Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF01 
Mechanism of action
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.

Pharmacodynamic effects
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations (r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results.
The readout for PT is to be done in seconds, because the INR is only calibrated and validated for coumarins and cannot be used for any other anticoagulant.
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95 percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for 15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15 to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from 14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s.
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e. at the time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough (16 - 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 to 26 s.
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC (Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to 
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation than the 4-factor PCC (see section 4.9).
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in routine clinical practice. However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-factor Xa tests (see section 5.2).

Paediatric population
PT (neoplastin reagent), aPTT, and anti-Xa assay (with a calibrated quantitative test) display a close correlation to plasma concentrations in children. The correlation between anti-Xa to plasma concentrations is linear with a slope close to 1. Individual discrepancies with higher or lower anti-Xa values as compared to the corresponding plasma concentrations may occur. There is no need for routine monitoring of coagulation parameters during clinical treatment with rivaroxaban. However, if clinically indicated, rivaroxaban concentrations can be measured by calibrated quantitative anti-Factor Xa tests in mcg/L (see Table 8 in section 5.2 for ranges of observed rivaroxaban plasma concentrations in children). The lower limit of quantifications must be considered when the anti-Xa test is used to quantify plasma concentrations of rivaroxaban in children. No threshold for efficacy or safety events has been established.

Clinical efficacy and safety
Treatment of VTE and prevention of VTE recurrence in paediatric patients A total of 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in 6 open-label, multicentre paediatric studies. Body weight-adjusted dosing in patients from birth to less than 18 years resulted in rivaroxaban exposure similar to that observed in adult DVT patients treated with rivaroxaban 20 mg once daily as confirmed in the phase III study (see section 5.2).

The EINSTEIN Junior phase III study was a randomised, active-controlled, open-label multicentre clinical study in 500 paediatric patients (aged from birth to < 18 years) with confirmed acute VTE.
There were 276 children aged 12 to < 18 years, 101 children aged 6 to < 12 years, 69 children aged 2 to < 6 years, and 54 children aged < 2 years.

Index VTE was classified as either central venous catheter-related VTE (CVC-VTE; 90/335 patients in the rivaroxaban group, 37/165 patients in the comparator group), cerebral vein and sinus thrombosis (CVST; 74/335 patients in the rivaroxaban group, 43/165 patients in the comparator group), and all others including DVT and PE (non-CVC-VTE; 171/335 patients in the rivaroxaban group, 85/165 patients in the comparator group). The most common presentation of index thrombosis in children aged 12 to < 18 years was non-CVC-VTE in 211 (76.4%); in children aged 6 to < 12 years and aged 2 to < 6 years was CVST in 48 (47.5%) and 35 (50.7%), respectively; and in children aged < 2 years was CVC-VTE in 37 (68.5%). There were no children < 6 months with CVST in the rivaroxaban group. 22 of the patients with CVST had a CNS infection (13 patients in the rivaroxaban group and 9 patients in comparator group).

VTE was provoked by persistent, transient, or both persistent and transient risk factors in 438 (87.6%) children.

Patients received initial treatment with therapeutic doses of UFH, LMWH, or fondaparinux for at least 5 days, and were randomised 2:1 to receive either body weight-adjusted doses of rivaroxaban or comparator group (heparins, VKA) for a main study treatment period of 3 months (1 month for children < 2 years with CVC-VTE). At the end of the main study treatment period, the diagnostic imaging test, which was obtained at baseline, was repeated, if clinically feasible. The study treatment could be stopped at this point, or at the discretion of the Investigator continued for up to 12 months (for children < 2 years with CVC-VTE up to 3 months) in total.

The primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was the composite of major bleeding and clinically relevant non-major bleeding (CRNMB). All efficacy and 
safety outcomes were centrally adjudicated by an independent committee blinded for treatment allocation. The efficacy and safety results are shown in Tables 6 and 7 below.

Recurrent VTEs occurred in the rivaroxaban group in 4 of 335 patients and in the comparator group in 5 of 165 patients. The composite of major bleeding and CRNMB was reported in 10 of 329 patients (3%) treated with rivaroxaban and in 3 of 162 patients (1.9%) treated with comparator. Net clinical benefit (symptomatic recurrent VTE plus major bleeding events) was reported in the rivaroxaban group in 4 of 335 patients and in the comparator group in 7 of 165 patients. Normalisation of the thrombus burden on repeat imaging occurred in 128 of 335 patients with rivaroxaban treatment and in 43 of 165patients in the comparator group. These findings were generally similar among age groups.
There were 119 (36.2%) children with any treatment-emergent bleeding in the rivaroxaban group and 45 (27.8%) children in the comparator group.

Table 6: Efficacy results at the end of the main treatment period
Event                                                   Rivaroxaban               Comparator N=335*                    N=165*
Recurrent VTE (primary efficacy outcome)                4                         5 (1.2%, 95% CI             (3.0%, 95% CI
0.4% – 3.0%)              1.2% - 6.6%)
Composite: Symptomatic recurrent VTE +                  5                         6 asymptomatic deterioration on repeat imaging            (1.5%, 95% CI             (3.6%, 95% CI 0.6% – 3.4%)              1.6% – 7.6%)
Composite: Symptomatic recurrent VTE +                  21                        19 asymptomatic deterioration + no change on repeat        (6.3%, 95% CI             (11.5%, 95% CI imaging                                                 4.0% – 9.2%)              7.3% – 17.4%) Normalisation on repeat imaging                         128                       43 (38.2%, 95% CI            (26.1%, 95% CI
33.0% - 43.5%)            19.8% - 33.0%)
Composite: Symptomatic recurrent VTE + major              4                       7 bleeding (net clinical benefit)                           (1.2%, 95% CI           (4.2%, 95% CI 0.4% - 3.0%)            2.0% - 8.4%)

Fatal or non-fatal pulmonary embolism                     1                       1 (0.3%, 95% CI           (0.6%, 95% CI
0.0% – 1.6%)            0.0% – 3.1%)
*     FAS = full analysis set, all children who were randomised


Table 7: Safety results at the end of the main treatment period
Rivaroxaban            Comparator
N=329*                 N=162*
Composite: Major bleeding + CRNMB (primary safety         10                     3 outcome)                                                  (3.0%, 95% CI          (1.9%, 95% CI 1.6% - 5.5%)           0.5% - 5.3%)
Major bleeding                                            0                      2 (0.0%, 95% CI          (1.2%, 95% CI
0.0% - 1.1%)           0.2% - 4.3%)
Any treatment-emergent bleedings                          119 (36.2%)            45 (27.8%) *     SAF = safety analysis set, all children who were randomised and received at least 1 dose of study medicinal product

The efficacy and safety profile of rivaroxaban was largely similar between the paediatric VTE population and the DVT/PE adult population, however, the proportion of subjects with any bleeding was higher in the paediatric VTE population as compared to the DVT/PE adult population.


Thromboprophylaxis in Paediatric Patients with Congenital Heart Disease after the Fontan Procedure
The efficacy and safety of rivaroxaban for thromboprophylaxis in 110 paediatric patients with congenital heart disease who have undergone the Fontan procedure within 4 months prior to enrolment was evaluated in a prospective, open-label, 2-part (part B active-controlled) study (UNIVERSE) where rivaroxaban was used for thromboprophylaxis for 12 months compared with acetylsalicylic acid in children 2 to 8 years of age with single ventricle physiology who had the Fontan procedure. Patients received either body weight-adjusted doses of rivaroxaban ([n=76], exposures to match that of 10 mg daily dose in adults) or acetylsalicylic acid ([n=34] approximately 5 mg/kg). The dosing studied in UNIVERSE for thromboprophylaxis was thus lower and cannot be derived from the approved paediatric dose for the treatment of VTE.
Few thromboembolic events were observed in the UNIVERSE study (rivaroxaban group (1 [1.6%]) vs acetylsalicylic acid group (3 [8.8%])) and the amount of bleeding events was similar between study arms with 5 (7.8%) clinically relevant bleedings (including 1 major) in the rivaroxaban group versus 3 (8.8%; none of which major) in the acetylsalicylic acid group.

Patients with high risk triple positive antiphospholipid syndrome
In an investigator sponsored, randomised open-label multicentre study with blinded endpoint adjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis, diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for all 3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies). The study was terminated prematurely after the enrolment of 120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 569 days. 59 patients were randomised to rivaroxaban 20 mg (15 mg for patients with creatinine clearance (CrCl) < 50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 12% of patients randomised to rivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). No events were reported in patients randomised to warfarin. Major bleeding occurred in 4 patients (7%) of the rivaroxaban group and 2 patients (3%) of the warfarin group.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
The following information is based on the data obtained in adults.
Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours after tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the 2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions.
Due to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg tablet under fasting conditions. When rivaroxaban 20 mg tablets are taken together with food increases in mean AUC by 39% were observed when compared to tablet intake under fasting conditions, indicating almost complete absorption and high oral bioavailability.
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state.
Under fed conditions rivaroxaban 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality.
At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and decreased absorption rate with increased dose.
Bioequivalence was demonstrated for the granules for oral suspension formulation compared to the marketed tablet at the 10 mg dose in fasted state as well as for the 20 mg dose in fed state.
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 30% to 40%.
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the stomach should be avoided since this can result in reduced absorption and related rivaroxaban exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube 
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable to lower rivaroxaban doses.

Paediatric population
Children received a rivaroxaban tablet or oral suspension during or closely after feeding or food intake and with a typical serving of liquid to ensure reliable dosing in children. As in adults, rivaroxaban is readily absorbed after oral administration as a tablet or granules for oral suspension formulation in children. No difference in the absorption rate nor in the extent of absorption between the tablet and granules for oral suspension formulation was observed. No PK data following intravenous administration to children is available so the absolute bioavailability of rivaroxaban in children is unknown. A decrease in the relative bioavailability for increasing doses (in mg/kg bodyweight) was found, suggesting absorption limitations for higher doses, even when taken together with food.
Rivaroxaban oral suspension should be taken with feeding or with food (see section 4.2).

Distribution
Plasma protein binding in adults is high at approximately 92% to 95%, with serum albumin being the main binding component. The volume of distribution is moderate with Vss being approximately 50 litres.

Paediatric population
No data on rivaroxaban plasma protein binding specific to children is available. No PK data following intravenous administration of rivaroxaban to children is available. Vss estimated via population PK modelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight and can be described with an allometric function, with an average of 113 L for a subject with a body weight of 82.8 kg.

Biotransformation and elimination
In adults, of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion.
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
Unchanged rivaroxaban is the most important compound in human plasma, with no major or active circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be classified as a low-clearance substance. After intravenous administration of a 1 mg dose the elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly.

Paediatric population
No metabolism data specific to children is available. No PK data following intravenous administration of rivaroxaban to children is available. CL estimated via population PK modelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight and can be described with an allometric function, with an average of 8 L/h for a subject with body weight of 82.8 kg. The geometric mean values for disposition half-lives (t1/2) estimated via population PK modelling decrease with decreasing age and ranged from 4.2 h in adolescents to approximately 3 h in children aged 2-12 years down to 1.9 and 1.6 h in children aged 0.5-< 2 years and less than 0.5 years, respectively.

Special populations
Hepatic impairment
No clinical data is available in children with hepatic impairment. In adults, cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor changes in rivaroxaban 
pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. There are no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between concentration and PT.
Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section 4.3).

Renal impairment
No clinical data is available in children 1 year or older with moderate or severe renal impairment (glomerular filtration rate < 50 mL/min/1.73 m2) or in children younger than 1 year with serum creatinine results above 97.5th percentile (see section 4.4).
In adults, there was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 mL/min), moderate (creatinine clearance 30 - 49 mL/min) and severe (creatinine clearance 15 - 29 mL/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively.
There are no data in patients with creatinine clearance < 15 mL/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.

Gender
In adults, there were no clinically relevant differences in pharmacokinetics and pharmacodynamics between male and female patients. An exploratory analysis did not reveal relevant differences in rivaroxaban exposure between male and female children.

Different weight categories
In adults, extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban plasma concentrations (less than 25%). In children, rivaroxaban is dosed based on body weight. An exploratory analysis in children did not reveal a relevant impact of underweight or obesity on rivaroxaban exposure.

Inter-ethnic differences
In adults, no clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and pharmacodynamics.
An exploratory analysis did not reveal relevant inter-ethnic differences in rivaroxaban exposure among Japanese, Chinese or Asian children outside Japan and China compared to the respective overall paediatric population.

Pharmacokinetic data in patients
In paediatric patients with acute VTE receiving body weight-adjusted rivaroxaban leading to an exposure similar to that in adult DVT patients receiving a 20 mg once daily dose, the geometric mean concentrations (90% interval) at sampling time intervals roughly representing maximum and minimum concentrations during the dose interval are summarised in Table 8.



Table 8: Summary statistics (geometric mean (90% interval)) of rivaroxaban steady state plasma concentrations (mcg/L) by dosing regimen and age
Time intervals o.d.            N      12 -               N       6 -< 12 years
< 18 years
2.5-4h post     171 241.5                 24      229.7
(105-484)                  (91.5-777)
20-24h post 151 20.6                      24      15.9
(5.69-66.5)               (3.42-45.5) b.i.d.          N      6 -< 12 years N            2 -< 6 years     N 0.5 -< 2 years 2.5-4h post     36     145.4              38      171.8            2     n.c.
(46.0-343)                 (70.7-438)
10-16h post 33         26.0               37      22.2             3     10.7 (7.99-94.9)                (0.25-127)             (n.c.-n.c.) t.i.d.          N      2 -< 6 years       N       Birth -          N 0.5 -< 2 years N Birth - < 2 years                                 < 0.5 years
0.5-3h post     5      164.7              25      111.2            13 114.3              12 108.0 (108-283)                  (22.9-320)             (22.9-346)         (19.2-320) 7-8h post       5      33.2               23      18.7             12 21.4               11 16.1 (18.7-99.7)                (10.1-36.5)            (10.5-65.6)        (1.03-33.6) o.d. = once daily, b.i.d. = twice daily, t.i.d. three times daily, n.c. = not calculated Values below lower limit of quantification (LLOQ) were substituted by ½ LLOQ for the calculation of statistics (LLOQ = 0.5 mcg/L).

Pharmacokinetic/pharmacodynamic relationship
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between rivaroxaban concentration and factor Xa activity was best described by an Emax model. For PT, the linear intercept model generally described the data better. Depending on the different PT reagents used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and the slope was around 3 to 4 s/(100 mcg/L). The results of the PK/PD analyses in Phase II and III were consistent with the data established in healthy subjects.