Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antithrombotic agents direct factor Xa inhibitors, ATC code: B01AF02 

Mechanism of action
Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. It does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development. Preclinical studies of apixaban in animal models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis at doses that preserved haemostasis.

Pharmacodynamic effects
The pharmacodynamic effects of apixaban are reflective of the mechanism of action (FXa inhibition).
As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability. They are not recommended to assess the pharmacodynamic effects of apixaban. In the thrombin generation assay, apixaban reduced endogenous thrombin potential, a measure of thrombin generation in human plasma.


Apixaban also demonstrates anti-Factor Xa activity as evident by reduction in Factor Xa enzyme activity in multiple commercial anti-Factor Xa kits, however results differ across kits. Data from clinical studies are only available for the Rotachrom® Heparin chromogenic assay. anti-Factor Xa activity exhibits a close direct linear relationship with apixaban plasma concentration, reaching maximum values at the time of apixaban peak plasma concentrations. The relationship between apixaban plasma concentration and anti-Factor Xa activity is approximately linear over a wide dose range of apixaban.


Table 3 below shows the predicted steady state exposure and anti-Factor Xa activity for each indication.
In patients taking apixaban for the prevention of VTE following hip or knee replacement surgery, the results demonstrate a less than 1.6-fold fluctuation in peak-to-trough levels. In nonvalvular atrial fibrillation patients taking apixaban for the prevention of stroke and systemic embolism, the results demonstrate a less than 1.7-fold fluctuation in peak-to-trough levels. In patients taking apixaban for the treatment of DVT and PE or prevention of recurrent DVT and PE, the results demonstrate a less than 2.2-fold fluctuation in peak-to-trough levels.



Table 3: Predicted apixaban steady-state exposure and anti- Factor Xa activity 

Apix.                            Apix.           Apix. Anti- Factor   Apix. Anti- Factor Cmax (ng/mL)                     Cmin (ng/mL)            Xa Activity Max      Xa Activity Min (IU/mL)              (IU/mL)
Median [5th, 95th Percentile]
Prevention of VTE: elective hip or knee replacement surgery
2.5 mg twice daily                    77 [41, 146]                     51 [23, 109]           1.3 [0.67, 2.4]     0.84 [0.37, 1.8]
Prevention of stroke and systemic embolism: NVAF
2.5 mg twice daily*                  123 [69, 221]                     79 [34, 162]            1.8 [1.0, 3.3]      1.2 [0.51, 2.4]
5 mg twice daily                     171 [91, 321]                    103 [41, 230]            2.6 [1.4, 4.8]      1.5 [0.61, 3.4] Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) 2.5 mg twice daily                    67 [30, 153]                      32 [11, 90]           1.0 [0.46, 2.5]     0.49 [0.17, 1.4]
5 mg twice daily                     132 [59, 302]                     63 [22, 177]           2.1 [0.91, 5.2]      1.0 [0.33, 2.9] 10 mg twice daily                    251 [111, 572]                   120 [41, 335]           4.2 [1.8, 10.8]      1.9 [0.64, 5.8] * Dose adjusted population based on 2 of 3 dose reduction criteria in the ARISTOTLE study.


Although treatment with apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery.

Clinical efficacy and safety

Prevention of VTE (VTEp): elective hip or knee replacement surgery
The apixaban clinical program was designed to demonstrate the efficacy and safety of apixaban for the prevention of VTE in a broad range of adult patients undergoing elective hip or knee replacement.
A total of 8,464 patients were randomised in two pivotal, double-blind, multi-national studies, comparing apixaban 2.5 mg given orally twice daily (4,236 patients) or enoxaparin 40 mg once daily (4,228 patients). Included in this total were 1,262 patients (618 in the apixaban group) of age 75 or older, 1,004 patients (499 in the apixaban group) with low body weight (≤ 60 kg), 1,495 patients (743 in the apixaban group) with BMI ≥ 33 kg/m2, and 415 patients (203 in the apixaban group) with moderate renal impairment.

The ADVANCE-3 study included 5,407 patients undergoing elective hip replacement, and the ADVANCE-2 study included 3,057 patients undergoing elective knee replacement. Subjects received either apixaban 2.5 mg given orally twice daily (po bid) or enoxaparin 40 mg administered subcutaneously once daily (sc od). The first dose of apixaban was given 12 to 24 hours post-surgery, 
whereas enoxaparin was started 9 to 15 hours prior to surgery. Both apixaban and enoxaparin were given for 32-38 days in the ADVANCE-3 study and for 10-14 days in the ADVANCE-2 study.

Based on patient medical history in the studied population of ADVANCE-3 and ADVANCE-2 (8,464 patients), 46% had hypertension, 10% had hyperlipidemia, 9% had diabetes, and 8% had coronary artery disease.

Apixaban demonstrated a statistically superior reduction in the primary endpoint, a composite of all VTE/all cause death, and in the Major VTE endpoint, a composite of proximal DVT, non-fatal PE, and VTE-related death, compared to enoxaparin in both elective hip or knee replacement surgery (see Table 4).

Table 4: Efficacy Results from Pivotal phase III Studies
Study                                  ADVANCE-3 (hip)                    ADVANCE-2 (knee) Study treatment                 Apixaban     Enoxaparin    p-       Apixaban   Enoxaparin   p- Dose                           2.5 mg po       40 mg sc   value    2.5 mg po    40 mg sc   value Duration of treatment          twice daily    once daily           twice daily once daily 35 ± 3 d       35 ± 3 d             12 ± 2 d    12 ± 2 d
Total VTE/all-cause death
Number of                     27/1949        74/1917              147/976        243/997 events/subjects                1.39%          3.86%               15.06%         24.37% <0.000                                  <0.000
Event Rate
1                                      1
Relative Risk                   0.36                                 0.62 95% CI                      (0.22, 0.54)                         (0.51, 0.74) Major VTE
Number of                     10/2199        25/2195              13/1195        26/1199 events/subjects                0.45%          1.14%                1.09%          2.17% Event Rate                                             0.0107                                  0.0373 Relative Risk                   0.40                                 0.50 95% CI                      (0.15, 0.80)                         (0.26, 0.97) 
The safety endpoints of major bleeding, the composite of major and clinically relevant non-major (CRNM) bleeding, and all bleeding showed similar rates for patients treated with apixaban 2.5 mg compared with enoxaparin 40 mg (see Table 5). All the bleeding criteria included surgical site bleeding.

Table 5: Bleeding Results from Pivotal phase III Studies*
ADVANCE-3                          ADVANCE-2
Apixaban        Enoxaparin         Apixaban     Enoxaparin
2.5 mg po         40 mg sc         2.5 mg po    40 mg sc once twice daily35     once daily        twice daily       daily
±3d            35 ± 3 d          12 ± 2 d      12 ± 2 d
All treated           n = 2673         n = 2659          n = 1501       n = 1508 Treatment Period  1

Major                 22 (0.8%)        18 (0.7%)          9 (0.6%)     14 (0.9%) Fatal                     0               0                  0             0 Major + CRNM         129 (4.8%)       134 (5.0%)         53 (3.5%)     72 (4.8%) All                 313 (11.7%)      334 (12.6%)       104 (6.9%)     126 (8.4%) Post-surgery treatment period 2
Major                  9 (0.3%)        11 (0.4%)          4 (0.3%)      9 (0.6%) Fatal                     0               0                  0             0 Major + CRNM          96 (3.6%)       115 (4.3%)         41 (2.7%)     56 (3.7%) All                  261 (9.8%)      293 (11.0%)         89 (5.9%)    103 (6.8%) * All the bleeding criteria included surgical site bleeding
1 Includes events occurring after first dose of enoxaparin (pre-surgery) 2 Includes events occurring after first dose of apixaban (post-surgery)


The overall incidences of adverse reactions of bleeding, anaemia and abnormalities of transaminases (e.g., ALT levels) were numerically lower in patients on apixaban compared to enoxaparin in the phase II and phase III studies in elective hip and knee replacement surgery.

In the knee replacement surgery study during the intended treatment period, in the apixaban arm 4 cases of PE were diagnosed against no cases in the enoxaparin arm. No explanation can be given to this higher number of PE.

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) A total of 23,799 patients were randomised in the clinical program (ARISTOTLE: apixaban versus warfarin, AVERROES: apixaban versus ASA) including 11,927 randomised to apixaban. The program was designed to demonstrate the efficacy and safety of apixaban for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF) and one or more additional risk factors, such as:
• prior stroke or transient ischaemic attack (TIA)
• age ≥ 75 years
• hypertension
• diabetes mellitus
• symptomatic heart failure (NYHA Class ≥ II)

ARISTOTLE study
In the ARISTOTLE study a total of 18,201 patients were randomised to double-blind treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [4.7%], see section 4.2) or warfarin (target INR range 2.0-3.0), patients were exposed to study active substance for a mean of 20 months.
The mean age was 69.1 years, the mean CHADS2 score was 2.1 and 18.9 % of patients had prior stroke or TIA.
In the study, apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke (haemorrhagic or ischaemic) and systemic embolism (see Table 6) compared with warfarin.

Table 6: Efficacy Outcomes in Patients with Atrial Fibrillation in the ARISTOTLE Study Apixaban Warfarin              Hazard Ratio
N=9120        N=9081            (95% CI)     p-value n (%/yr)     n (%/yr)
Stroke or systemic embolism 212 (1.27) 265 (1.60) 0.79 (0.66, 0.95) 0.0114 Stroke
Ischaemic or unspecified 162 (0.97) 175 (1.05) 0.92 (0.74, 1.13)
Haemorrhagic               40 (0.24)     78 (0.47) 0.51 (0.35, 0.75)
Systemic embolism             15 (0.09)     17 (0.10) 0.87 (0.44, 1.75) 
For patients randomised to warfarin, the median percentage of time in therapeutic range (TTR) (INR 2- 3) was 66%.
Apixaban showed a reduction of stroke and systemic embolism compared to warfarin across the different levels of center TTR; within the highest quartile of TTR according to center, the hazard ratio for apixaban vs warfarin was 0.73 (95% CI, 0.38, 1.40).

Key secondary endpoints of major bleeding and all cause death were tested in a pre-specified hierarchical testing strategy to control the overall type 1 error in the trial. Statistically significant superiority was also achieved in the key secondary endpoints of both major bleeding and all-cause death (see Table 7). With improving monitoring of INR the observed benefits of apixaban compared to warfarin regarding all cause death diminish.

Table 7: Secondary Endpoints in Patients with Atrial Fibrillation in the ARISTOTLE Study Apixaban                 Warfarin               Hazard Ratio           p-value N = 9088                N = 9052                 (95% CI) n (%/year)             n (%/year)
     Bleeding Outcomes
Major*                       327 (2.13)        462 (3.09)          0.69 (0.60, 0.80)      < 0.0001 Fatal                     10 (0.06)         37 (0.24)
Intracranial              52 (0.33)        122 (0.80)
Major +                      613 (4.07)        877 (6.01)          0.68 (0.61, 0.75)      < 0.0001 CRNM†
All                          2356 (18.1)      3060 (25.8)          0.71 (0.68, 0.75)      < 0.0001 Other Endpoints
All-cause death              603 (3.52)        669 (3.94)          0.89 (0.80, 1.00)       0.0465 Myocardial              90 (0.53)              102 (0.61)       0.88 (0.66, 1.17) infarction
*Major bleeding defined per International Society on Thrombosis and Haemostasis (ISTH) criteria.
† Clinically Relevant Non-Major


The overall discontinuation rate due to adverse reactions was 1.8% for apixaban and 2.6% for warfarin in the ARISTOTLE study.

The efficacy results for prespecified subgroups, including CHADS2 score, age, body weight, gender, status of renal function, prior stroke or TIA and diabetes were consistent with the primary efficacy results for the overall population studied in the trial.

The incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal bleeding) was 0.76%/year with apixaban and 0.86%/year with warfarin.

The major bleeding results for prespecified subgroups including CHADS2 score, age, body weight, gender, status of renal function, prior stroke or TIA and diabetes were consistent with the results for the overall population studied in the trial.

AVERROES study
In the AVERROES study a total of 5,598 patients considered to be unsuitable for VKA by the investigators were randomised to treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [6.4%], see section 4.2) or ASA. ASA was given at a once daily dose of 81 mg (64%), 162 (26.9%), 243 (2.1%), or 324 mg (6.6%) at the discretion of the investigator. Patients were exposed to study active substance for a mean of 14 months. The mean age was 69.9 years, the mean CHADS2 score was 2.0 and 13.6% of patients had prior stroke or TIA.

Common reasons for unsuitability for VKA therapy in the AVERROES study included unable/unlikely to obtain INRs at requested intervals (42.6%), patient refused treatment with VKA (37.4%), CHADS2 score = 1 and physician did not recommend VKA (21.3%), patient could not be relied on to adhere to VKA medication instruction (15.0%), and difficulty/expected difficulty in contacting patient in case of urgent dose change (11.7%).

AVERROES was stopped early based on a recommendation by the independent Data Monitoring Committee due to clear evidence of reduction of stroke and systemic embolism with an acceptable safety profile.
The overall discontinuation rate due to adverse reactions was 1.5% for apixaban and 1.3% for ASA in the AVERROES study.

In the study, apixaban achieved statistically significant superiority in the primary endpoint of prevention of stroke (haemorrhagic, ischaemic or unspecified) or systemic embolism (see Table 8) compared to ASA.

Table 8: Key Efficacy Outcomes in Patients with Atrial Fibrillation in the AVERROES Study 


                                     Apixaban        ASA                 Hazard Ratio
N = 2807        N = 2791            (95% CI)              p-value n (%/year)      n (%/year)
Stroke or systemic embolism*       51 (1.62)       113 (3.63)       0.45 (0.32, 0.62)      < 0.0001 Stroke
Ischaemic or unspecified        43 (1.37)       97 (3.11)           0.44 (0.31, 0.63) Haemorrhagic                    6 (0.19)        9 (0.28)            0.67 (0.24, 1.88) Systemic embolism               2 (0.06)        13 (0.41)           0.15 (0.03, 0.68) Stroke, systemic embolism,      132 (4.21)      197 (6.35)          0.66 (0.53, 0.83)      0.003 MI, or vascular death*†
Myocardial infarction           24 (0.76)       28 (0.89)           0.86 (0.50, 1.48) Vascular Death                  84 (2.65)       96 (3.03)           0.87 (0.65, 1.17) All-cause death†                111 (3.51)      140 (4.42)          0.79 (0.62, 1.02)      0.068 * Assessed by sequential testing strategy designed to control the overall type I error in the trial.
† Secondary endpoint.


There was no statistically significant difference in the incidence of major bleeding between apixaban and ASA (see Table 9).


Table 9: Bleeding Events in Patients with Atrial Fibrillation in the AVERROES Study Apixaban                ASA                    Hazard Ratio            p-value N = 2798                N = 2780               (95%CI) n(%/year)               n (%/year)
Major*                45 (1.41)               29 (0.92)              1.54 (0.96, 2.45)       0.0716 Fatal, n              5 (0.16)                5 (0.16)
Intracranial, n       11 (0.34)               11 (0.35)
Major + CRNM†         140 (4.46)              101 (3.24)             1.38 (1.07, 1.78)       0.0144 All                   325 (10.85)             250 (8.32)             1.30 (1.10, 1.53)       0.0017 *Major bleeding defined per International Society on Thrombosis and Haemostasis (ISTH) criteria.
† Clinically Relevant Non-Major

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) The clinical program (AMPLIFY: apixaban versus enoxaparin/warfarin, AMPLIFY-EXT: apixaban versus placebo) was designed to demonstrate the efficacy and safety of apixaban for the treatment of DVT and/or PE (AMPLIFY), and extended therapy for the prevention of recurrent DVT and/or PE following 6 to 12 months of anticoagulant treatment for DVT and/or PE (AMPLIFY-EXT). Both studies were randomised, parallel-group, double-blind, multinational trials in patients with symptomatic proximal DVT or symptomatic PE. All the key safety and efficacy endpoints were adjudicated by an independent blinded committee.

AMPLIFY study
In the AMPLIFY study a total of 5,395 patients were randomised to treatment with apixaban 10 mg twice daily orally for 7 days followed by apixaban 5 mg twice daily orally for 6 months, or enoxaparin 1 mg/kg twice daily subcutaneously for at least 5 days (until INR≥ 2) and warfarin (target INR range 2.0-3.0) orally for 6 months.

The mean age was 56.9 years and 89.8% of randomised patients had unprovoked VTE events.

For patients randomised to warfarin, the mean percentage of time in therapeutic range (INR 2.0-3.0) was 60.9. Apixaban showed a reduction in recurrent symptomatic VTE or VTE- related death across the different levels of center TTR; within the highest quartile of TTR according to center, the relative risk for apixaban vs enoxaparin/warfarin was 0.79 (95% CI, 0.39, 1.61).

In the study, apixaban was shown to be non-inferior to enoxaparin/warfarin in the combined primary endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related death (see Table 10).

Table 10: Efficacy Results in the AMPLIFY Study
Apixaban        Enoxaparin/Warfari                 Relative Risk n
N=2609                                               (95% CI)
N=2635 n (%) n (%)
VTE or VTE-related           59 (2.3)             71 (2.7)                   0.84 (0.60, 1.18)* death
DVT                    20 (0.7)             33 (1.2)
PE                     27 (1.0)             23 (0.9)
VTE-related            12 (0.4)             15 (0.6) death
VTE or all-cause             84 (3.2)             104 (4.0)                   0.82 (0.61, 1.08) death
VTE or CV-related            61 (2.3)             77 (2.9)                    0.80 (0.57, 1.11) death
VTE, VTE-related             73 (2.8)             118 (4.5)                   0.62 (0.47, 0.83) death, or major bleeding

* Noninferior compared to enoxaparin/warfarin (p-value <0.0001)
Apixaban efficacy in initial treatment of VTE was consistent between patients who were treated for a PE [Relative Risk 0.9; 95% CI (0.5, 1.6)] or DVT [Relative Risk 0.8; 95% CI (0.5, 1.3)]. Efficacy across subgroups, including age, gender, body mass index (BMI), renal function, extent of index PE, location of DVT thrombus, and prior parenteral heparin use was generally consistent.

The primary safety endpoint was major bleeding. In the study, apixaban was statistically superior to enoxaparin/warfarin in the primary safety endpoint [Relative Risk 0.31, 95% confidence interval (0.17, 0.55), P-value <0.0001] (see Table 11).

Table 11: Bleeding Results in the AMPLIFY Study
Apixaban                 Enoxaparin/           Relative Risk
N=2676                    Warfarin               (95% CI) n (%)                 N=2689 n (%)
Major                           15 (0.6)                  49 (1.8)           0.31 (0.17, 0.55) Major + CRNM                    115 (4.3)                 261 (9.7)          0.44 (0.36, 0.55) Minor                          313 (11.7)                505 (18.8)          0.62 (0.54, 0.70) All                            402 (15.0)                676 (25.1)          0.59 (0.53, 0.66) 

The adjudicated major bleeding and CRNM bleeding at any anatomical site were generally lower in the apixaban group as compared to the enoxaparin/warfarin group. Adjudicated ISTH major gastrointestinal bleeding occurred in 6 (0.2%) apixaban-treated patients and 17 (0.6%) enoxaparin/warfarin-treated patients.


AMPLIFY-EXT study
In the AMPLIFY-EXT study a total of 2,482 patients were randomised to treatment with apixaban 2.5 mg twice daily orally, apixaban 5 mg twice daily orally, or placebo for 12 months after completing 6 to 
12 months of initial anticoagulant treatment. Of these, 836 patients (33.7%) participated in the AMPLIFY study prior to enrollment in the AMPLIFY-EXT study.

The mean age was 56.7 years and 91.7% of randomised patients had unprovoked VTE events.

In the study, both doses of apixaban were statistically superior to placebo in the primary endpoint of symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death (see Table 12).


Table 12: Efficacy Results in the AMPLIFY-EXT Study
Apixaban              Apixaban                Placebo                           Relative Risk (95% CI) 2.5 mg                5.0 mg                                            Apix 2.5 mg                    Apix 5.0 mg (N=840)               (N=813)                 (N=829)                    vs. Placebo                    vs. Placebo n (%)
Recurrent                     19 (2.3)               14 (1.7)               77 (9.3)                       0.24                             0.19 VTE or all-
(0.15, 0.40)¥                  (0.11, 0.33)¥ cause death
DVT*                    6 (0.7)                7 (0.9)               53 (6.4) PE*                     7 (0.8)                4 (0.5)               13 (1.6) All-cause               6 (0.7)                3 (0.4)               11 (1.3) death
Recurrent                     14 (1.7)               14 (1.7)               73 (8.8)                       0.19                             0.20 VTE or VTE-
(0.11, 0.33)                    (0.11, 0.34) related death
Recurrent                     14 (1.7)               14 (1.7)               76 (9.2)                       0.18                             0.19 VTE or CV-
(0.10, 0.32)                    (0.11, 0.33) related death
Nonfatal DVT†                  6 (0.7)                8 (1.0)               53 (6.4)                       0.11                             0.15 (0.05, 0.26)                    (0.07, 0.32)
Nonfatal      PE†              8 (1.0)                4 (0.5)               15 (1.8)                       0.51                             0.27 (0.22, 1.21)                    (0.09, 0.80)
VTE-related                    2 (0.2)                3 (0.4)                7 (0.8)                       0.28                             0.45 death
(0.06, 1.37)                    (0.12, 1.71)
¥ p-value <0.0001
* For patients with more than one event contributing to the composite endpoint, only the first event was reported (eg, if a subject experienced both a DVT and then a PE, only the DVT was reported)
† Individual subjects could experience more than one event and be represented in both classifications 

Apixaban efficacy for prevention of a recurrence of a VTE was maintained across subgroups, including age, gender, BMI, and renal function.

The primary safety endpoint was major bleeding during the treatment period. In the study, the incidence in major bleeding for both apixaban doses was not statistically different from placebo. There was no statistically significant difference in the incidence of major + CRNM, minor, and all bleeding between the apixaban 2.5 mg twice daily and placebo treatment groups (see Table 13).

Table 13: Bleeding Results in the AMPLIFY-EXT Study
Apixaban               Apixaban                 Placebo                             Relative Risk (95% CI) 2.5 mg                  5.0 mg                                            Apix 2.5 mg                      Apix 5.0 mg (N=840)                 (N=811)                 (N=826)                    vs. Placebo                       vs. Placebo 
Apixaban           Apixaban        Placebo                Relative Risk (95% CI) n (%)
Major              2 (0.2)           1 (0.1)         4 (0.5)            0.49                  0.25 (0.09, 2.64)         (0.03, 2.24)
Major +            27 (3.2)         35 (4.3)        22 (2.7)            1.20                  1.62 CRNM
(0.69, 2.10)         (0.96, 2.73)
Minor              75 (8.9)         98 (12.1)       58 (7.0)            1.26                  1.70 (0.91, 1.75)         (1.25, 2.31)
All               94 (11.2)      121 (14.9)         74 (9.0)            1.24                  1.65 (0.93, 1.65)         (1.26, 2.16)

Adjudicated ISTH major gastrointestinal bleeding occurred in 1 (0.1%) apixaban-treated patient at the 5 mg twice daily dose, no patients at the 2.5 mg twice daily dose, and 1 (0.1%) placebo-treated patient.

Paediatric Population
There is no authorised paediatric indication (see section 4.2).

Prevention of VTE in paediatric patients with acute lymphoblastic leukaemia or lymphoblastic lymphoma (ALL, LL)
In the PREVAPIX-ALL study, a total of 512 patients age ≥ 1 to < 18 with newly diagnosed ALL or LL, undergoing induction chemotherapy including asparaginase via an indwelling central venous access device, were randomised 1:1 to open-label thromboprophylaxis with apixaban or standard of care (with no systemic anticoagulation). Apixaban was administered according to a fixed-dose, body weight-tiered regimen designed to produce exposures comparable to those seen in adults who received 2.5 mg twice daily (see Table 14). Apixaban was provided as a 2.5 mg tablet, 0.5 mg tablet, or
0.4 mg/mL oral solution. The median duration of exposure in the apixaban arm was 25 days.

Table 14: Apixaban dosing in the PREVAPIX-ALL study
Weight Range                   Dose schedule
6 to < 10.5 kg                        0.5 mg twice daily
10.5 to < 18 kg                       1 mg twice daily
18 to < 25 kg                         1.5 mg twice daily
25 to < 35 kg                         2 mg twice daily
≥ 35 kg                            2.5 mg twice daily

The primary efficacy endpoint was a composite of adjudicated symptomatic and asymptomatic non- fatal deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, and venous thromboembolism-related death. The incidence of the primary efficacy endpoint was 31 (12.1%) in the apixaban arm versus 45 (17.6%) in the standard of care arm. The relative risk reduction did not achieve significance.

Safety endpoints were adjudicated according to ISTH criteria. The primary safety endpoint, major bleeding, occurred in 0.8% of patients in each treatment arm. CRNM bleeding occurred in 11 patients (4.3%) in the apixaban arm and 3 patients (1.2%) in the standard of care arm. The most common CRNM bleeding event contributing to the treatment difference was mild to moderate intensity epistaxis. Minor bleeding events occurred in 37 patients in the apixaban arm (14.5%) and 20 patients (7.8%) in the standard of care arm.

Prevention of thromboembolism (TE) in paediatric patients with congenital or acquired heart disease SAXOPHONE was a randomised 2:1 open-label, multi-center comparative study of patients 28 days to < 18 years of age with congenital or acquired heart disease who require anticoagulation. Patients received either apixaban or standard of care thromboprophylaxis with a vitamin K antagonist or low molecular weight heparin. Apixaban was administered according to a fixed-dose, body weight-tiered regimen designed to produce exposures comparable to those seen in adults who received a dose of 5 mg twice daily (see Table 15). Apixaban was provided as a 5 mg tablet, 0.5 mg tablet, or 0.4 mg/mL oral solution. The mean duration of exposure in the apixaban arm was 331 days.

Table 15: Apixaban dosing in the SAXOPHONE study
Weight Range                    Dose schedule
6 to < 9 kg                 1 mg twice daily
9 to < 12 kg                1.5 mg twice daily
12 to < 18 kg                 2 mg twice daily
18 to < 25 kg                 3 mg twice daily
25 to < 35 kg                 4 mg twice daily
≥ 35 kg                   5 mg twice daily

The primary safety endpoint, a composite of adjudicated ISTH defined major and CRNM bleeding, occurred in 1 (0.8%) of 126 patients in the apixaban arm and 3 (4.8%) of 62 patients in the standard of care arm. The secondary safety endpoints of adjudicated major, CRNM, and all bleeding events were similar in incidence across the two treatment arms. The secondary safety endpoint of drug discontinuation due to adverse event, intolerability, or bleeding was reported in 7 (5.6%) subjects in the apixaban arm and 1 (1.6%) subject in the standard of care arm. No patients in either treatment arm experienced a thromboembolic event. There were no deaths in either treatment arm.

This study was prospectively designed for descriptive efficacy and safety because of the expected low incidence of TE and bleeding events in this population. Due to the observed low incidence of TE in this study a definitive risk benefit assessment could not be established.
The European Medicines Agency has deferred the obligation to submit the results of studies for the treatment of venous thromboembolism with apixaban in one or more subsets of the paediatric population (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is rapidly absorbed with maximum concentrations (Cmax) appearing 3 to 4 hours after tablet intake. Intake with food does not affect apixaban AUC or Cmax at the 10 mg dose. Apixaban can be taken with or without food.

Apixaban demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral doses up to 10 mg. At doses ≥ 25 mg apixaban displays dissolution limited absorption with decreased bioavailability. Apixaban exposure parameters exhibit low to moderate variability reflected by a within- subject and inter-subject variability of ~20% CV and ~30% CV, respectively.

Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL of water, exposure was comparable to exposure after oral administration of 2 whole 5 mg tablets.
Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets with 30 g of apple puree, the Cmax and AUC were 21% and 16% lower, respectively, when compared to administration of 2 whole 5 mg tablets. The reduction in exposure is not considered clinically relevant.



Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of G5W and delivered via a nasogastric tube, exposure was similar to exposure seen in other clinical studies involving healthy subjects receiving a single oral 5 mg apixaban tablet dose.

Given the predictable, dose-proportional pharmacokinetic profile of apixaban, the bioavailability results from the conducted studies are applicable to lower apixaban doses.


Distribution
Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 litres.

Biotransformation and elimination

Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, approximately 25% was recovered as metabolites, with the majority recovered in faeces. Renal excretion of apixaban accounts for approximately 27% of total clearance. Additional contributions from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, respectively.

Apixaban has a total clearance of about 3.3 L/h and a half-life of approximately 12 hours.

O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is metabolised mainly via CYP3A4/5 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. Unchanged apixaban is the major active substance -related component in human plasma with no active circulating metabolites present. Apixaban is a substrate of transport proteins, P-gp and breast cancer resistance protein (BCRP).

Elderly

Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 32% higher and no difference in Cmax.


Renal impairment
There was no impact of impaired renal function on peak concentration of apixaban. There was an increase in apixaban exposure correlated to decrease in renal function, as assessed via measured creatinine clearance. In individuals with mild (creatinine clearance 51-80 mL/min), moderate (creatinine clearance 30-50 mL/min) and severe (creatinine clearance 15-29 mL/min) renal impairment, apixaban plasma concentrations (AUC) were increased 16, 29, and 44% respectively, compared to individuals with normal creatinine clearance. Renal impairment had no evident effect on the relationship between apixaban plasma concentration and anti-Factor Xa activity.

In subjects with end-stage renal disease (ESRD), the AUC of apixaban was increased by 36% when a single dose of apixaban 5 mg was administered immediately after haemodialysis, compared to that seen in subjects with normal renal function. Haemodialysis, started two hours after administration of a single dose of apixaban 5 mg, decreased apixaban AUC by 14% in these ESRD subjects, corresponding to an apixaban dialysis clearance of 18 mL/min. Therefore, haemodialysis is unlikely to be an effective means of managing apixaban overdose.

Hepatic impairment
In a study comparing 8 subjects with mild hepatic impairment, Child-Pugh A score 5 (n = 6) and score 6 (n = 2), and 8 subjects with moderate hepatic impairment. Child-Pugh B score 7 (n = 6) and score 8 (n = 2), to 16 healthy control subjects, the single-dose pharmacokinetics and pharmacodynamics of apixaban 5 mg were not altered in subjects with hepatic impairment. Changes in anti-Factor Xa activity and INR were comparable between subjects with mild to moderate hepatic impairment and healthy subjects.


Gender
Exposure to apixaban was approximately 18% higher in females than in males.



Ethnic origin and race
The results across phase 1 studies showed no discernible difference in apixaban pharmacokinetics between White/Caucasian, Asian and Black/African American subjects. Findings from a population pharmacokinetic analysis in patients who received apixaban were generally consistent with the phase 1 results.

Body weight
Compared to apixaban exposure in subjects with body weight of 65 to 85 kg, body weight > 120 kg was associated with approximately 30% lower exposure and body weight < 50 kg was associated with approximately 30% higher exposure.

Pharmacokinetic/pharmacodynamic relationship
The pharmacokinetic /pharmacodynamic (PK/PD) relationship between apixaban plasma concentration and several PD endpoints (anti-Factor Xa activity, INR, PT, aPTT) has been evaluated after administration of a wide range of doses (0.5 – 50 mg). The relationship between apixaban plasma concentration and anti-Factor Xa activity was best described by a linear model. The PK/PD relationship observed in patients was consistent with that established in healthy subjects.