulmonary embolism (PE) and/or deep vein thrombosis (DVT). A treatment regimen that included an initial course of heparin followed by oral Lixiana 60 mg (30 mg dose reduced) once a day was effective in treating patients with VTE and in safely reducing the rate of recurrence of such events while mitigating the incidence of clinically significant bleeding events. Lixiana 60 mg (30 mg dose reduced) was non-inferior to warfarin for recurrence of VTE (Lixiana, 3.2%; warfarin, 3.5%; HR = 0.89; 95% CI: 0.70-1.13; p<0.0001 for non-inferiority to a pre-specified margin of 1.5). Relative efficacy was maintained across a wide spectrum of VTE manifestations ranging from limited proximal DVT to severe PE. Lixiana was superior to warfarin in regard to clinically relevant bleeding, and especially those more severe and fatal bleeding complications (such as intracranial) associated with standard warfarin VTE anticoagulant therapy (Lixiana, 8.5%; warfarin, 10.3%; HR = 0.81; 95% CI: 0.71-0.94; p = 0.004 for superiority).

In both studies, the most common adverse reactions related to bleeding in the Lixiana 60 mg (30 mg dose-reduced) group included cutaneous soft tissue hemorrhage (≤5.9%) and epistaxis (≤4.7%), while vaginal hemorrhage (9.0%) was the most common bleeding-related adverse reaction in the HOKUSAI-VTE study only. In the ENGAGE AF-TIMI 48 study, the site of major bleeds was mostly in the gastrointestinal (GI) tract, followed by intracranial, and intra-ocular. There were more major GI bleeds in the Lixiana 60 mg (30 mg dose-reduced) group than the warfarin group (1.5% and 1.2% per year, respectively). The rate of GI bleeding was consistent with data for other Health Canada approved novel oral anticoagulants (NOACs) available in Canada. Gastrointestinal and vaginal bleeding are readily diagnosed and treated, and rarely result in long-term disability or death unlike intracranial hemorrhage, where Lixiana had significantly fewer intracranial hemorrhage bleeding events.

A Risk Management Plan (RMP) for Lixiana was submitted by Daiichi Sankyo, Inc. 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.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Lixiana has been deemed acceptable.

Overall, the therapeutic benefits seen in the pivotal studies are positive and the benefits of Lixiana therapy are considered to outweigh the potential risks. Lixiana has an acceptable safety profile based on the non-clinical data and clinical studies. Lixiana has been shown to be non-inferior to warfarin for the prevention of stroke and systemic embolic events in patients with atrial fibrillation, as well as the treatment and prevention of venous thromboembolism, but with a lower overall risk of bleeding. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Lixiana 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 Lixiana?

 

Submission Milestones: Lixiana

Submission Milestone Date
Pre-submission meeting: 2015-05-06
Submission filed: 2015-09-03
Screening  
Screening Deficiency Notice issued: 2015-10-16
Response filed: 2015-11-27
Screening Acceptance Letter issued: 2015-12-10
Review  
Biopharmaceutics Evaluation complete: 2016-10-04
Quality Evaluation complete: 2016-10-27
Clinical Evaluation complete: 2016-11-01
Labelling Review complete: 2016-10-05
Notice of Compliance issued by Director General, Therapeutic Products Directorate 2016-11-04

 

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?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Lixiana?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Lixiana is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Lixiana is a highly selective, direct and reversible inhibitor of factor Xa, the serine protease located in the final common pathway of the coagulation cascade. Lixiana inhibits free factor Xa, and prothrombinase activity. Inhibition of factor Xa in the coagulation cascade reduces thrombin generation and prolongs clotting time and reduces the risk of formation or provoked thrombus formation.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Lixiana for the specified indication.

Potential factors affecting the pharmacokinetics and/or pharmacodynamics include dosing and frequency, body weight, renal clearance and P-gp inhibitors. For these factors edoxaban must be reduced by 50% to avoid the risk of over-exposure. edoxaban is primarily eliminated by the kidneys (50% of the absorbed dose) but also through metabolic and biliary pathways. Renal dose adjustments reflect the increased exposure of edoxaban with the degree of renal impairment. edoxaban is a substrate of the efflux transporter, P-glycoprotein (P-gp). In general, P-gp inhibitors increased the exposure of edoxaban ; the increase was less than 2-fold.

A pivotal bridging study to evaluate comparative bioavailability, as well as a dose-proportionality study and a food-effect study were assessed. The standards for comparative bioavailability for edoxaban following administration of a single dose of one 60 mg Lixiana tablet (proposed commercial formulation) versus two 30 mg Lixiana tablets (administered in Phase III clinical studies) under fasted condition were met. The dose-proportionality study demonstrated that the pharmacokinetics of edoxaban were linear in the therapeutic dose range of 15 to 60 mg. The food-effect study demonstrated that the drug exposure pharmacokinetic parameters support the administration of Lixiana with or without food.

For further details, please refer to the Lixiana Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical development program of Lixiana included two pivotal studies: the ENGAGE AF-TIMI 48 study and the HOKUSAI-VTE study.

  • The ENGAGE AF-TIMI 48 study was designed to demonstrate the efficacy and safety of two dose regimens of Lixiana compared to warfarin for the prevention of stroke and systemic embolism events (SEE) in patients with nonvalvular atrial fibrillation and at moderate to high risk of stroke and SEE.
  • The HOKUSAI-VTE study was designed to demonstrate the efficacy and safety of Lixiana in the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and the prevention of recurrent DVT and PE.
Efficacy in Patients with Atrial Fibrillation

The ENGAGE AF-TIMI 48 study (a pivotal, Phase III, multicentre, randomized, double-blind, double-dummy, parallel-group, active-controlled study) enrolled 21,105 patients (age ≥1 years) with documented atrial fibrillation (AF) within the preceding 12 months and in whom anticoagulant therapy was indicated. Eligible subjects were at a medium to high risk for stroke and SEE.

Patients were randomized to receive either Lixiana 30 mg (15 mg dose-reduced) once daily, Lixiana 60 mg (30 mg dose-reduced) once daily, or warfarin. Patients in both Lixiana groups had their dose halved, if one or more of the following clinical factors, known to increase drug exposure, were present at randomization or during the study: moderate renal impairment (creatinine clearance [CrCL] of 30-50 mL/min), low body weight (≤60 kg) or concomitant use of specific P-glycoprotein (P-gp) inhibitors (verapamil, quinidine, dronedarone). The most common reason for dose reduction was a CrCL ≤50 mL/min at randomization (19% of patients).

Patients were well balanced with respect to demographic and baseline characteristics. The percentages of patients ≥75 years of age and ≥80 years of age were approximately 40% and 17%, respectively. Concomitant diseases of patients in this study included hypertension (94%), congestive heart failure (58%), and prior stroke or transient ischemic attack (28%). At baseline, approximately 30% of patients were on aspirin and approximately 2% of patients were taking a thienopyridine.

The primary efficacy endpoint was the composite of stroke and SEE that occurred during treatment or within 3 days from the last dose taken. Secondary efficacy endpoints included: composite of stroke, SEE, and cardiovascular (CV) mortality; major adverse cardiovascular event (MACE), which is the composite of non-fatal myocardial infarction (MI), non-fatal stroke, non-fatal SEE, and death due to CV cause or bleeding; and composite of stroke, SEE, and all-cause mortality. The median study drug exposure for both the Lixiana 60 mg and 30 mg treatment groups was 2.5 years.

Both Lixiana 60 mg and 30 mg group regimens were non-inferior to warfarin for the primary efficacy endpoint with the upper boundary of the 97.5% confidence interval (CI) below the pre-specified non-inferiority margin of 1.38. Adjudicated stroke or SEE occurred in 253 patients in the Lixiana 30 mg regimen (1.61% per year), 182 patients in the Lixiana 60 mg regimen (1.18% per year), and 232 patients in the warfarin group (1.50% per year). Compared to warfarin-treated patients, the Hazard Ratio (HR) in the Lixiana 30 mg regimen was 1.07 (97.5% CI: 0.87, 1.31, p = 0.005 for non-inferiority) and in the Lixiana 60 mg regimen it was 0.79 (97.5% CI: 0.63, 0.98, p<0.0001 for non-inferiority).

Hemorrhagic stroke contributed to most of the composite efficacy outcomes (ischemic stroke and SEE) which showed a relative risk reduction of approximately 50% with the Lixiana 60 mg regimen compared to warfarin. The other efficacy outcomes such as ischemic stroke, fatal stroke and disabling stroke were neutral or similar between the Lixiana 60 mg regimen and warfarin.

Secondary endpoint analysis showed that the 30 mg and 60 mg regimens of Lixiana provided substantial absolute risk reductions (approximately 0.45% difference) in CV mortality and intracerebral hemorrhage (ICH). Conversely, more patients in the Lixiana 30 mg regimen experienced ischemic strokes on-treatment (1.43% per year) when compared to warfarin (0.93% per year), and an increase in the relative risk of 54%. This was also confirmed when examining other ischemic events, where the Lixiana 30 mg regimen was associated with a higher risk of MI compared to warfarin (HR 1.19, 95% CI: 0.95, 1.48). This risk was not seen in the Lixiana 60 mg regimen. In fact, the HR for MACE was 0.89 (95% CI: 0.81, 0.97) and for the combined endpoint of stroke, SEE, and all-cause mortality, the HR was 0.90 (95% CI: 0.82, 0.98) in favour of the Lixiana 60 mg regimen. These findings indicate that to protect against ischemic events, the Lixiana 60 mg regimen is preferable to the Lixiana 30 mg regimen.

Patients who received Lixiana 30 mg (dose-reduced patients in the 60 mg group) had an event rate of 1.79% per year for the primary endpoint, compared with an event rate of 2.21% per year for the matching dose-reduced patients in the warfarin group. Compared to patients who were treated with warfarin, the HR for the patients who received Lixiana 30 mg (dose-reduced patients in the 60 mg group) was 0.81 (95% CI: 0.58, 1.13). The 30 mg dose may be the appropriate choice for patients at high-risk for bleeding or for other fragile patients.

The efficacy results for sub-group analyses (with dose reduction as required), including age, body weight, prior stroke or transient ischemic attack (TIA), diabetes, and P-gp inhibitors were generally consistent with the primary efficacy results for the overall population in the study. However, there was a statistically significant interaction between the effects of Lixiana versus warfarin on the primary efficacy endpoint based on renal function (HR was 1.41 in favour of warfarin for the subgroup with creatinine clearance (CrCL) ≥80 mL/min) and geographical regions (HR was 1.47 in favour of warfarin for Western Europe). This observation could be due in part to excellent performance of warfarin in these patients. As a result of lower rates of major bleeding in patients with higher levels of CrCL, the net clinical outcome (stroke, major bleeding or death) remained favourable for Lixiana compared to warfarin. A post-authorization study is planned to investigate if improved protective effects against stroke could possibly be achieved by using a higher dose of edoxaban (75 mg) in patients with normal kidney function (CrCl >100 mL/min). The results of this study are expected by the end of 2019.

In conclusion, the ENGAGE AF-TIMI 48 study results demonstrated that Lixiana 60 mg once daily and Lixiana 30 mg once daily were non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with AF. Both Lixiana regimens also provided significant reductions in the risk of haemorrhagic stroke, cardiovascular mortality, major bleeding, and intracranial bleeding.

Efficacy in Patients with Venous Thromboembolism

The pivotal HOKUSAI-VTE study (a randomized, double-blind, matching placebo, parallel group, active-controlled study) randomized 8,292 patients with venous thromboembolism (VTE) to receive initial heparin therapy (enoxaparin or unfractionated heparin for 5-10 days) followed by Lixiana 60 mg once daily or the comparator. In the comparator group, patients received initial heparin therapy concurrently with warfarin, titrated to a target international normalized ratio (INR) of 2.0 to 3.0, followed by warfarin alone. The treatment duration was from 3 months up to 12 months, determined by the investigator based on the patient's clinical features. Patients were excluded if they required thrombectomy, insertion of a caval filter, use of a fibrinolytic agent, had a creatinine clearance <30 mL/min, significant liver disease, or active bleeding. The primary efficacy endpoint was the recurrence of symptomatic VTE, defined as the composite of recurrent symptomatic DVT, non-fatal symptomatic PE and fatal PE during the 12-month study period. Secondary efficacy outcomes included the composite clinical outcome of recurrent VTE and all-cause mortality.

Patients in the Lixiana 60 mg treatment group had their dose halved if one or more of the following were present: moderate renal impairment (CrCL 30-50 mL/min); body weight ≤0 kg; concomitant use of specific P-gp inhibitors (verapamil and quinidine or the short-term concomitant administration of azithromycin, clarithromycin, erythromycin, oral itraconazole or oral ketoconazole).

In the HOKUSAI-VTE study, Lixiana was demonstrated to be non-inferior to warfarin for the primary efficacy outcome, recurrent VTE, which occurred in 130 of 4,118 patients (3.2%) in the Lixiana group versus 146 of 4,122 patients (3.5%) in the warfarin group (HR [95% CI]: 0.89 [0.70,1.13]; p <0.0001 for non-inferiority to a pre-specified margin of 1.5). In the warfarin group, the median time in therapeutic range (TTR, INR 2.0 to 3.0) was 63.5%. For patients with PE (with or without DVT), 47 (2.8%) in the Lixiana group and 65 (3.9%) in the warfarin group had a recurrent VTE (HR [95% CI]: 0.73 [0.50, 1.06]). For patients with DVT, 83 (3.4 %) in the Lixiana group and 81 (3.3%) in the warfarin group had a recurrent VTE (HR [95% CI]: 1.02 [0.75, 1.38]). For patients who received the 30 mg dose (predominantly patients with a body weight of &le:60 kg or moderate renal impairment) 22 (3.0%) in the Lixiana group and 30 (4.2%) in the warfarin group had a recurrent VTE.

The rate of the composite endpoint of recurrent VTE and all-cause mortality was the same between the treatment groups (5.5%) (HR: [95% CI]:1.00 [0.83, 1.20]). But a numerical increase in the MI rate was noted in the Lixiana group (20/4,118) compared to warfarin group (13/4,122) for the on-treatment study period. This increase in MI was not observed in the ENGAGE AF-TIMI 48 study where the HR of 0.94 favours the Lixiana 60 mg regimen. Overall the annual incidence of MI was very low and the HR was not statistically significant. In the HOKUSAI-VTE study, the composite endpoint of MACE was 1.2% in the Lixiana group and 1.0% in the warfarin group.

The efficacy results of subgroup analyses, including elderly patients, patients with history of cancer, and patients using concomitant P-gp inhibitors, were generally consistent with the primary efficacy results for the overall population in the study. The HR in the subgroup of patients with CrCL ≥80 mL/min was 1.05 for the Lixiana group compared to the warfarin group. Most importantly, for patients with PE, the patients in the CrCL ≥80 mL/min group performed well and similar to the patients in the warfarin group (HR of 0.99). In addition, VTE was reduced in the Lixiana group by 47% compared to warfarin, in fragile patients (defined as ≥75 years old and/or had body weight ≤50 kg and/or had CrCL ≥30 to ≤50 mL/min). The low rate of recurrent VTE in the Lixiana group (2.5%) and the high rate of recurrent VTE in the warfarin group (4.8%) indicate that these fragile patients are at high risk for recurrent VTE and may benefit from Lixiana therapy.

In conclusion, the HOKUSAI-VTE study results demonstrated that Lixiana 60 mg after an initial heparin course offers non-inferior efficacy with significantly less bleeding compared to well-managed warfarin for the treatment and prevention of recurrent VTE. Due to the design of the HOKUSAI-VTE study and the enrollment of a representative study population including patients with severe PE, these results are generalizable across the broad spectrum of patients with VTE. The HOKUSAI-VTE study data also support the use of Lixiana 30 mg once daily as a clinically useful and important alternative in select higher-risk patients.

Indication

The New Drug Submission for Lixiana was filed with the following indications:

  • Prevention of stroke and systemic embolic events in patients with nonvalvular atrial fibrillation (NVAF).
  • Treatment of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), and the prevention of recurrent VTE.

The final recommended indication is as follows:

Lixiana (edoxaban ) is indicated for:

  • Prevention of stroke and systemic embolic events in patients with atrial fibrillation, in whom anticoagulation is appropriate.
  • Treatment of venous thromboembolism (VTE) (deep vein thrombosis [DVT], pulmonary embolism [PE]) and the prevention of recurrent DVT and PE.

For more information, refer to the Lixiana Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The ENGAGE AF-TIMI 48 and HOKUSAI-VTE studies (described in the Clinical Efficacy section) provided the primary source of data for the safety analyses. Safety data from other clinical studies and from post-marketing data were considered supportive.

In the pivotal, double-blind, randomized ENGAGE AF-TIMI 48 study, a total of 21,026 patients with documented atrial fibrillation (AF) received at least one dose of Lixiana 60 mg (number of patients [n] = 7,012), Lixiana 30 mg (n = 7,002), or warfarin (n = 7,012). The duration of Lixiana exposure was ≥360 days for 11,479 patients and ≥720 days for 10,075 patients. Median study drug exposure for the Lixiana and warfarin treatment group was 2.5 years. Adverse reactions were experienced by 2,256 (32.2%) of the patients treated with Lixiana 60 mg (30 mg dose-reduced). The most common adverse reactions reported were anemia (5.2%), abnormal liver function test (4.8%), rash (4.2%), cutaneous soft tissue haemorrhage (3.8%), lower gastrointestinal (GI) haemorrhage (2.7%), epistaxis (2.6%), macroscopic hematuria/urethral (1.9%), and upper GI haemorrhage (1.2%). The site of major bleeds was mostly in the GI tract, followed by intracranial, and intraocular. There were more major GI bleeds in the Lixiana 60 mg (30 mg dose-reduced) group than the warfarin group (1.5% and 1.2% per year, respectively). A higher proportion of Lixiana-treated patients reported anemia-related events: 8.2% (578/7012) of the patients treated with Lixiana 60 mg (30 mg dose-reduced) as compared to 5.6% (396/7012) of warfarin-treated patients. Similarly, more anemia and anemia-related events were reported to be serious or severe for the Lixiana 60 mg (30 mg dose-reduced) group (1.4%) compared to the warfarin group (0.7%). The majority of the bleeding events that occurred in patients treated with Lixiana 60 mg (30 mg dose-reduced) with either serious or severe anemia/anemia-related events were from the GI tract.

In the ENGAGE AF-TIMI 48 study, Lixiana demonstrated superiority compared with warfarin in reducing bleeding events and cardiovascular (CV) mortality. The superior safety profile of fewer bleeding events compared with warfarin was demonstrated for all categories of bleeding events including major bleeds, intracerebral hemorrhage (ICH), fatal bleeds, life-threatening bleeds, clinically relevant non-major (CRNM) bleeds, or any confirmed bleed. Fewer Lixiana-treated patients died from any cause than warfarin-treated patients. The annualized rates of major bleeding (primary safety endpoint) in the Lixiana 60 mg and warfarin groups were 2.75% and 3.43% per year, respectively (HR 0.80, 95% CI: 0.71, 0.91; p = 0.0009) and 1.61% per year with Lixiana 30 mg (HR 0.47; 95% CI: 0.41, 0.55; p<0.0001). Annualized event rates for major plus CRNM bleeding in the Lixiana 60 mg, Lixiana 30 mg, and warfarin groups were 11.1%, 8.0%, and 13.0%, respectively.

In the pivotal double-blind randomized HOKUSAI-VTE study, patients with acute, symptomatic DVT involving the popliteal, femoral or iliac veins, or PE requiring anticoagulant therapy were treated with Lixiana (n = 4,118) or warfarin (n = 4,122) after a heparin-based initial treatment of ≥5 days. These 8,240 patients comprised the safety population. The median time on treatment was 8.8 months in both groups. The duration of drug exposure for Lixiana was ≤6 months for 1,561 (37.9%) of the patients, >6 months for 2,557 (62.1%) of the patients and 12 months for 1,661 (40.3%) of the patients. Adverse reactions were experienced by 1,249 (30.3%) of the patients treated with Lixiana 60 mg (30 mg dose-reduced). The most common treatment-emergent adverse drug reactions were vaginal haemorrhage (9.0%), and abnormal liver function test (7.8%), cutaneous soft tissue haemorrhage (5.9%), epistaxis (4.7%), rash (3.6), lower GI haemorrhage (3.4%), oral/pharyngeal haemorrhage (3.4%), puncture site haemorrhage (1.4%), macroscopic hematuria/urethral (2.2%), and anemia (1.7%).

Lixiana compared favourably to warfarin with regard to the primary safety endpoint of clinically relevant bleeding events in patients with acute VTE (DVT and/or PE). The Lixiana 60 mg (30 mg dose-reduced) regimen was demonstrated to be superior to warfarin for the primary safety endpoint, which occurred in 349 of 4,118 patients (8.5%) in the Lixiana group and in 423 of 4,122 patients (10.3%) in the warfarin group (HR, 0.81; 95% CI: 0.71-0.94; p = 0.004 for superiority). Superiority for bleeding was also demonstrated for the Lixiana 30 mg (dose-reduced patients in the 60 mg group) (HR, 0.62; 95% CI: 0.44-0.86). The risk reduction with Lixiana was demonstrated consistently across all pre-specified bleeding categories. Lixiana patients had numerically less fatal bleeding, less fatal and non-fatal ICH bleeding, and less critical site bleeding events compared to warfarin patients.

As in the ENGAGE AF-TIMI 48 study, numerically higher rates of GI tract and vaginal bleeding events were noted in the Lixiana group. In a recent meta-analysis of the six contemporary randomized clinical studies using NOACs other than Lixiana, GI bleeding was more prominent in the NOAC group vs. warfarin (HR for NOAC = 1.30, 95% CI: 0.97-1.73). A sex-based meta-analysis also recently documented that bleeding complications occurred more frequently in women receiving NOACs for VTE than men.

In conclusion, the submitted data support the safety of Lixiana for the prevention of stroke and systemic embolic events in patients with atrial fibrillation, as well as for the treatment of VTE, and the prevention of recurrent DVT and PE. The ENGAGE AF-TIMI 48 study provides evidence that the full-dose Lixiana offers a safer alternative to warfarin with at least equal efficacy. The HOKUSAI-VTE study also demonstrated that Lixiana was superior to warfarin with regards to clinically relevant bleeding, and especially those more severe and fatal bleeding complications (such as intracranial) associated with standard warfarin VTE anticoagulant therapy (8.5% Lixiana, 10.3% warfarin; HR = 0.81; 95% CI: 0.71-0.94; p = 0.004 for superiority). Overall Lixiana has been shown to be non-inferior to warfarin for efficacy for both the atrial fibrillation and the venous thromboembolism indications, but with a lower overall risk of bleeding. Appropriate warnings and precautions are in place in the approved Lixiana Product Monograph to address the identified safety concerns.

For more information, refer to the Lixiana Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

Primary and secondary pharmacodynamic studies showed that edoxaban , the medicinal ingredient of Lixiana, was highly specific for human factor Xa (FXa) and inhibited both free FXa and prothrombinase. edoxaban also inhibited FXa activity. edoxaban prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) of human plasma and was an effective anti-thrombotic compound.

Aside from the expected anticoagulant effects of edoxaban which led to hemorrhagic findings, there were no special hazards identified for humans, except in reproductive and developmental toxicity studies. In rabbits, ≥200 mg/kg/day edoxaban caused maternal and fetal developmental toxicity, including a higher proportion of pregnant females dying or aborting during the study; increased early resorptions, increased post-implantation losses, reduced mean numbers of viable fetuses, and lower mean fetal weights compared to controls; and increased incidence of one soft tissues developmental variation of absent or small gallbladder. In rats, 300 mg/kg/day edoxaban caused an increase in fetal mortality. These adverse events were observed at doses at least 20 times higher than at the human therapeutic dose. The Lixiana Product Monograph contains a contraindication statement for pregnancy.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Lixiana Product Monograph. In view of the intended use of Lixiana, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Lixiana Product Monograph to address the identified safety concerns.

For more information, refer to the Lixiana 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 Lixiana 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 36 months is acceptable when the packaged product is stored at controlled room temperature (15°C to 30°C).

Proposed limits of drug-related impurities are considered adequately qualified i.e., within International Council for Harmonisation (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.

The excipients used in the drug product formulation are not of animal or human origin.

 

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