Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors; ATC code: B01AF03 Mechanism of action

Edoxaban is a highly selective, direct and reversible inhibitor of FXa, the serine protease located in the final common pathway of the coagulation cascade. Edoxaban inhibits free FXa, and prothrombinase activity. Inhibition of FXa in the coagulation cascade reduces thrombin generation, prolongs clotting time and reduces the risk of thrombus formation.
Pharmacodynamic effects

Edoxaban produces rapid onset of pharmacodynamic effects within 1 - 2 hours, which corresponds with peak edoxaban exposure (Cmax). The pharmacodynamic effects measured by anti-FXa assay are predictable and correlate with the dose and the concentration of edoxaban. As a result of FXa inhibition, edoxaban also prolongs clotting time in tests such as PT, and aPTT. Changes observed in these clotting tests are expected at the therapeutic dose, however, these changes are small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of edoxaban.

Effects of coagulation markers when switching from rivaroxaban, dabigatran, or apixaban to edoxaban
In clinical pharmacology studies, healthy subjects received rivaroxaban 20 mg once daily, dabigatran 150 mg twice daily, or apixaban 5 mg twice daily, followed by a single dose of edoxaban 60 mg on day 4. The effect on PT and other coagulation biomarkers (e.g. anti-FXa, aPTT) was measured.
Following the switch to edoxaban on day 4 the PT was equivalent to day 3 of rivaroxaban and apixaban. For dabigatran higher aPTT activity was observed after edoxaban administration with prior dabigatran treatment compared to that after treatment with edoxaban alone. This is considered to be due to the carry-over effect of dabigatran treatment, however, this did not lead to a prolongation of bleeding time.
Based on these data, when switching from these anticoagulants to edoxaban, the first dose of edoxaban can be initiated at the time of the next scheduled dose of the previous anticoagulant (see section 4.2).

Clinical efficacy and safety

Prevention of stroke and systemic embolism
The edoxaban clinical programme for atrial fibrillation was designed to demonstrate the efficacy and safety of two dose groups of edoxaban compared to warfarin for the prevention of stroke and systemic embolism in subjects with NVAF and at moderate to high risk of stroke and systemic embolic events (SEE).

In the pivotal ENGAGE AF-TIMI 48 study (an event-driven, Phase 3, multi-centre, randomised, double-blind double-dummy parallel-group study), 21,105 subjects, with a mean congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke (CHADS2) score of 2.8, were randomised to either edoxaban 30 mg once daily treatment group, or edoxaban 60 mg once daily treatment group or warfarin. Subjects in both edoxaban treatment groups had their dose halved if one or more of the following clinical factors were present: moderate renal impairment (CrCl 30 – 50 mL/min), low body weight ( 60 kg) or concomitant use of specific P-gp inhibitors (verapamil, quinidine, dronedarone).

The primary efficacy endpoint was the composite of stroke and SEE. 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; composite of stroke, SEE, and all-cause mortality.

The median study medicinal product exposure for both the edoxaban 60 mg and 30 mg treatment groups was 2.5 years. The median study follow-up for both the edoxaban 60 mg and 30 mg treatment groups was 2.8 years. The median subject-year exposure was 15,471, and 15,840 for the 60 mg and 30 mg treatment groups, respectively; and the median subject-year follow-up was 19,191 and 19,216 for the 60 mg and 30 mg treatment groups, respectively.

In the warfarin group, the median TTR (time in therapeutic range, INR 2.0 to 3.0) was 68.4%.
The main analysis of efficacy was aimed to show the non-inferiority of edoxaban versus warfarin on first stroke or SEE that occurred during treatment or within 3 days from the last dose taken in the modified intention to treat (mITT) population. Edoxaban 60 mg was non-inferior to warfarin for the primary efficacy endpoint of stroke or SEE (upper limit of the 97.5% CI of the hazard ratio (HR) was below the pre-specified non-inferiority margin of 1.38) (Table 4).
Table 4: Strokes and SEE in the ENGAGE AF–TIMI 48 study - mITT, on-treatment Edoxaban 60 mg
Warfarin
Primary endpoint                          (30 mg dose reduced)
(N = 7,012)
(N = 7,012)
First stroke/SEEa n                                                 182                              232 Event rate (%/yr)b                                1.18                             1.50 HR (97.5% CI)                               0.79 (0.63, 0.99) p-value for non-inferiority c
<0.0001
First ischaemic stroke n                                                 135                              144 Event rate (%/yr)b                                0.87                             0.93 HR (95% CI)                                 0.94 (0.75, 1.19)
First haemorrhagic stroke n                                                  40                               76 Event rate (%/yr) b
0.26                             0.49
HR (95% CI)                                 0.53 (0.36, 0.78)
First SEE n (%/yr)a                                       8 (0.05)                         13 (0.08) HR (95% CI)                                 0.62 (0.26, 1.50)
Abbreviations: HR = hazard ratio versus warfarin, CI = confidence interval, n = number of events, mITT = modified intent to treat, N = number of subjects in mITT population, SEE = systemic embolic event, yr = year.
a
A subject can be represented in multiple rows.
b
The event rate (%/yr) is calculated as number of events/subject-year exposure.
c
The two-sided p-value is based on the non-inferiority margin of 1.38.

During the overall study period in the ITT population (analysis set to show superiority), adjudicated stroke or SEE occurred in 296 subjects in the edoxaban 60 mg group (1.57% per year), and 337 subjects in the warfarin group (1.80% per year). Compared to warfarin-treated subjects, the HR in the edoxaban 60 mg group was 0.87 (99% CI: 0.71, 1.07, p = 0.08 for superiority).

In subgroup analyses, for subjects in the 60 mg treatment group who were dose reduced to 30 mg in the ENGAGE AF-TIMI 48 study (for body weight ≤ 60 kg, moderate renal impairment, or concomitant use of P-gp inhibitors), the event rate was: 2.29% per year for the primary endpoint, compared to the event rate of 2.66% per year for the matching subjects in the warfarin group [HR (95% CI): 0.86 (0.66, 1.13)].

The efficacy results for pre-specified major subgroups (with dose reduction as required), including age, body weight, gender, status of renal function, prior stroke or TIA, diabetes and P-gp inhibitors were generally consistent with the primary efficacy results for the overall population studied in the trial.

The HR (edoxaban 60 mg vs. warfarin) for the primary endpoint in the centres with a lower average time of INR in the therapeutic range (INR TTR) for warfarin was 0.73 – 0.80 for the lowest 3 quartiles (INR TTR ≤ 57.7% to ≤ 73.9%). It was 1.07 in centres with the best control of warfarin therapy (4 th quartile with > 73.9% of INR values in the therapeutic range).
There was a statistically significant interaction between the effect of edoxaban versus warfarin on the main study outcome (stroke/SEE) and renal function (p-value 0.0042; mITT, overall study period).

Table 5 shows ischaemic strokes/SEE by CrCl category in NVAF patients in ENGAGE AF-TIMI 48.
There is a decreasing event rate at increasing CrCl in both treatment groups.
Table 5: Number of ischaemic strokes/SEE by CrCl category in the ENGAGE AF-TIMI 48, mITT analysis set overall study
CrCl              Edoxaban 60 mg                      Warfarin subgroup               (N = 7,012)                     (N = 7,012)
(mL/min) n     Number        Event        n     Number         Event       HR (95% CI) of events      rate              of events       rate
(%/year)                           (%/year)
≥ 30 to ≤ 50     1,302       63         1.89      1,305       67          2.05      0.93 (0.66, 1.31) > 50 to ≤ 70     2,093       85         1.51      2,106       95          1.70      0.88 (0.66, 1.18) > 70 to ≤ 90     1,661       45         0.99      1,703       50          1.08      0.92 (0.61, 1.37) > 90 to ≤ 110     927        27         1.08       960        26          0.98      1.10 (0.64, 1.89) > 110 to ≤ 130 497           14         1.01       469        10          0.78      1.27 (0.57, 2.85) > 130             462        10         0.78       418         3          0.25             --* Abbreviations: CrCl = creatinine clearance; N = number of subjects in mITT population overall study period; mITT = modified intent to treat; n = number of patients in subgroup; HR = hazard ratio versus warfarin; CI = confidence interval.
*HR not computed if number of events < 5 in one treatment group.

Within renal function subgroups, results for the secondary efficacy endpoints were consistent with those for the primary endpoint.

Superiority testing was performed on the ITT overall study period.
Stroke and SEE occurred in fewer subjects in the edoxaban 60 mg treatment group than in the warfarin group (1.57% and 1.80% per year, respectively), with a HR of 0.87 (99% CI: 0.71, 1.07, p = 0.0807 for superiority).

The pre-specified composite endpoints for the comparison of the edoxaban 60 mg treatment group to warfarin for stroke, SEE, and CV mortality HR (99% CI) was 0.87 (0.76, 0.99), MACE 0.89 (0.78, 1.00), and stroke, SEE, and all-cause mortality 0.90 (0.80, 1.01).

The results for all-cause mortality (adjudicated deaths) in the ENGAGE AF-TIMI 48 study were 769 (3.99% per year) for subjects taking edoxaban 60 mg (30 mg dose reduced) as opposed to 836 (4.35% per year) for warfarin [HR (95% CI): 0.91 (0.83, 1.01)].
All-cause mortality (adjudicated deaths) per renal subgroups (edoxaban vs. warfarin): CrCl 30 to ≤ 50 mL/min [HR (95% CI): 0.81 (0.68, 0.97)]; CrCl > 50 to < 80 mL/min [HR (95% CI): 0.87 (0.75, 1.02)]; CrCl ≥ 80 mL/min [HR (95% CI): 1.15 (0.95, 1.40)].

Edoxaban 60 mg (30 mg dose reduced) resulted in a lower rate of cardiovascular mortality compared to warfarin [HR (95% CI): 0.86 (0.77, 0.97)].
Adjudicated efficacy cardiovascular mortality per renal subgroups (edoxaban vs. warfarin): CrCl 30 to ≤ 50 mL/min [HR (95% CI): 0.80 (0.65, 0.99)]; CrCl > 50 to < 80 mL/min [HR (95% CI): 0.75 (0.62, 0.90)]; CrCl ≥ 80 mL/min [HR (95% CI): 1.16 (0.92, 1.46)].

The primary safety endpoint was major bleeding.

There was a significant risk reduction in the edoxaban 60 mg treatment group compared with the warfarin group in major bleeding (2.75%, and 3.43% per year, respectively) [HR (95% CI): 0.80 (0.71,
0.91); p = 0.0009], ICH (0.39%, and 0.85% per year, respectively) [HR (95% CI): 0.47 (0.34, 0.63); p < 0.0001], and other types of bleeding (Table 6).

The reduction in fatal bleeds was also significant for the edoxaban 60 mg treatment group compared with the warfarin group (0.21%, and 0.38%) [HR (95% CI): 0.55 (0.36, 0.84); p = 0.0059 for superiority], primarily because of the reduction in fatal ICH bleeds [HR (95% CI): 0.58 (0.35, 0.95); p = 0.0312].
Table 6: Bleeding events in ENGAGE AF-TIMI 48 study - safety analysis on-treatment Edoxaban 60 mg
Warfarin
(30 mg dose reduced)
(N = 7,012)
(N = 7,012)
Major bleeding n                                                    418                              524 Event rate (%/yr)  a
2.75                            3.43
HR (95% CI)                                   0.80 (0.71, 0.91) p-value                                             0.0009
ICH b
 n                                                61                              132 Event rate (%/yr) a
0.39                            0.85
HR (95% CI)                              0.47 (0.34, 0.63)
Fatal bleeding n                                                     32                              59 Event rate (%/yr)  a
0.21                            0.38
HR (95% CI)                                   0.55 (0.36, 0.84)
CRNM Bleeding n                                                   1,214                            1,396 Event rate (%/yr)a                                   8.67                            10.15 HR (95% CI)                                   0.86 (0.80, 0.93)
Any confirmed bleedingc n                                                   1,865                            2,114 Event rate (%/yr)a                                  14.15                            16.40 HR (95% CI)                                   0.87 (0.82, 0.92)
Abbreviations: ICH = intracranial haemorrhage, HR = hazard ratio versus warfarin, CI = confidence interval, CRNM = clinically relevant non-major, n = number of subjects with events, N = number of subjects in safety population, yr = year.
a
The event rate (%/yr) is calculated as number of events/subject-year exposure.
b
ICH includes primary haemorrhagic stroke, subarachnoid haemorrhage, epi-/subdural haemorrhage, and ischaemic stroke with major haemorrhagic conversion. All ICHs reported on the adjudicated cerebrovascular and non-intracranial bleed electronic case report forms (eCRF) confirmed by the adjudicators are included in ICH counts.
c
'Any confirmed bleeding includes those that the adjudicator defined as clinically overt.

Note: A subject can be included in multiple sub-categories if he/she had an event for those categories.
The first event of each category is included in the analysis.

Tables 7, 8 and 9 show major, fatal and intracranial bleedings, respectively, by CrCl category in NVAF patients in ENGAGE AF-TIMI 48. There is a decreasing event rate at increasing CrCl in both treatment groups.
Table 7: Number of major bleeding events by CrCl category in ENGAGE AF-TIMI 48, safety analysis on-treatmenta
CrCl               Edoxaban 60 mg                   Warfarin subgroup                (N = 7,012)                  (N = 7,012)
(mL/min) n     Number       Event      n     Number       Event        HR (95% CI) of events     rate            of events     rate
(%/year)                       (%/year)
≥ 30 to ≤ 50     1,302       96        3.91    1,305      128         5.23     0.75 (0.58, 0.98) > 50 to ≤ 70     2,093      148        3.31    2,106      171         3.77     0.88 (0.71, 1.10) > 70 to ≤ 90     1,661      108        2.88    1,703      119         3.08     0.93 (0.72, 1.21) > 90 to ≤ 110     927        29        1.33     960       56          2.48     0.54 (0.34, 0.84) > 110 to ≤ 130    497        20        1.70     469       24          2.14     0.79 (0.44, 1.42) > 130             462        13        1.18     418       21          2.08     0.58 (0.29, 1.15) 
Table 8: Number of fatal bleeding events by CrCl category in ENGAGE AF-TIMI 48, safety analysis on-treatmenta
CrCl               Edoxaban 60 mg                   Warfarin subgroup                (N = 7,012)                  (N = 7,012)
(mL/min) n     Number       Event      n     Number       Event        HR (95% CI) of events     rate            of events     rate
(%/year)                       (%/year)
≥ 30 to ≤ 50     1,302        9        0.36    1,305       18         0.72     0.51 (0.23, 1.14) > 50 to ≤ 70     2,093        8        0.18    2,106       23         0.50     0.35 (0.16, 0.79) > 70 to ≤ 90     1,661       10        0.26    1,703        9         0.23     1.14 (0.46, 2.82) > 90 to ≤ 110     927         2        0.09     960         3         0.13            --* > 110 to ≤ 130    497         1        0.08     469        5          0.44            --* > 130             462         2        0.18     418         0         0.00            --* 
Table 9: Number of intracranial bleeding events by CrCl category in ENGAGE AF-TIMI 48, safety analysis on-treatmenta
CrCl               Edoxaban 60 mg                   Warfarin subgroup                (N = 7,012)                  (N = 7,012)
(mL/min) n     Number       Event      n     Number       Event        HR (95% CI) of events     rate            of events     rate
(%/year)                       (%/year)
≥ 30 to ≤ 50     1,302       16        0.64    1,305       35         1.40     0.45 (0.25, 0.81) > 50 to ≤ 70     2,093       19        0.42    2,106       51         1.10     0.38 (0.22, 0.64) > 70 to ≤ 90     1,661       17        0.44    1,703       35         0.89     0.50 (0.28, 0.89) > 90 to ≤ 110     927         5        0.23     960         6         0.26     0.87 (0.27, 2.86) > 110 to ≤ 130    497         2        0.17     469        3          0.26            --* > 130             462         1        0.09     418         1         0.10            --* 
Abbreviations: N = number of subjects in mITT population overall study period; mITT = modified intent to treat; n = number of patients in subgroup; HR = hazard ratio versus warfarin; CI = confidence interval.
*HR not computed if number of events < 5 in one treatment group.
a
On-Treatment: Time from first dose of study medicinal product to last dose plus 3 days.
In subgroup analyses, for subjects in the 60 mg treatment group who were dose reduced to 30 mg in the ENGAGE AF-TIMI 48 study for body weight ≤ 60 kg, moderate renal impairment, or concomitant use of P-gp inhibitors, 104 (3.05% per year) of edoxaban 30 mg dose reduced subjects and 166 (4.85% per year) of warfarin dose reduced subjects had a major bleeding event [HR (95% CI): 0.63 (0.50, 0.81)].

In the ENGAGE AF-TIMI 48 study there was a significant improvement in net clinical outcome (first stroke, SEE, major bleed, or all-cause mortality; mITT population, overall study period) in favour of edoxaban, HR (95% CI): 0.89 (0.83, 0.96); p = 0.0024, when edoxaban 60 mg treatment group was compared to warfarin.

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTE) The edoxaban clinical programme for VTE was designed to demonstrate the efficacy and safety of edoxaban in the treatment of DVT and PE, and the prevention of recurrent DVT and PE.

In the pivotal Hokusai-VTE study, 8,292 subjects were randomised to receive initial heparin therapy (enoxaparin or unfractionated heparin) followed by edoxaban 60 mg once daily or the comparator. In the comparator arm, subjects received initial heparin therapy concurrently with warfarin, titrated to a target 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.

The majority of edoxaban treated patients were Caucasians (69.6%) and Asians (21.0%); 3.8% were Black, and 5.3% were categorised as Other race.

The duration of therapy was at least 3 months for 3,718 (91.6%) edoxaban subjects versus 3,727 (91.4%) of warfarin subjects; at least 6 months for 3,495 (86.1%) of edoxaban subjects versus 3,491 (85.6%) of warfarin subjects; and 12 months for 1,643 (40.5%) edoxaban subjects versus 1,659 (40.4%) of warfarin subjects.

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 in subjects during the 12-month study period. Secondary efficacy outcomes included the composite clinical outcome of recurrent VTE and all-cause mortality.

Edoxaban 30 mg once daily was used for subjects with one or more of the following clinical factors: moderate renal impairment (CrCl 30 - 50 mL/min); body weight ≤ 60 kg; concomitant use of specific P-gp inhibitors.

In the Hokusai-VTE study (Table 10) edoxaban was demonstrated to be non-inferior to warfarin for the primary efficacy outcome, recurrent VTE, which occurred in 130 of 4,118 subjects (3.2%) in the edoxaban group versus 146 of 4,122 subjects (3.5%) in the warfarin group [HR (95% CI): 0.89 (0.70, 1.13); p < 0.0001 for non-inferiority]. In the warfarin group, the median TTR (INR 2.0 to 3.0) was 65.6%. For subjects presenting with PE (with or without DVT), 47 (2.8%) of edoxaban and 65 (3.9%) of warfarin subjects had a recurrent VTE [HR (95% CI): 0.73 (0.50, 1.06)].
Table 10: Efficacy results from the Hokusai-VTE study - mITT population, overall study period Primary endpointa                Edoxaban 60 mg                                       Edoxaban vs (30 mg dose reduced)            Warfarin                Warfarin
(N = 4,118)               (N = 4,122)            HR (95% CI)b p-valuec
All subjects with                    130 (3.2)                 146 (3.5)           0.89 (0.70, 1.13) symptomatic recurrent                                                              p-value < 0.0001 VTEc, n (%)                                                                        (non-inferiority) PE with or without DVT              73 (1.8)                  83 (2.0) Fatal PE or death where           24 (0.6)                  24 (0.6)
PE cannot be ruled out
Non-fatal PE                      49 (1.2)                  59 (1.4)
DVT only                            57 (1.4)                  63 (1.5) Abbreviations: CI = confidence interval; DVT = deep vein thrombosis; mITT = modified intent-to- treat; HR = Hazard ratio vs. warfarin; n = number of subjects with events; N = number of subjects in mITT population; PE = pulmonary embolism; VTE = venous thromboembolic events.
a
The primary efficacy endpoint is adjudicated symptomatic recurrent VTE (i.e., the composite endpoint of DVT, non-fatal PE, and fatal PE).
b
The HR, two-sided CI are based on the Cox proportional hazards regression model including treatment and the following randomisation stratification factors as covariates: presenting diagnosis (PE with or without DVT, DVT only), baseline risk factors (temporary factors, all others), and the need for 30 mg edoxaban/edoxaban placebo dose at randomisation (yes/no).
c
The p-value is for the pre-defined non-inferiority margin of 1.5.

For the subjects who were dose reduced to 30 mg (predominantly low body weight or renal function) 15 (2.1%) edoxaban and 22 (3.1%) of warfarin subjects had a recurrent VTE [HR (95% CI): 0.69 (0.36, 1.34)].

The secondary composite endpoint of recurrent VTE and all-cause mortality occurred in 138 subjects (3.4%) in the edoxaban group and 158 subjects (3.9%) in the warfarin group [HR (95% CI): 0.87 (0.70, 1.10)].

The results for all-cause mortality (adjudicated deaths) in Hokusai-VTE were 136 (3.3%) for subjects taking edoxaban 60 mg (30 mg dose reduced) as opposed to 130 (3.2%) for warfarin.

In a pre-specified subgroup analysis of PE subjects 447 (30.6%) and 483 (32.2%) of edoxaban and warfarin treated subjects, respectively, were identified as having PE and N-terminal pro–B-type natriuretic peptide (NT-proBNP) ≥ 500 pg/mL. The primary efficacy outcome occurred in 14 (3.1%) and 30 (6.2%) of edoxaban and warfarin subjects, respectively [HR (95% CI): 0.50 (0.26, 0.94)].

The efficacy results for pre-specified major subgroups (with dose reduction as required), including age, body weight, gender and status of renal function were consistent with the primary efficacy results for the overall population studied in the trial.

The primary safety endpoint was clinically relevant bleeding (major or clinically relevant non-major).

Table 11 summarises adjudicated bleeding events for the safety analysis set on-treatment period.
There was a significant risk reduction in the edoxaban group compared with warfarin for the primary safety endpoint of clinically relevant bleeding, a composite of major bleeding or clinically relevant non-major (CRNM) bleeding, which occurred in 349 of 4,118 subjects (8.5%) in the edoxaban group and in 423 of 4,122 subjects (10.3%) in the warfarin group [HR (95% CI): 0.81 (0.71, 0.94); p = 0.004 for superiority].
Table 11: Bleeding events in Hokusai-VTE study - safety analysis on-treatment perioda Edoxaban 60 mg
Warfarin
(30 mg dose reduced)
(N = 4,122)
(N = 4,118)
Clinically relevant bleeding
(Major and CRNM)b, n (%) n                                                 349 (8.5)                       423 (10.3) HR (95% CI)                                   0.81 (0.71, 0.94) p-value                                    0.004 (for superiority)
Major bleeding n (%) n                                                  56 (1.4)                        66 (1.6) HR (95% CI)                                   0.84 (0.59, 1.21)
ICH fatal                                        0                             6 (0.1) ICH non-fatal                                 5 (0.1)                         12 (0.3) CRNM bleeding n                                                 298 (7.2)                        368 (8.9) HR (95% CI)                                   0.80 (0.68, 0.93)
All bleeding n                                                895 (21.7)                      1,056 (25.6) HR (95% CI)                                   0.82 (0.75, 0.90)
Abbreviations: ICH = intracranial haemorrhage, HR = hazard ratio vs. warfarin; CI = confidence interval; N = number of subjects in safety population; n = number of events; CRNM = clinically relevant non-major a
On-treatment period: time from first dose of study medicinal product to last dose plus 3 days.
b
Primary safety endpoint: clinically relevant bleeding (composite of major and clinically relevant non-major bleeding).

In subgroup analyses, for subjects who were dose reduced to 30 mg in the Hokusai-VTE study for body weight ≤ 60 kg, moderate renal impairment, or concomitant use of P-gp inhibitors, 58 (7.9%) of edoxaban 30 mg dose reduced subjects and 92 (12.8%) of warfarin subjects had a major bleeding or CRNM event [HR (95%): 0.62 (0.44, 0.86)].

In the Hokusai-VTE study the net clinical outcome (recurrent VTE, major bleed, or all-cause mortality; mITT population, overall study period) HR (95% CI) was 1.00 (0.85, 1.18) when edoxaban was compared to warfarin.

Prevention of stroke and systemic embolism in NVAF patients with high CrCl (CrCl > 100 mL/min) A dedicated randomised, double-blind trial (E314) was conducted in 607 NVAF patients with high CrCl (CrCl > 100 mL/min as measured by the Cockcroft-Gault formula) with the primary aim to evaluate the PK/PD of an edoxaban 60 mg once daily vs 75 mg once daily regimen. In addition to the primary PK/PD endpoint, the study included the evaluation of clinical endpoints of stroke and bleeding over a 12-months treatment period.

An edoxaban dose of 75 mg QD in the high CrCl sub-group (> 100 mL/min) provided an ~25% increase in exposure as compared to an edoxaban dose of 60 mg QD as predicted.

The number of subjects experiencing the adjudicated composite endpoint of stroke/transient ischaemic attack (TIA)/systemic embolic event (SEE) efficacy events was limited and included 2 stroke events in the edoxaban 60 mg group (0.7%; 95% CI: 0.1% to 2.4%) and 3 stroke events in the edoxaban 75 mg group (1%; 95% CI: 0.2% to 2.9%).
Adjudicated major bleeding events occurred in 2 (0.7%; 95% CI: 0.1% to 2.4%) subjects in the edoxaban 60 mg group compared to 3 (1.0%; 95% CI: 0.2% to 2.9%) subjects in the edoxaban 75 mg group. Of the 2 major bleeds in the edoxaban 60 mg group, one was in a critical area/organ (intraocular) and the other major bleed was an intramuscular bleed. Of the 3 major bleeds in the edoxaban 75 mg group, 2 occurred in a critical area/organ (intracerebral/ 1 fatal outcome) and 1 was an upper gastrointestinal (GI) bleed (life-threatening). There were also 9 (3%) clinically relevant non- major (CRNM) bleedings in the edoxaban 60 mg group and 7 (2.3%) CRNM bleedings in the edoxaban 75 mg group.

In addition to the E314 clinical trial, a prospective, multinational, multi-centre, post authorisation, observational study (ETNA-AF) was conducted in 10 European countries and has included 13,980 subjects. Within this population 1,826 had a CrCl > 100 ml/min and received edoxaban 60 mg in accordance with dosing criteria outlined in the SmPC. The annual rates of the composite of ischaemic stroke or systemic embolism were 0.39%/y, and major bleeding events occurred in 0.73%/y.

Given the totality of the data from ENGAGE AF, E314 and ETNA-AF, patients with NVAF and high CrCl treated with edoxaban 60 mg are expected to have an annual rate of ischaemic stroke/systemic embolism ≤ 1%. Increasing the dose above 60 mg in NVAF patients with high CrCl (> 100 mL/min) is not expected to provide more protection against stroke and can be associated with increased adverse events. As such, an edoxaban 60 mg once daily regimen is recommended in these patients after a careful evaluation of the individual thromboembolic and bleeding risk (see section 4.4.).

Patients undergoing cardioversion
A multicentre, prospective, randomised, open-label study with blinded endpoint evaluation (ENSURE- AF) was conducted which randomised 2199 subjects (oral anticoagulant naïve and pre-treated) with NVAF scheduled for cardioversion, to compare edoxaban 60 mg once daily with enoxaparin/warfarin to maintain a therapeutic INR of 2.0 to 3.0 (randomised 1:1), mean TTR on warfarin was 70.8%. A total of 2149 subjects were treated with either edoxaban (N = 1067) or enoxaparin/warfarin (N = 1082). Subjects in the edoxaban treatment group received 30 mg once daily if one or more of the following clinical factors were present: moderate renal impairment (CrCl 30 – 50 mL/min), low body weight ( 60 kg) or concomitant use of specific P-gp inhibitors. The majority of subjects in the edoxaban and warfarin groups had cardioversion performed (83.7% and 78.9%, respectively) or were auto-converted (6.6% and 8.6%, respectively). TEE-guided (within 3 days of initiation) or conventional cardioversion (at least 21 days of pre-treatment) was employed. Subjects were maintained on treatment for 28 days post cardioversion.

The primary efficacy outcome consisted of a composite of all stroke, SEE, MI and CV mortality. A total of 5 (0.5%, 95% CI 0.15% - 1.06%) events occurred in subjects in the edoxaban group (N = 1095) and 11 (1.0%, 95% CI 0.50% - 1.78%) events in the warfarin group (N = 1104); odds ratio (OR) 0.46 (95% CI 0.12 - 1.43); ITT analysis set overall study period with mean duration of 66 days.

The primary safety outcome was a composite of major and CRNM bleeding. A total of 16 (1.5%, 95% CI 0.86% - 2.42%) events occurred in subjects in the edoxaban (N = 1067) group and 11 (1.0%, 95% CI 0.51% - 1.81%) events in the warfarin (N = 1082) group; OR 1.48 (95% CI 0.64 - 3.55); safety analysis set on-treatment period.

This exploratory study showed low rates of major and CRNM bleeding and thromboembolism in the two treatment groups in the setting of cardioversion.

Paediatric population
The safety, efficacy, pharmacokinetics and pharmacodynamics of edoxaban in paediatric subjects from birth to 18 years of age with VTE and cardiac diseases at risk of thrombotic events were evaluated in two Phase 3 studies , Hosukai VTE OPEDIATRICS and ENNOBLE-ATE(see section 4.2).
The pivotal paediatric study, Hokusai VTE PEDIATRICS, is described below.

The pivotal study (Hokusai VTE PEDIATRICS) was a Phase 3, open-label, randomised, multi-centre, controlled study to evaluate the pharmacokinetics and pharmacodynamics of edoxaban and compare the efficacy and safety of edoxaban with standard of care (control group) anticoagulant therapy in paediatric subjects from birth to less than 18 years of age with confirmed venous thromboembolism (VTE).

The primary efficacy endpoint was the composite endpoint of symptomatic recurrent venous thromboembolic disease, death as result of VTE, and no change or extension of thrombotic burden during the first 3-month period (intended duration of treatment was 6 to 12 weeks for paediatric patients from birth to less than 6 months of age).

The edoxaban doses tested in the Hokusai VTE PEDIATRICS were established according to age and weight. Dose reductions were recommended based on clinical factors, including renal function and concomitant use of P-gp inhibitors (Table 12).

Table 12: Edoxaban dose tested in the Hokusai VTE PEDIATRICS study
Age at Date of Body Weight              Dose       Dose (Suspension)a              Dose Reductionb Consent                                 (Tablet) a

12 to <18 yrs. ≥60 kg                   60 mg      NA                              45 mg ≥30 and <60 kg           45 mg      NA                              30 mg <5th percentile for age 30 mg       NA                              NA 
6 to <12 yrs.     <60 kg; dosed based on    NA            1.2 mg/kg                0.8 mg/kg mg/kg                                   (maximum 45 mg)          (maximum 45 mg) 2 to <6 yrs.      Dosed based on mg/kg      NA            1.4 mg/kg                0.7 mg/kg
(maximum 45 mg)          (maximum: 24 mg)

6 months to       Dosed based on mg/kg      NA            1.5 mg/kg                0.75 mg/kg <2 yrs.                                                   (maximum 45 mg)          (maximum: 24 mg) 
>28 days to       Dosed based on mg/kg      NA            0.8 mg/kg                0.4 mg/kg <6 months                                                 (maximum 12 mg)          (maximum 6 mg) 
Birth              Dosed based on mg/kg NA                0.4 mg/kg                0.4 mg/kg (38 weeks of                                              (maximum 6 mg)           (maximum 6 mg) gestation) to
≤28 days
NA = not applicable; yrs. = years a
Subjects were instructed to take edoxaban (tablets or granules) orally once a day, at the same time every day, with or without food. Tablets were to be swallowed with a glass of water.
b based on clinical factors, including renal function (moderate-severe renal impairment with estimated glomerular filtration rate (eGFR) 10-20, 20-35, 30-50 mL/min/1.73m2 for subjects aged >4 and ≤8 weeks, >8 weeks and ≤2 years, >2 and ≤12 years; eGFR 35-55 mL/min/1.73m 2 for boys >12 and <18 years; and eGFR 30-50 mL/min/1.73m2 for girls >12 and <18 years) and concomitant use of P-gp inhibitors (e.g.: ciclosporin, dronedarone, erythromycin, ketoconazole).

A total of 290 subjects were randomised into the study: 147 in the edoxaban group and 143 in the standard of care control group, of which 286 subjects took at least one dose of study medication (mITT); 145 subjects in the edoxaban group and 141 subjects in the control group. Approximately half of the overall subjects were male (52.4%) and the majority of subjects treated were white (177 [61.9%] subjects). The mean weight was 45.35 kg and the mean BMI was 20.4 kg/m 2. In total, 167 (58.4%) subjects were in the 12 to <18 years cohort, 44 (15.4%) subjects were in the 6 to <12 years cohort, 31 (10.8%) subjects were in the 2 to <6 years cohort, 28 (9.8%) subjects were in the 6 months to <2 years cohort, and 16 (5.6%) subjects were in the 0 to <6 months cohort. A total of, 28 (19.3%) children in the edoxaban group and 31 (22.0%) children in the control group had a medical history of neoplasms. The type of index event was DVT with or without PE in 125 (86.2%) of 145 children of the edoxaban group and 121 (85.8%) of 141 children in the control group, while the remaining cases, 20 (13.8%) in the edoxaban group and 20 (14.2%) in the control group were PE without DVT. DVTs were most frequently localized in the lower extremities (50 (34.5%) and 44 (31.2%) cases in the edoxaban and control groups, respectively), upper extremities (22 (15.2%) vs 24 (17.0%)), and cerebral venous sinus (27 (18.6%) vs.
21 (14.9%)).

The HR for the edoxaban group versus the standard of care control group was 1.01 (95% CI: 0.59 to 1.72). The upper bound of the 95% CI (1.72) exceeded the predefined non-inferiority margin of 1.5, hence the non-inferiority of edoxaban versus standard of care was not confirmed (see Table 13).

Table 13: Adjudicated Composite Primary Efficacy Endpoint – Main Treatment Period (mITT Analysis Set)
Edoxaban                    Standard of care
(N = 145)                      (N = 141)
Subjects with events (n, %)                       26 (17.9)                      31 (22.0) Symptomatic recurrent VTE (n, %)                   5 (3.4)                        2 (1.4) PE with or without DVT (n, %)                      0                            1 (0.7) Fatal PE (n, %)                              0                               0 Nonfatal PE (n, %)                           0                             1(0.7) DVT only (n, %)                                  5 (3.4)                        1 (0.7) Fatal DVT (n, %)                             0                               0 Nonfatal DVT (n, %)                        4 (2.8)                           0 Unexplained death which                    1 (0.7)                        1 (0.7) VTE cannot be ruled out (n,
%)
No change or extension of thrombotic              21 (14.5)                      29 (20.6) burden based on imaging (n, %)
Hazard ratioa                                       1.01                             - 2-sided 95% CI for hazard ratio               (0.59, 1.72)                         -
CI = confidence interval; DVT = deep vein thrombosis; mITT = Modified Intent-to-Treat; PE = pulmonary embolism; VTE = venous thromboembolism.
a
Edoxaban-to-standard of care hazard ratio.
Note: Adjudicated composite primary efficacy endpoint includes symptomatic recurrent VTE, death as a result of VTE, and no change or extension of thrombotic burden based on imaging.
Note: Main Treatment Period is defined as from randomization to Month 3 Visit + 3 days.

The primary safety endpoint was a combination of major and CRNM bleeding events, occurring during the Main Treatment Period (3 months + 3 days).

The safety results were comparable between the edoxaban and standard of care control groups. A total of 3 (2.1%) subjects in the edoxaban group and 5 (3.5%) subjects in the control group experienced at least 1 adjudicated confirmed major and CRNM bleeding event during the Main Treatment Period and On- Treatment [HR (95% CI): 0.60 (0.139, 2.597)].

Pharmacokinetic Properties

     5.2     Pharmacokinetic properties

Absorption

Edoxaban is absorbed with peak plasma concentrations within 1 - 2 hours following oral administration of edoxaban tablets. The absolute bioavailability is approximately 62%. Food increases peak exposure of edoxaban tablets to a varying extent, but has minimal effect on total exposure.
Edoxaban was administered with or without food in the ENGAGE AF-TIMI 48 and the Hokusai-VTE studies as well as paediatric efficacy and safety studies. Edoxaban is poorly soluble at pH of 6.0 or higher. Co-administration of proton- pump inhibitors had no relevant impact on edoxaban exposure.

In a study with 30 healthy subjects, both mean AUC and Cmax values for 60 mg edoxaban administered as a crushed tablet orally mixed in apple puree or via nasogastric tube suspended in water were bioequivalent to the intact tablet. Given the predictable, dose-proportional pharmacokinetic profile of edoxaban, the bioavailability results from this study are likely applicable to lower edoxaban doses.

Distribution

Disposition is biphasic. The volume of distribution is 107 (19.9) L mean (SD).
In vitro plasma protein binding is approximately 55%. There is no clinically relevant accumulation of edoxaban (accumulation ratio 1.14) with once daily dosing. Steady state concentrations are achieved within 3 days.

Biotransformation

Unchanged edoxaban is the predominant form in plasma. Edoxaban is metabolised via hydrolysis (mediated by carboxylesterase 1), conjugation or oxidation by CYP3A4/5 (< 10%). Edoxaban has three active metabolites, the predominant metabolite (M-4), formed by hydrolysis, is active and reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5%. Edoxaban is a substrate for the efflux transporter P-gp, but not a substrate for uptake transporters such as organic anion transporter polypeptide OATP1B1, organic anion transporters OAT1 or OAT3 or organic cation transporter OCT2. Its active metabolite is a substrate for OATP1B1.

Elimination

In healthy subjects, the total clearance is estimated as 22 (± 3) L/hour; 50% is renally cleared (11 L/hour). Renal clearance accounts for approximately 35% of the administered dose. Metabolism and biliary/intestinal excretion account for the remaining clearance. The t½ for oral administration is 10 - 14 hours.

Linearity/non-linearity

Edoxaban displays approximately dose-proportional pharmacokinetics for doses of 15 mg to 60 mg in healthy subjects.

Special populations

Elderly
After taking renal function and body weight into account, age had no additional clinically significant effect on edoxaban pharmacokinetics in a population pharmacokinetic analysis of the pivotal Phase 3 study in NVAF (ENGAGE AF-TIMI 48).

Renal impairment
The plasma AUCs for subjects with mild (CrCl > 50 - 80 mL/min), moderate (CrCl 30 - 50 mL/min) and severe (CrCl < 30 mL/min but not undergoing dialysis) renal impairment were increased by 32%, 74%, and 72%, respectively, relative to subjects with normal renal function. In patients with renal impairment the metabolite profile changes and a higher quantity of active metabolites are formed.
There is a linear correlation between edoxaban plasma concentration and anti-FXa activity regardless of renal function.
Subjects with ESRD undergoing peritoneal dialysis had 93% higher total exposure compared with healthy subjects.
Population PK modeling indicates that exposure approximately doubles in patients with severe renal impairment (CrCl 15 – 29 mL/min) relative to patients with normal renal function.

Table 12 below shows the edoxaban anti-FXa activity by CrCl category for each indication.

Table 14: Edoxaban anti-FXa activity by CrCl
Edoxaban             CrCl                Edoxaban                    Edoxaban dose             (mL/min)          Anti-FXa activity           Anti-FXa activity post-dose (IU/mL)1          pre-dose (IU/mL)2
Median [2.5 – 97.5% range]
Prevention of stroke and systemic embolism: NVAF
30 mg once daily ≥ 30 to ≤ 50                      2.92                      0.53 [0.33 – 5.88]             [0.11 – 2.06]
60 mg once daily * > 50 to ≤ 70                    4.52                      0.83 [0.38 – 7.64]             [0.16 – 2.61]
> 70 to ≤ 90                  4.12                      0.68
[0.19 – 7.55]             [0.05 – 2.33]
> 90 to ≤ 110                 3.82                      0.60
[0.36 – 7.39]             [0.14 – 3.57]
> 110 to ≤ 130                3.16                      0.41
[0.28 – 6.71]             [0.15 – 1.51]
> 130                         2.76                      0.45
[0.12 – 6.10]             [0.00 – 3.10]
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTE) 30 mg once daily ≥ 30 to ≤ 50                      2.21                      0.22 [0.14 – 4.47]             [0.00 – 1.09]
60 mg once daily * > 50 to ≤ 70                    3.42                      0.34 [0.19 – 6.13]             [0.00 – 3.10]
> 70 to ≤ 90                  2.97                      0.24
[0.24 – 5.82]             [0.00 – 1.77]
> 90 to ≤ 110                 2.82                      0.20
[0.14 – 5.31]             [0.00 – 2.52]
> 110 to ≤ 130                2.64                      0.17
[0.13 – 5.57]             [0.00 – 1.86]
> 130                         2.39                      0.13
[0.10 – 4.92]             [0.00 – 2.43]
*
Dose reduction to 30 mg for low body weight ≤ 60 kg or specific concomitant P-gp inhibitors 1
Post-dose is equivalent to Cmax (post-dose samples were drawn 1 – 3 hours after edoxaban administration)
2
Pre-dose is equivalent to Cmin

Although treatment with edoxaban does not require routine monitoring, the effect on anticoagulation can be estimated by a calibrated quantitative anti-FXa assay which may be useful in exceptional situations where knowledge of edoxaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery (see also section 4.4).

A 4 hour haemodialysis session reduced total edoxaban exposures by less than 9%.
 Hepatic impairment
Patients with mild or moderate hepatic impairment exhibited comparable pharmacokinetics and pharmacodynamics to their matched healthy control group. Edoxaban has not been studied in patients with severe hepatic impairment (see section 4.2).

Gender
After accounting for body weight, gender had no additional clinically significant effect on edoxaban pharmacokinetics in a population pharmacokinetic analysis of the Phase 3 study in NVAF (ENGAGE AF-TIMI 48).

Ethnic origin
In a population pharmacokinetic analysis of the ENGAGE AF-TIMI 48 study, peak and total exposure in Asian patients and non-Asian patients were comparable.

Paediatric population
The pharmacokinetics of edoxaban was evaluated in 208 paediatric subjects across 3 clinical studies (Hokusai VTE PEDIATRICS, ENNOBLE-ATE, and a single-dose PK/PD study) using a population pharmacokinetic (PopPK) model. The pharmacokinetic data of 141 paediatric subjects enrolled in Hokusai VTE PEDIATRICS and ENNOBLE-ATE were included in the PopPK analysis. The exposure of edoxaban in paediatric subjects tended to be within the range of exposures observed in adult patients, but there was a 20-30% underexposure in adolescents aged 12 to <18 years compared to adults who received the edoxaban 60 mg tablets. In Hokusai VTE PEDIATRICS and ENNOBLE-ATE, the observed geometric mean trough exposures of edoxaban in the paediatric population were 7.8 ng/mL in subjects 0 to <6 months of age (N = 9), 8.6 ng/mL in subjects 6 months to <2 years of age (N = 19), 7.4 ng/mL in subjects 2 to <6 years of age (N = 36), 13.7 ng/mL in subjects 6 to <12 years of age (N = 38), and 10.8 ng/mL in subjects 12 to <18 years of age (N = 39).

Body weight
In a population pharmacokinetic analysis of the ENGAGE AF-TIMI 48 study in NVAF, C max and AUC in patients with median low body weight (55 kg) were increased by 40% and 13%, respectively, as compared with patients with median high body weight (84 kg). In Phase 3 clinical studies (both NVAF and VTE indications) patients with body weight ≤ 60 kg had a 50% edoxaban dose reduction and had similar efficacy and less bleeding when compared to warfarin.

Pharmocokinetic/pharmacodynamic relationship(s)
PT, INR, aPTT and anti-FXa correlate linearly with edoxaban concentrations. in adults. A linear correlation was also observed between anti-FXa activities and the plasma concentrations of edoxaban in paediatric patients from birth to 18 years of age. Overall, the PK-PD relationships were similar between paediatric patients from birth to 18 years of age and adult VTE patients. However, the variability in PD generated considerable uncertainty in the assessment of this relationship.