Riva Rox Aban Practical Guide 06072012

Rivaroxaban: A Practical Guide V1.
0 – 6 July 2012
RIVAROXABAN
A Practical Guide V1.0 – 06 July 2012
1
Rivaroxaban: A Practical Guide V1.0 – 6 July 2012
Writing and Review Committee

Christophe Beauloye, Cliniques Universitaires St Luc, Woluwé-St-Lambert
Jean-Michel Dogné, FUNDP, Namur
Jonathan Douxfils, FUNDP, Namur
Marnix Goethals, H.-Hartziekenhuis, Roeselare-Menen
Philippe Hainaut, Cliniques Universitaires St Luc, Woluwé-St-Lambert
Hein Heidbuchel, Universitaire Ziekenhuizen, Leuven
Cédric Hermans, Cliniques Universitaires St Luc, Woluwé-St-Lambert
Brigitte Ickx, Hospital Erasme, ULB, Bruxelles
Kristin Jochmans, Universitaire Ziekenhuis, Brussel
Serge Motte, Hospital Erasme, ULB, Bruxelles
François Mullier, Centre Hospitalier Universitaire Mont-Godinne, Yvoir ; FUNDP, Namur
André Peeters, Cliniques Universitaires St Luc, Woluwé-St-Lambert
Christophe Scavée, Cliniques Universitaires St Luc, Woluwé-St-Lambert
Peter Sinnaeve, Universitaire Ziekenhuizen, Leuven
Muriel Sprynger, Centre Hospitalier Universitaire du Sart Tilman, Liège
Vincent Thijs, Universitaire Ziekenhuizen, Leuven
Chantal Vandenbroeck, Universitair Ziekenhuis Antwerpen, Edegem
Erik Vandermeulen,Universitaire Ziekenhuizen, Leuven
Peter Verhamme, Universitaire Ziekenhuizen, Leuven
2
Table of Contents
Writing and Review Committee ................................................................................................. 2
List of Figures.............................................................................................................................. 5
List of Tables ............................................................................................................................... 6
List of Abbreviations ................................................................................................................... 7
Disclaimer ................................................................................................................................... 9
Preamble .................................................................................................................................. 10
Guide to treatment with rivaroxaban ...................................................................................... 11
1. How to initiate and follow-up patients on rivaroxaban? ............................................. 11
1.1. Dosing schemes in the different indications.......................................................... 11
1.2. How to switch between different anticoagulant therapies? ................................. 12
1.2.1. Switch from another anti-thrombotic agent to rivaroxaban ......................... 12
Vitamin K antagonist to rivaroxaban ........................................................................ 12
Low molecular weight heparin to rivaroxaban ........................................................ 13
Intravenous unfractioned heparin to rivaroxaban ................................................... 14
Dabigatran to rivaroxaban ....................................................................................... 14
Low dose acetylsalicylic acid to rivaroxaban............................................................ 15
1.2.2. Switch from rivaroxaban to another anti-thrombotic agent ......................... 15
Rivaroxaban to vitamin K antagonist ....................................................................... 15
Rivaroxaban to low molecular weight heparin ........................................................ 16
Rivaroxaban to intravenous unfractioned heparin .................................................. 17
Rivaroxaban to dabigatran ....................................................................................... 17
1.2.3. Summary switching schemes ......................................................................... 18
2. Is there a need for biological measurement of the anticoagulant effect of
rivaroxaban? ......................................................................................................................... 19
2.1. Is routine laboratory monitoring required for rivaroxaban? ................................. 19
2.2. Performing point measurements in specific clinical situations ............................. 19
2.2.1. Prothrombin time and international normalized ratio .................................. 20
2.2.2. Anti-Factor Xa chromogenic assays ................................................................ 21
2.3. Summary on the impact of rivaroxaban on standard coagulation tests ............... 22
3. Drug-drug interactions ................................................................................................. 23
3
4. How to manage bleeding complications under rivaroxaban? ..................................... 26

5. What in case of an overdose without bleeding? ......................................................... 28
6. Patients undergoing an intervention or surgery .......................................................... 29
6.1. Elective procedures................................................................................................ 29
6.1.1. Minor interventions without significant bleeding risk ................................... 29
When to interrupt rivaroxaban? .............................................................................. 29
When to restart rivaroxaban? .................................................................................. 30
6.1.2. Interventions with increased bleeding risk .................................................... 30
When to interrupt rivaroxaban therapy? ................................................................. 30
When to restart rivaroxaban? .................................................................................. 30
6.2. Urgent surgical interventions ................................................................................ 31
6.3. Specific situations .................................................................................................. 32
6.3.1. Neuraxial (spinal/epidural) anaesthesia ......................................................... 32
7. Patients with atrial fibrillation and coronary heart disease......................................... 33
7.1. Acute management of acute coronary syndrome ................................................. 33
7.2. Long-term treatment after acute coronary syndrome .......................................... 33
8. Cardioversion in a rivaroxaban treated patient ........................................................... 34
9. Patients presenting with non-hemorrhagic stroke while on rivaroxaban ................... 35
9.1. Acute phase............................................................................................................ 35
9.2. Post-acute phase .................................................................................................... 35
9.3. Initiation of rivaroxaban following an ischaemic stroke or transient ischemic
attack 35
10. Renal and hepatic (dys)function .............................................................................. 36
10.1. Renal (dys)function ............................................................................................ 36
10.2. Hepatic (dys)function ......................................................................................... 37
11. Patient education ..................................................................................................... 37
References ................................................................................................................................ 38
4
List of Figures
FIGURE 1: HOW TO SWITCH FROM VKA TO RIVAROXABAN? ............................................................................... 13
FIGURE 2: HOW TO SWITCH FROM LMWH TO RIVAROXABAN? ........................................................................... 13
FIGURE 3: HOW TO SWITCH FROM INTRAVENOUS UFH TO RIVAROXABAN? ...................................................... 14
FIGURE 4: HOW TO SWITCH FROM DABIGATRAN TO RIVAROXABAN BASED ON PATIENT’S RENAL FUNCTION? 15
FIGURE 5: HOW TO SWITCH FROM RIVAROXABAN TO VKA? ............................................................................... 16
FIGURE 6: HOW TO SWITCH FROM RIVAROXABAN TO LMWH? ........................................................................... 16
FIGURE 7: HOW TO SWITCH FROM RIVAROXABAN TO INTRAVENOUS UFH? ...................................................... 17
FIGURE 8: HOW TO SWITCH FROM RIVAROXABAN TO DABIGATRAN? ................................................................ 17
FIGURE 9: PHARMACOKINETIC PROFILE RIVAROXABAN: INHIBITION OF FXA ACTIVITY IS DOSE DEPENDENT .... 19
FIGURE 10: INFLUENCE OF RIVAROXABAN ON PROTHROMBIN TIME .................................................................. 20
FIGURE 11: RELATIONSHIP BETWEEN THE RIVAROXABAN PLASMA CONCENTRATION AND THE TIME AFTER
ADMINISTRATION ........................................................................................................................................ 22
FIGURE 12: PHARMACODYNAMIC PROFILE OF RIVAROXABAN IN A ONE AND TWICE DAILY DOSING REGIMEN
RESPECTIVELY IN THE LOWER AND UPPER PICTURES ................................................................................. 26
FIGURE 13: ADDITIONAL MEASURES ARE ADDED STEPWISE DEPENDING ON THE SEVERITY OF BLEEDING ........ 28
FIGURE 14: INTERRUPTING RIVAROXABAN FOR INTERVENTIONS WITH A BLEEDING RISK .................................. 31
5
List of Tables
TABLE 1: PHARMACOKINETIC AND PHARMACODYNAMIC CHARACTERISTICS OF RIVAROXABAN 10
TABLE 2: DOSING SCHEMES IN THE DIFFERENT INDICATIONS OF RIVAROXABAN 11
TABLE 3: RELATION BETWEEN INR MEASURES UNDER VKA TREATMENT AND INITIATION OF RIVAROXABAN 12
TABLE 4: SUMMARY SWITCHING SCHEME BETWEEN THE DIFFERENT ANTICOAGULANTS 18
TABLE 5: SENSITIVITY OF DIFFERENT PT-REAGENTS TO RIVAROXABAN 21
TABLE 6: IMPACT OF RIVAROXABAN ON THE DIFFERENT STANDARD COAGULATION TESTS 22
TABLE 7: DRUG-DRUG INTERACTIONS BASED ON THE CYP3A4 AND P-GP INTERACTIONS 25
TABLE 8: RECOMMENDED A-SPECIFIC PRO-HEMOSTATIC AGENTS 27
TABLE 9: RECOMMENDATIONS IN CASE OF PROCEDURES AND SURGICAL INTERVENTIONS 32
TABLE 10: RECOMMENDED TREATMENT DOSES FOR PATIENTS WITH RENAL IMPAIRMENT 36
6
List of Abbreviations
µg microgram
ACS acute coronary syndrome
AF atrial fibrillation
aPTT activated partial thromboplastin time
ASA acetylsalicylic acid
AUC area under the curve
bid bis in die (twice daily)
CHD coronary heart disease
CrCl creatinine clearance
CT computed tomography
CYP3A4 cytochrome P450 3A4
DVT deep vein thrombosis
DRVVT dilute Russell’s viper venom
EMA European Medicines Agency
G gram
H hour
H2O water
ICH intracranial hemorrhage
INR international normalized ratio
IV intravenous
kg kilogram
l liter
LMWH low molecular weight heparin
mg milligram
min minute
ml milliliter
MRI magnetic resonance image
ng nanogram
NOAC new oral anticoagulant
NSAIDs non-steroidal anti-inflammatory drugs
OAC oral anticoagulant
od omne in die (once daily)
PCC prothrombin complex concentrate
PCI percutaneous coronary intervention
PD pharmacodynamic
PE pulmonary embolism
P-gp P-glycoprotein
PK pharmacokinetic
POC point-of-care
PT prothrombin time
7
RBPA red blood loss per anum

sec seconds
SmPC summary of product characteristics
SPAF stroke prevention in atrial fibrillation
T1/2 half-life
TEE transesophagal echocardiogram
TGA thrombin generation assay
TIA transient ischemic attack
Tmax time to reach maximum (peak) plasma concentration
U Units
UFH unfractionated heparin
VKA vitamin K antagonist
VTE venous thromboembolism
8
Disclaimer
Current practical guide was developed to enhance the understanding on when and how to
prescribe rivaroxaban. It is based on available scientific literature, existing guidelines and/or
the Summary of Product Characteristics (SmPC) of rivaroxaban. Some advice also comes
from clinical experience and the extrapolation of existing knowledge about the concerned
indications, coagulation system and anticoagulant drugs. This guide should not be
considered as a formal recommendation but rather as an addition to the regular product
information, providing pragmatic advice for the use of rivaroxaban in daily practice. The
authors cannot be held liable for the management resulting from this guidance.
Please note that the guidance provided in this document reflects our current state of
knowledge about rivaroxaban but is likely to change in the future.
9
Preamble
Rivaroxaban has been approved by the European Medicines Agency (EMA) for the
prevention of venous thromboembolism (VTE) in patients undergoing elective hip or knee
replacement surgery since 20081. In December 2011, rivaroxaban was approved for the
prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation
with at least one risk factor (congestive heart failure, hypertension, age ≥ 75 years, diabetes
mellitus, prior stroke or transient ischaemic attack). A third approval was granted by the
EMA for the treatment of deep vein thrombosis (DVT), and the prevention of recurrent DVT
and pulmonary embolism (PE) following an acute DVT1.
This new oral anticoagulant (NOAC) is the first available oral, direct and selective Factor Xa
inhibitor. It has a predictable pharmacokinetic profile across a wide spectrum of patients
(age, gender, weight and race). Its absolute bioavailability exceeds 80 %. Since at the higher
doses (15mg and 20mg), the absorption decreases somewhat, the intake of the drug with
food is preferred2. Rivaroxaban is rapidly absorbed with maximum concentrations appearing
2 to 4 hours after oral intake3. The half-life (T½) of rivaroxaban is 5 to 13 hours3, 8.
Parameter Rivaroxaban
Mode of action Inhibition of free, prothombinase bound and clot-associated
Factor Xa4
Type of inhibition Direct, selective, competitive and reversible5
Oral bioavailability 80–100%
Plasma protein binding 92–95%
T½ (h) 5-9 (young healthy)
11–13 (elderly)6
Renal clearance 33%7
Tmax (h) 2–43, 8
9
Table 1: Pharmacokinetic and pharmacodynamic characteristics of rivaroxaban
About one-third of the drug is excreted unchanged in the urine while the remaining two-
thirds are metabolized to inactive metabolites in the liver which then become eliminated via
the kidney or the colon in an approximate 50% ratio9. Rivaroxaban has a low propensity for
drug-drug interactions with the frequently used medications (table 1)9.
10
Guide to treatment with rivaroxaban

1. How to initiate and follow-up patients on rivaroxaban?
1.1.Dosing schemes in the different indications
Rivaroxaban may be used for the indications mentioned in table 2. The dose regimens are
presented as recommended in the summary of product characteristics (SmPC). In some
patient populations, the optimal dose for efficacy (prevention of thrombosis) and safety
(bleeding) may not be well-defined at this stage of clinical development (see also sections 7,
8 and 10 on acute coronary syndrome , cardioversion, kidney and liver function
respectively)9.
Indication Dose and regimen Duration of therapy

Prevention of VTE after elective 10 mg od 5 weeks*
hip replacement surgery
Prevention of VTE after elective 10 mg od 2 weeks*

knee replacement surgery
Acute treatment of proximal Intensified regimen of 15 mg 3 weeks
DVT bid
Continued treatment and 20 mg od At least 3 months

prevention of recurrent DVT 15 mg od for patients with 3 months of therapy for VTE caused by
and PE moderate to severe renal transient risk factors (recent surgery,
impairment** trauma, immobilization,…) or in case of
increased bleeding risk
For idiopathic VTE or when permanent risk

factors are present, the risks and benefits
of continued anticoagulant treatment
need to be evaluated
Prevention of stroke and 20 mg od Clinical judgment applies: rivaroxaban is
systemic embolism in patients 15 mg od for patients with recommended for long term use, provided
with non-valvular AF moderate to severe renal the benefit of prevention of stroke and
impairment** systemic embolism outweighs the risk of
bleeding
* The registered duration of thromboprophylaxis with rivaroxaban for VTE prevention is 2 weeks after elective knee
replacement and 5 weeks after elective hip replacement. Individual patient management may differ from the registered
durations.
**Moderate renal impairment: CrCl: 30 - 49 ml/min, Severe renal impairment: CrCl: 15 - 29 ml/min, see further
considerations in section 11.
9
Table 2: Dosing schemes in the different indications of rivaroxaban
11
Taking into account the short half-life of all NOACs, compliance is of major importance for
these drugs. The intake at a similar time each day is therefore highly recommended (see also
section 11 on patient education).
1.2.How to switch between different anticoagulant therapies?
In certain situations, switching from one anticoagulant to another one will be needed. It is
important to safeguard the continuation of anticoagulant therapy while minimizing the risk
for bleeding during any transition to an alternate anticoagulant.
1.2.1. Switch from another anti-thrombotic agent to rivaroxaban
Vitamin K antagonist to rivaroxaban
Following discontinuation of a vitamin K antagonist (VKA), an international normalized ratio

(INR) determination is important for the timing of the initiation of rivaroxaban. Rivaroxaban
can safely be initiated once the INR is lower than 2.5. It is recommended to repeat an INR
measurement in case of an INR exceeding 2.5 before initiating rivaroxaban, though
individual patient management may vary depending on the INR and the half-life of the VKA
(table 3 and figure 1).
Switching recommendations
INR < 2 Start rivaroxaban immediately
INR 2.0 – 2.5 Start rivaroxaban the next day

Repeat the INR measurement after stopping VKA for 1 to 3 days, taking into
account the INR and the half-life of the VKA
INR > 2.5 acenocoumarol (Sintrom®): 8-14 hours

warfarin (Marevan®): 38-42 hours
phenprocoumon (Marcoumar®) : 120-200 hours
Table 3: Relation between INR measures under VKA treatment and initiation of rivaroxaban
12
Figure 1: How to switch from VKA to rivaroxaban?
Low molecular weight heparin to rivaroxaban
Rivaroxaban can be started at the time of the next planned administration of low molecular
weight heparin (LMWH) (figure 2).
Figure 2: How to switch from LMWH to rivaroxaban?
13
Intravenous unfractioned heparin to rivaroxaban
Following the short half-life of intravenous unfractioned heparin (IV UFH) (T½ of ±2 hours),
rivaroxaban can be started once the IV UFH is discontinued (figure 3).
Figure 3: How to switch from intravenous UFH to rivaroxaban?
Dabigatran to rivaroxaban
When switching from dabigatran to rivaroxaban, renal function, dabigatran half-life and the
daily dose need to be taken into consideration. Renal clearance of dabigatran is
approximately 80%10. In patients with normal renal function (≥50ml/min CrCL) the half-life
equals 13-15 hours while for patients with a creatinine clearance of 30 to 50ml/min the T ½
increases to approximately 18 hours10.
Currently, there is no clinical data available on how to switch from dabigatran to

rivaroxaban. The following guidance is based on expert consensus (figure 4).
For patients with a normal renal function (≥50ml/min CrCL), rivaroxaban 20 mg od
can be initiated 12 to 24 hours after the last intake of dabigatran.
For patients with moderate renal impairment (30-50ml/min CrCL), the time window
between the last intake of dabigatran and the initiation of rivaroxaban 15 mg od is
recommended to be at least 24 to 48 hours.
For patients with severe renal impairment (15-29ml/min CrCL) caution is advised.
When considering a treatment switch from dabigatran to rivaroxaban 15 mg od, a
longer delay (at least 48h) might be preferred.
14
* Caution is advised when considering a treatment switch from dabigatran to rivaroxaban 15 mg od for patients with severe
renal impairment (15-29ml/min CrCL)
Figure 4: How to switch from dabigatran to rivaroxaban based on patient’s renal function?
Low dose acetylsalicylic acid to rivaroxaban
Considering the increased bleeding risk with combined therapy of acetylsalicylic acid (ASA)
and rivaroxaban, the need for concomitant low-dose ASA after initiating rivaroxaban needs
to be carefully evaluated. In the absence of a specific indication for continuing ASA, ASA
should no longer be administered after initiating rivaroxaban (see also sections 3 and 7 on
drug-drug interactions and Acute Coronary Syndrome respectively).
1.2.2. Switch from rivaroxaban to another anti-thrombotic agent
Rivaroxaban to vitamin K antagonist
The onset of action of VKAs generally is delayed. For this reason, rivaroxaban and the VKA
should be administered concomitantly until the INR reaches the therapeutic range (figure 5).
Because rivaroxaban may also increase the INR, INR testing should be performed just before
the next intake of rivaroxaban to minimize the impact of rivaroxaban on the INR
measurement (see also section 2 on measurement of anticoagulant effect).
A loading dose is not recommended for acenocoumarol (Sintrom®) and warfarin (Marevan®).
15
Figure 5: How to switch from rivaroxaban to VKA?
Rivaroxaban to low molecular weight heparin
LMWH can be started at the time of the next planned administration of rivaroxaban (i.e. 24h
for the SPAF indication and the prevention and continued treatment of VTE and 12h in the
acute treatment of VTE) (Figure 6).
Figure 6: How to switch from rivaroxaban to LMWH?
16
Rivaroxaban to intravenous unfractioned heparin
IV UFH can be started at the time of the next planned administration of rivaroxaban (i.e. 24h
for the SPAF and the prevention and continued treatment of VTE and 12h in the acute
treatment of VTE) (Figure 7).
Figure 7: How to switch from rivaroxaban to intravenous UFH?
Rivaroxaban to dabigatran
Dabigatran can be initiated at the time the next dose of rivaroxaban would normally have
been taken within the approved indications (figure 8).
Figure 8: How to switch from rivaroxaban to dabigatran?
17
1.2.3. Summary switching schemes
TO RIVAROXABAN
Rivaroxaban can be initiated once the INR is lower than 2.5
INR < 2.0 Start rivaroxaban immediately

VKA
INR 2.0 – 2.5 Start rivaroxaban the next day
INR > 2.5 Repeat INR after 1-3 days, considering VKA half-life
LMWH Start rivaroxaban at planned next administration of LMWH
IV UFH Start rivaroxaban immediately after stopping IV UFH

FROM
When switching from rivaroxaban to dabigatran the renal function is an important parameter
≥50ml/min CrCL start rivaroxaban 20mg od 12-24 hours after last dabigatran intake
Dabigatran
30-50ml/min CrCL start rivaroxaban 15mg od 24-48 hours after last dabigatran intake
15-29ml/min CrCL start rivaroxaban 15mg od at the earliest 48 hours after last dabigatran intake
In the absence of a specific indication for continuing ASA, ASA should no longer be administered
ASA
after initiating rivaroxaban
TO
VKA LMWH DABIGATRAN IV UFH
Rivaroxaban and the VKA

FROM RIVAROXABANN
should be administered
Initiate LMWH at the Initiate dabigatran at Initiate IV UFH at the
concomitantly until the INR
time the next the time the next time the next
exceeds 2.0
rivaroxaban would rivaroxaban would rivaroxaban would
Important! INR testing to be
have been taken have been taken have been taken
performed just before the next
intake of rivaroxaban)
Table 4: Summary switching scheme between the different anticoagulants
18
2. Is there a need for biological measurement of the

anticoagulant effect of rivaroxaban?
2.1.Is routine laboratory monitoring required for rivaroxaban?
Because of its predictable pharmacokinetic profile, rivaroxaban does not require routine
coagulation monitoring. Furthermore and importantly, in routine clinical practice neither
the rivaroxaban dose nor the dosing intervals need to be altered in response to changes in
laboratory coagulation parameters. Routine monitoring tests are not designed for the new
oral anticoagulants.
Nevertheless, in some clinical circumstances, a point measurement to assess the rivaroxaban
plasma concentration may still be useful and desired (see also section 2.3).
2.2.Performing point measurements in specific clinical situations
As expected based on rivaroxaban’s mode of action and its pharmacokinetic profile,

inhibition of Factor Xa activity is dose-dependent (Figure 9). This dose-dependency will
variably and inconsistently affect several clotting tests including the prothrombin time (PT),
International Normalized Ratio (INR) and the activated Partial Thromboplastin Time (aPTT)4,
5
. Therefore, when interpreting a coagulation assay in a rivaroxaban treated patient, the
pharmacokinetic profile of rivaroxaban (i.e. Tmax at 2 to 4 hours post-dose and the T1/2 of 5
to 13 hours) should be taken into account. The results from a coagulation assay obtained in
a blood sample taken 2 to 4 hours after rivaroxaban intake (Tmax) will likely differ from those
in a sample taken at trough levels. In clinical practice, this implies that the time delay
between rivaroxaban intake and blood sampling needs to be carefully recorded when
biological monitoring is performed.
Figure 9: Pharmacokinetic profile rivaroxaban: inhibition of FXa activity

8
is dose dependent
19
2.2.1. Prothrombin time and international normalized ratio
Prothrombin time
There are several commercial assays available to measure the prothrombin time (PT). When
performing these tests, it can be concluded that rivaroxaban prolongs the PT in a
concentration-dependent manner11, 12. The sensitivity of these assays for rivaroxaban
measurement varies greatly while at the same time this sensitivity is generally rather low
(figure 10 and table 5). Furthermore, inter- and intra-variability of these PT assays is high.
The interpretation of a PT point measurement therefore highly depends upon which assay is
being used and where it is being performed. The most sensitive PT assays will be able to
measure the presence of rivaroxaban in the blood at the higher concentrations namely
within a fairly short time frame after the drug has been taken (from 1 – 7 hours post-dose).
Therefore, at best, a PT test will be able to provide information on whether or not
rivaroxaban has actually been taken.
Figure 10: Influence of rivaroxaban on prothrombin time
A linear concentration-dependent prolongation of the PT is observed. The sensitivity (represented by

11, 12
the slope of the linear regression) depends on the reagent used .
Up to this date, there is no data available that associate PT changes with bleeding risk.
Neither is there data suggesting that PT is a valid marker for the anticoagulant efficacy. In
emergency situations in patients on rivaroxaban, a prolonged PT therefore may at most
suggest the recent intake of the drug; prolonged PT would suggest the likely intake of
rivaroxaban in the last 7 hours. Conversely, a non-delayed PT will only suggest that
rivaroxaban was likely taken more than approximately 7 hours ago. Due to this limitation,
the planning of an urgent surgical/invasive procedure based on the results of the PT/aPTT
20
(as for VKAs and unfractionated heparin) is not a validated strategy and cannot be
recommended at the current time
Reagent Sensitivity
Triniclot PT Excel S +++++
Neoplastin R ++++
Recombiplastin ++++
Neoplastin CI+ +++
Triniclot PT HTF ++
Triniclot PT Excel ++
Innovin +
Table 5: Sensitivity of different PT-reagents to rivaroxaban
International normalized ratio (INR)

Conversion from PT to INR was specifically developed for VKAs and is not valid for
measuring rivaroxaban.
2.2.2. Anti-Factor Xa chromogenic assays
The anti-Factor Xa chromogenic assays have been specifically developed for the quantitative
determination of rivaroxaban using standardized anti-Factor Xa method and rivaroxaban
calibrators and controls.
Rivaroxaban plasma concentration measurements using anti-Xa tests may be more accurate;
however they provide no information on the actual anticoagulant effect of rivaroxaban.
Furthermore no target drug concentration ranges have currently been defined for the
different indications.
In patients with a thrombotic event and/or a bleeding complication, a point measurement of
rivaroxaban may provide the clinician useful information on the anticoagulant status of the
patient at the moment the blood sample was obtained. Measuring rivaroxaban could be
considered before (semi-) urgent surgery, in patients with renal and/or hepatic impairment
or suspected drug-drug interactions.
As an example, figure 11 shows the rivaroxaban plasma concentration-time profiles for a
virtually simulated population with atrial fibrillation with-or without renal impairment (15mg
or 20mg respectively)12.
21
Figure 11: Relationship between the rivaroxaban plasma concentration

12
and the time after administration
2.3.Summary on the impact of rivaroxaban on standard coagulation tests
Rivaroxaban interferes with many of the coagulation tests, as outlined in table 6.
Standard coagulation test Impact of rivaroxaban

PT Time prolonged ++ (may vary depending on the reagents used)
aPTT Time prolonged +
PT-based coagulation factors (II, V, VII, X) Limited decrease -
aPTT-based coagulation factors (VIII, IX, Limited decrease -
XI)
POC test for INR measurement aPTT Unpredictable
Thrombin Generation Assay Decreased/Influenced (depending on the parameter used)
Activated Clotting Time Unpredictable
Thrombo-elastogram In vitro data only, all parameters influenced (R, K, Angle, MA)
Fibrinogen (Clauss method) Not influenced
D-Dimer Not influenced
Thrombin time Not influenced
Ecarin clotting time Not influenced
Lupus anticoagulants (DRVVT) False positive results expected
Antithrombin anti-Xa based Increase with appr.10%/100µg/L rivaroxaban
Antithrombin anti-IIa based Not affected
11, 13, 14
Table 6: Impact of rivaroxaban on the different standard coagulation tests
22
3. Drug-drug interactions
Rivaroxaban is metabolized via CYP3A4 and is a substrate of the transporter proteins P-gp (P-
glycoprotein). Consequently, drugs that are strong inhibitors or inducers of CYP3A4 and/or
P-gp may cause a clinically relevant effect on the pharmacokinetic and/or pharmacodynamic
properties of rivaroxaban and are not recommended for concomitant use. Apart from this,
rivaroxaban has a low propensity for drug-drug interactions with frequently used
medications.
Interactions with co-medications that have been noted along with effects on the
pharmacokinetic and pharmacodynamic properties of rivaroxaban are described in table 7.
23
Concomitant CYP 3A4 P-gp Mean X-fold Mean X-fold
Recommendation
Medications interaction interaction change in AUC change in Cmax
Inhibitors of CYP3A4 and/or P-gp
Azole-antimycotics
Ketoconazole (400mg OD)
Itraconazole It is not recommended to co-administer these drugs with

Strong Strong 2.6 1.7 rivaroxaban due to significant increases in pharmacodynamic
Voriconazole
effects which may lead to an increased bleeding risk.
Posaconazole
Fluconazole is expected to have a weak increase of rivaroxaban
Fluconazole (400mg OD) Moderate - 1.4 1.3
exposure. This increase is not considered clinically relevant.
HIV protease inhibitors
It is not recommended to co-administer these drugs with
Ritonavir (600mg BID) Strong Strong 2.5 1.6
rivaroxaban due to an increased bleeding risk.
Macrolide antibiotics
Clarithromycin (500mg BID) Strong Moderate 1.5 1.4

No clinically relevant interactions have been noted and
rivaroxaban can be used in patients taking these
4. 10
medications Nevertheless, caution should be exercised
Erythromycin (500mg TID) Moderate Moderate 1.3 1.3
Inducers of CYP3A4
Rifampicin
Phenytoin
Carbamazepine
Phenobarbital Medications in this class should be co-administered with
Strong Strong 0,5 NA
St. John’s Wort caution.
24
Concomitant
Recommendation
Medications
Antithrombotic agents
Acetylsalicylic acid
Clopidogrel
Enoxaparin Care is to be taken, due to the increased bleeding risk.
Warfarin
Acenocoumarol
NSAID
There may be individuals with a more pronounced pharmacodynamic response.
NSAIDs
Care is to be taken if patients that are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet
Acetylsalicylic acid (500mg) aggregation inhibitors because these medicinal products typically increase the bleeding risk
Other commonly used medications
Midazolam
Digoxin No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with rivaroxaban when these drugs
were coadministered
Atorvastatin
Dronedarone Given the limited clinical data available with dronedarone, co-adminsitration with rivaroxaban should be avoided
Anti-acids (Aluminium-magnesium
®
hydroxide) (Maalox ) The change in gastric pH by pretreatment with ranitidine or Aluminium-magnesium hydroxide had no effect on the plasma-
concentration profiles of rivaroxaban. The absorption of rivaroxaban was unaltered by the concomitant administration of
Ranitidin these 2 drugs that alter intestinal pH.
2,9
Table 7: Drug-drug interactions based on the CYP3A4 and P-gP interactions
25
4. How to manage bleeding complications under

rivaroxaban?
The pharmacodynamic profile of rivaroxaban is important for the management of bleeding

complications. Rivaroxaban has a half-life of 5 to 9 hours in young healthy persons and 11 to
13 hours in elderly. Due to this short half-life discontinuation of the drug is usually
sufficient to reverse its impact on hemostasis. For this reason, determining the dose and
timing of the last intake of rivaroxaban will be crucial. With a peak plasma concentration of
2 to 4 hours after intake (figure 12) it is theoretically possible to reduce the absorption of
rivaroxaban when administering activated charcoal within the first 2 hours after intake. Due
to its high plasma binding capacities (92-95%), rivaroxaban cannot be removed by dialysis.
Figure 12: Pharmacodynamic profile of rivaroxaban in a one and twice daily dosing regimen respectively
3,8
in the lower and upper pictures
26
Currently, there is no specific antidote available for rivaroxaban. The antidotes available for
LMWH and VKA, protamine sulfate and vitamin K respectively, do not impact the
anticoagulation activity of rivaroxaban. Amongst the non-specific pro-coagulants, thus far
only Prothrombin Complex Concentrate (PCC) has shown a potential to reverse the
anticoagulant effects of rivaroxaban as assessed with thrombin generation assay (TGA) and
PT in a phase I clinical trial with 12 healthy volunteers15, 16.
Patients presenting with bleeding complications while on rivaroxaban should receive
individualized care based on the dose regimen, time of intake, drug compliance, possible
changes in co-morbidity impacting the plasma levels (e.g. overdose, renal or hepatic
function, drug-drug interactions) and the severity, source and location of the bleeding.
Regardless of the time of intake, the patient with a (suspected) bleeding should delay the
next administration. It is also possible that the treatment needs to be interrupted after
appropriate evaluation of the patient. The patient needs to be evaluated for associated
factors that increase the bleeding risk including a potential overdose, concomitant use of
antiplatelet or other antithrombotic agents, the use of non-steroidal anti-inflammatory
drugs (NSAIDs), co-existing bleeding disorders, renal or hepatic impairment.
There is insufficient (pre)clinical experience on the management of severe bleedings and the
guidance provided in table 8 and figure 13 is based on expert consensus and are not
clinically validated.
Hemostatic agent Recommendations

PCC: 4 factor concentrate The administration of Prothrombin Complex Concentrate (PCC) is suggested in
PPSB S.D.
® case of life-threatening bleeding. After an initial administration of 25U/kg of the
(flacon 20 ml - FIX ≥ 400IE) available PCC we recommend to clinically re-evaluate the need for a repeat
Confidex
® administration of PCCs*.
(flacon 20 ml - FIX 500IE)
®
Octaplex
(flacon 20 ml - FIX 400 à 620IE)
Desmopressin Desmopressin can be considered in case of associated coagulopathy or
® thrombopathy**.
Minirin
Amp (4 µg/ml) for iv. use A standard dose scheme for bleeding disorders is 0,03 µg/kg with a maximum of
20 µg.
Tranexamic Acid Tranexamic acid associated to direct anti-Xa (antithrombin-independent) oral
Exacyl® anticoagulants was effective in reducing postoperative blood loss, improving
21
hemoglobinemia at 5 days and reducing transfusion rates.
aPCC: activated prothrombin This writing group does not recommend the use of Feiba S-Tim 4® for life-threatening
concentrate (Feiba S-Tim 4®) bleedings in patients treated with rivaroxaban.
recombinant human FVIIa There is no clinical experience with rhFVIIa in rivaroxaban treated subjects. Due to the
(Novoseven®) short half-life of rhFVIIa, a repeat dose may be needed. This writing group does not
recommend the use of Novoseven® for life-threatening bleedings in patients treated with
rivaroxaban.
Table 8: Recommended a-specific pro-hemostatic agents
27
Figure 13: Additional measures are added stepwise depending on the

severity of bleeding
5. What in case of an overdose without bleeding?
Due to limited absorption of rivaroxaban at higher concentrations, a ceiling effect with no

further increase in average plasma exposure is expected at supra-therapeutic doses of 50 mg
rivaroxaban and above. The use of activated charcoal to reduce the absorption in case of a
rivaroxaban overdose can be considered within the first 2 to 4 hours after intake. We
28
propose to use in this case a suspension of 20g active charcoal / 240 ml H20, with a standard
dosing scheme for adults of 30 to 50 g.
Coagulation tests may help to estimate the plasma levels of rivaroxaban (see section 2).
6. Patients undergoing an intervention or surgery
To decide what to do with rivaroxaban treatment in case of surgical procedures, both

patient characteristics and surgical factors need to be taken into account. Points of
consideration are patient’s stroke risk (CHADS2, CHA2DS2-VASc), renal function
(<50ml/min), age (>75years), history of bleeding complications, risk of bleeding,
concomitant antiplatelet medication, and the existence of liver impairment.
We recommend an institutional guideline and a hospital broad policy on how to interrupt

rivaroxaban for surgical/invasive interventions. This could include the post-operative use of
LMWH according to hospital policy (prophylactic/intermediate dose) until the NOAC in the
recommended dose for the indication can be resumed (in general not before 48 hours after
the surgery). Alternatively, a reduced dosing regimen of the NOAC in that time period could
be considered (Table 9).
6.1.Elective procedures
6.1.1. Minor interventions without significant bleeding risk
Among minor interventions without significant bleeding risk we understand procedures for
e.g. cataract or glaucoma as well as dental interventions such as extraction of 1 to 3 teeth,
paradontal surgery, incision of an abscess or positioning of implants. In each situation, the
bleeding risk needs to be balanced against the thrombo-embolic risk.
When to interrupt rivaroxaban?
Rivaroxaban interruption may not be required for superficial interventions18. It is advised to

respect a time window of at least 18 hours between the last intake of rivaroxaban and the
scheduled procedure. An alternative recommendation for minor interventions could be to
respect a time window of at least 24 hours between the last intake of rivaroxaban and the
intervention.
29
Specifically with regards to dental interventions; tooth extractions should avoid the least
possible trauma and the wounds need to be sutured. When bleeding has stopped
completely, the patient can return home with instructions regarding post procedural care
and the measures to be taken in case of bleeding. Rinsing the mouth gently with 10 ml of
tranexamic acid 5%21, 4 times a day for 5 days is recommended. The patient has to contact
his dentist in case of bleeding that does not stop spontaneously.
When to restart rivaroxaban?
The next intake of rivaroxaban should be delayed until hemostasis has been assured.
Alternatively, one could wait to resume the intake of rivaroxaban until 24 hours after the
intervention.
6.1.2. Interventions with increased bleeding risk
When to interrupt rivaroxaban therapy?
Generally, if an invasive procedure or surgical intervention is planned, rivaroxaban should be

stopped at least 24 hours before the intervention. For procedures with high risk of bleeding,
or for patients that have a higher risk for bleeding complications, we recommend a time
window of at least 48 hours between the last intake of rivaroxaban and the scheduled
intervention (table 9, figure 16).
When to restart rivaroxaban?
Antithrombotic therapy should be restarted after the invasive procedure or surgical

intervention as soon as hemostasis is achieved and the risk for bleeding complications is
considered to be low.
For most procedures, it is appropriate to initiate a prophylactic dose of LMWH or

rivaroxaban 10mg (in case of total knee or hip replacement surgery) 6 to 10 hours after
surgery, whereas therapeutic anticoagulation is deferred until at least 48 hours.
Nevertheless, some surgical/invasive interventions that carry a high delayed bleeding risk
might require a longer interval before restarting anticoagulation therapy (table 9, figure 16).
NOTE: Due to the increased bleeding risk, co-administration of LMWH and rivaroxaban is not
recommended.
30
*Thromboprophylaxis with rivaroxaban low dose (10mg OD) only recommended in case of THR and TKR
9
surgery .
Figure 14: Interrupting rivaroxaban for interventions with a bleeding risk
6.2.Urgent surgical interventions
In an emergency situation, clinical judgment by the attending physician will be required to

assess the relative risk of deferring the procedure versus an increased risk of bleeding if the
procedure/surgery is performed in a patient with recent intake of rivaroxaban.
If the procedure can be postponed, it is recommended to defer until 24 hours after the last
intake of rivaroxaban. Caution is required if this is not possible. In case of an (anticipated)
serious bleeding, the bleeding management described in section 6.1 should be taken into
consideration.
When the timing of the last intake of rivaroxaban is not known, a sensitive PT can provide
semi-quantitative information with respect to rivaroxaban intake. It needs to be reminded
though that a non-delayed PT will only suggest that rivaroxaban was likely taken more than
approximately 7 hours ago (see also section 2). Due to this limitation, the planning of a
surgical/invasive procedure based on the results of the PT/aPTT (as for VKAs and
unfractionated heparin) is not a validated strategy and cannot be recommended at the
current time.
31
Time window between intake of rivaroxaban

and the procedure**
Before surgery After surgery
Minor Interventions ≥18h Hemostasis achieved

(without significant bleeding risk) (Alternatively ≥24h) (Alternatively ≥24h)
PROCEDURES
Standard
ELECTIVE
Major ≥24h ≥24h

patient/procedure**
intervention
≥48h
(with increased High risk (Thromboprophylaxis with
bleeding risk) ≥48h
patient/procedure** LMWH can be initiated 6-10h
after the surgery*)
Preferably 24h ≥48h

(Thromboprophylaxis with
URGENT PROCEDURES (See also section 4 on LMWH can be initiated 6-10h
Bleeding management) after the surgery*)
* Thromboprophylaxis with rivaroxaban low dose (10mg od) only recommended in case of THR and TKR
9, 17
surgery
** When determining the time window between the last intake of rivaroxaban and the procedure several
factors need to be taken into account. Points of consideration are patient’s stroke risk (CHADS2, CHA2DS2-
VASc), renal function (<50ml/min), age (>75years), history of bleeding complications, risk of bleeding,
concomitant antiplatelet medication, and the existence of liver impairment.
Table 9: Recommendations in case of procedures and surgical interventions
6.3.Specific situations
6.3.1. Neuraxial (spinal/epidural) anesthesia
The risk of adverse events such as the development of an epidural or spinal hematoma is
increased by the postoperative use of indwelling epidural catheters and the concomitant use
of antithrombotic agents.
The use of rivaroxaban in the presence of neuraxial anesthesia is not recommended by this
working group.
Especially an ongoing treatment with high dose rivaroxaban (15mg, 20mg) is an absolute
contraindication to the use of neuraxial anesthesia and the presence of an indwelling
neuraxial catheter. In a number of patients, and similar to VKAs, the interrupted treatment
may have to be bridged temporarily with IV UFH or LMWH. If a neuraxial block is considered
in those patients, the recommendations concerning IV UFH and LMWH apply.
32
When using low dose rivaroxaban (10mg) in the presence of neuraxial blocks, extreme
caution is mandatory. A minimum time interval of 22-26 hours should be respected before a
neuraxial catheter is removed.
Postoperatively, the next dose of rivaroxaban should only be given 6 hours after withdrawal
of the neuraxial catheter and taking into account the adequacy of surgical hemostasis. In
case of a bloody puncture the next administration of rivaroxaban should be postponed for at
least 24 hours19.
7. Patients with atrial fibrillation and coronary heart disease
7.1.Acute management of acute coronary syndrome
Patients with AF who develop an acute coronary syndrome (ACS) while on rivaroxaban
should be treated according to usual clinical practice. Consideration should be given to
temporarily suspend rivaroxaban treatment in the setting of ACS, should the treatment
involve invasive procedures, such as PCI or coronary artery bypass surgery, or if thrombolytic
therapy is to be initiated.
Please consider that rivaroxaban, relative to VKA, is a short acting agent, and that the timing
of the last dose might impact the level of anticoagulation prior to initiation of standard
parenteral anticoagulation as is used before and during (semi)urgent PCI. Recent intake of
rivaroxaban might increase the risk of bleeding when initiating standard (full-dose)
parenteral anticoagulant. The timing, choice and dose of standard anticoagulation needs to
be balanced against the last intake of rivaroxaban (timing and dose) and the bleeding risk.
Urgent/planned PCI with only anti-Xa drugs might carry a risk of stent thrombosis as
suggested by the Oasis V study with fondaparinux in monotherapy.
7.2.Long-term treatment after acute coronary syndrome
The addition of antiplatelet therapy to oral anticoagulants (OAC) therapy increases the risk
of bleeding. Following an ACS and/or PCI in patients with AF at moderate to high risk of
stroke (i.e. CHADS2 ≥2) triple therapy, OAC (i.e. VKA with a reduced target INR of 2.0 – 2.5 or
rivaroxaban), aspirin and a P2Y12-inhibitor (i.e. ticlopidine, clopidogrel, prasugrel, ticagrelor)
is often inevitable. This, however, exposes the patient to an increased risk of bleeding. As a
consequence, the duration of triple therapy should be limited to the absolute minimum,
based on patient and procedural characteristics. Drug-eluding stent are preferably avoided,
if possible, to reduce the duration of triple therapy. Once triple antiplatelet therapy can be
33
stopped after coronary stent implant, rivaroxaban 20 mg once daily (15 mg once daily for
patients with moderate or severe renal impairment) with aspirin (or clopidogrel) is the
recommended scheme after stent implanation and/or an ACS. No data exist on the safety
and efficacy of rivaroxban in monotherapy for patients with stable coronary heart disease
(i.e. ≥1 year after ACS): therefore, treatment decisions should be individualised, and guided
by the assessment of ischemic vs. bleeding risks.
There is currently very limited experience in combining full-dose rivaroxaban (20 mg once
daily) with dual antiplatelet therapy. To date, no dosing recommendation can be made for
rivaroxaban for stroke prevention in AF in patients requiring dual antiplatelet therapy after
ACS and/or PCI. The need for long term continuation of aspirin or the P2Y12-inhibitor on top
of full-dose rivaroxaban for stroke prevention needs to be balanced against an increased
bleeding risk. Physicians should ensure appropriate anticoagulation by following current
guideline recommendations.
8. Cardioversion in a rivaroxaban treated patient
There is limited clinical experience of using rivaroxaban with this type of patients since in the
ROCKET AF study planned cardioversion and/or ablation was an exclusion criterion 20. No
standardized protocols were used for these procedures, and study medication may have
been paused for the intervention with the patient having potentially been bridged with
another anticoagulant. Based on data analyzed to date, no firm clinical recommendations
can be made. As with VKA and LMWH, the duration and level of anticoagulation need to be
evaluated before considering a cardioversion in a compliant patient, taking into account that
rivaroxaban is a short acting agent.
Anticoagulation should be maintained for at least 4 weeks after successful cardioversion,

regardless of the baseline risk of stroke. Beyond 4 weeks, decisions on anticoagulation
should be made in accordance with CHADS2 and CHA2DS2-VASC. For patients with AF of
duration of 48h or less undergoing electrical or pharmacological cardioversion,
anticoagulation should be started at presentation and maintained for at least 4 weeks after
successful cardioversion. A similar scheme can be proposed for rivaroxaban but a TEE-based
strategy, with exclusion of intra-cardiac thrombi immediately before cardioversion, ican be
considered given absence of data and limited experience.
Switching to appropriate treatment with VKA can be an alternative, until further prospective
safety and efficacy data become available.
34
9. Patients presenting with non-hemorrhagic stroke while on

rivaroxaban
9.1.Acute phase
If a stroke occurs in a patient taking rivaroxaban, the drug intake should be interrupted and
intracranial hemorrhage should be excluded (using a CT or MRI scan).
 If intracranial hemorrhage (ICH) is present, consultation with a neurosurgeon is

recommended. Otherwise, ICH should be managed like any other serious or life-
threatening bleeding on rivaroxaban (see also section 4)
 An ischemic stroke should be treated according to usual clinical practice. The safety
of the use of thrombolytic therapy after recent intake of rivaroxaban is unclear. The
use of thrombolytic therapy should be individualized based on the neurological
evaluation and the timing of the last intake of rivaroxaban, if known
9.2.Post-acute phase
As non-compliance to the prescribed dose might be the underlying cause of stroke

recurrence, patient compliance should be checked and re-education of the patient might be
preferred (see section 11).
 Other possible causes for stroke (stenosis of the carotid artery or lacunar stroke)
need to be checked
 Based on the recommendations for the use of VKA, rivaroxaban treatment can be
restored for secondary stroke prevention, or alternate anticoagulant therapy can be
considered.
9.3.Initiation of rivaroxaban following an ischaemic stroke or transient

ischemic attack
Rivaroxaban has not been studied within the first 3 days after a transient ischemic attack
(TIA), two weeks after a stroke and within 3 months after a disabling stroke (mRS 4-5).
Although currently there is no published experience, it is felt that doctors should follow the
same rules they currently apply to initiate VKA, with the difference that rivaroxaban has a
quicker onset of action. In case of a TIA, anticoagulation treatment with rivaroxaban should
35
begin as soon as possible. Bridging with LMW heparin is generally not required as
rivaroxaban has a quick onset of action.
Rivaroxaban should not be initiated as long as there is a risk for hemorrhagic transformation.
10. Renal and hepatic (dys)function
10.1. Renal (dys)function
Rivaroxaban is partially cleared through the kidneys (33%). Decreased renal function
increases plasma levels of rivaroxaban and this may lead to an increased bleeding risk. No
dose adjustments are necessary for mild renal impairment (Creatinine Clearance , CrCl 50–80
ml/min). For patients with severe renal impairment (CrCl <30ml/min), no clinical data is
available. The recommended dosing for patients with moderate (CrCl 30-49 ml/min) to
severe (15-29 ml/min) renal impairment is shown in the table 12 for each indication. The use
of rivaroxaban is not recommended in patients with a CrCl below 15ml/min (Table 12).
Level of renal impairment Indication Dose

Moderate (CrCl 30–49 Prevention of VTE after elective 10 mg od (5 weeks)
ml/min) orthopedic (knee/hip) surgery
To be used with special caution in Acute treatment of proximal DVT Intensified treatment of 15mg bid
patients with moderate renal (3 weeks)
impairment concomitantly Continued treatment of DVT and 15 mg od for continuous
receiving other medicinal PE treatment (≥3months)
products which increase
Prevention of stroke in patients 15 mg od
rivaroxaban plasma
with non-valvular AF
concentrations
Severe (CrCl 15–29 ml/min)* Prevention of VTE after elective 10 mg od (5 weeks)
orthopedic (knee/hip) surgery
Use with caution
Acute treatment of proximal DVT Intensified treatment of 15mg bid
(3 weeks)
Continued treatment of DVT and 15 mg od for continuous

PE treatment (≥3months)
Prevention of stroke in patients 15 mg od
with non-valvular AF
Severe (CrCl <15 ml/min) Use of rivaroxaban at the above doses is not recommended for patients
with CrCl rates < 15 ml/min
Contraindication
*Although severe renal impairment defined as a CrCl of 15-29 ml/min was not included in the fase III clinical
trials, this specific group was included in the SmPC.
9
Table 10: Recommended treatment doses for patients with renal impairment
36
10.1. Hepatic (dys)function
As per summary of product characteristics rivaroxaban can be used in patients with mild
hepatic impairment (Child-Pugh A; unless there is evidence of coagulopathy). Use of
rivaroxaban in patients with hepatic impairment associated with coagulopathy or a clinically
relevant bleeding risk (e.g. Child-Pugh B and C) is not recommended.
11. Patient education
Patient education will be a very important aspect when introducing rivaroxaban or other
new oral anticoagulants. Such an education can be an effective strategy to adequately use
the drug. It should ideally offer an understanding of the disease and the pharmacological
characteristics of rivaroxaban. More specifically, the need for compliance, signs of bleeding
and instructions on when to seek medical attention should be discussed with the patient.
A patient alert card, containing basic information and instructions on rivaroxaban, was
developed to inform the health care professionals about the patient‘s anticoagulation
treatment. Additionally, this document contains the contact information of the treating
physician in case of emergency. Preferably the patient should carry the patient alert card at
all times and present it to every health care professional.
37
References
1. European public assessment report (EPAR) FOR Xarelto EMA/44192/. 2012.
2. Kubitza D, Becka M, Zuehlsdorf M and Mueck W. Effect of food, an antacid, and the
H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct
factor Xa inhibitor, in healthy subjects. J Clin Pharmacol. 2006; 46: 549-58.
3. Kubitza D, Becka M, Voith B, Zuehlsdorf M and Wensing G. Safety,
pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct
factor Xa inhibitor. Clin Pharmacol Ther. 2005; 78: 412-21.
4. Perzborn E, Roehrig S, Straub A, Kubitza D, Mueck W and Laux V. Rivaroxaban: a new
oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol. 2010; 30: 376-81.
5. Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel
antithrombotic agent BAY 59-7939--an oral, direct Factor Xa inhibitor. J Thromb Haemost.
2005; 3: 514-21.
6. Kubitza D, Becka M, Roth A and Mueck W. Dose-escalation study of the
pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr
Med Res Opin. 2008; 24: 2757-65.
7. Weinz C, Schwarz T, Kubitza D, Mueck W and Lang D. Metabolism and excretion of
rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab
Dispos. 2009; 37: 1056-64.
8. Kubitza D, Becka M, Wensing G, Voith B and Zuehlsdorf M. Safety,
pharmacodynamics, and pharmacokinetics of BAY 59-7939--an oral, direct Factor Xa
inhibitor--after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005; 61: 873-
80.
9. Xarelto - Summary of product characteristics.
10. Dabigatran - Summary of Product Characteristics.
11. Douxfils J, Mullier F and al e. Thromb Haemost. 2012 submitted.
12. Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P and Misselwitz F.
Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein
thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke
prevention. Clin Pharmacokinet. 2011; 50: 675-86.
13. Asmis LM, Alberio L, Angelillo-Scherrer A, et al. Rivaroxaban: Quantification by anti-
FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res.
2012; 129: 492-8.
14. Hillarp A, Baghaei F, Fagerberg Blixter I, et al. Effects of the oral, direct factor Xa
inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost. 2011; 9:
133-9.
15. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR and Levi M.
Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized,
placebo-controlled, crossover study in healthy subjects. Circulation. 2011; 124: 1573-9.
16. Levi M, Eerenberg E and Kamphuisen PW. Bleeding risk and reversal strategies for old
and new anticoagulants and antiplatelet agents. J Thromb Haemost. 2011; 9: 1705-12.
17. Eikelboom JW and Weitz JI. New oral anticoagulants for thromboprophylaxis in
patients having hip or knee arthroplasty. BMJ. 2011; 342: c7270.
38
18. Beleid bij tandheelkundige ingrepen tijdens antitrombotische behandeling. Acta

richtlijn. 2010.
19. Bayer. Xarelto: EPAR - Product Information. 2009.
20. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular
atrial fibrillation. N Engl J Med. 2011; 365: 883-91.
21. Clavé A, Fazilleau F, Dumser D, Lacroix J. Efficacy of tranexamic acid on blood loss
after primary cementless total hip replacement with rivaroxaban thromboprophylaxis: A
case-control study in 70 patients. Orthop Traumatol Surg Res. 2012
39

Riva Rox Aban Practical Guide 06072012

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Riva Rox Aban Practical Guide 06072012

Uploaded by

Copyright:

Available Formats

Rivaroxaban: A Practical Guide V1.

Writing and Review Committee

4. How to manage bleeding complications under rivaroxaban? ..................................... 26

RBPA red blood loss per anum

Guide to treatment with rivaroxaban

1.1.Dosing schemes in the different indications

Indication Dose and regimen Duration of therapy

Prevention of VTE after elective 10 mg od 2 weeks*

Continued treatment and 20 mg od At least 3 months

For idiopathic VTE or when permanent risk

1.2.How to switch between different anticoagulant therapies?

1.2.1. Switch from another anti-thrombotic agent to rivaroxaban

Vitamin K antagonist to rivaroxaban

Following discontinuation of a vitamin K antagonist (VKA), an international normalized ratio

INR 2.0 – 2.5 Start rivaroxaban the next day

INR > 2.5 acenocoumarol (Sintrom®): 8-14 hours

Figure 1: How to switch from VKA to rivaroxaban?

Low molecular weight heparin to rivaroxaban

Figure 2: How to switch from LMWH to rivaroxaban?

Intravenous unfractioned heparin to rivaroxaban

Figure 3: How to switch from intravenous UFH to rivaroxaban?

Currently, there is no clinical data available on how to switch from dabigatran to

Low dose acetylsalicylic acid to rivaroxaban

1.2.2. Switch from rivaroxaban to another anti-thrombotic agent

Rivaroxaban to vitamin K antagonist

Figure 5: How to switch from rivaroxaban to VKA?

Rivaroxaban to low molecular weight heparin

Figure 6: How to switch from rivaroxaban to LMWH?

Rivaroxaban to intravenous unfractioned heparin

Figure 7: How to switch from rivaroxaban to intravenous UFH?

Figure 8: How to switch from rivaroxaban to dabigatran?

1.2.3. Summary switching schemes

Rivaroxaban can be initiated once the INR is lower than 2.5

INR < 2.0 Start rivaroxaban immediately

LMWH Start rivaroxaban at planned next administration of LMWH

IV UFH Start rivaroxaban immediately after stopping IV UFH

VKA LMWH DABIGATRAN IV UFH

Rivaroxaban and the VKA

Table 4: Summary switching scheme between the different anticoagulants

2. Is there a need for biological measurement of the

2.1.Is routine laboratory monitoring required for rivaroxaban?

2.2.Performing point measurements in specific clinical situations

As expected based on rivaroxaban’s mode of action and its pharmacokinetic profile,

Figure 9: Pharmacokinetic profile rivaroxaban: inhibition of FXa activity

2.2.1. Prothrombin time and international normalized ratio

Figure 10: Influence of rivaroxaban on prothrombin time

A linear concentration-dependent prolongation of the PT is observed. The sensitivity (represented by

International normalized ratio (INR)

2.2.2. Anti-Factor Xa chromogenic assays

Figure 11: Relationship between the rivaroxaban plasma concentration

2.3.Summary on the impact of rivaroxaban on standard coagulation tests

Rivaroxaban interferes with many of the coagulation tests, as outlined in table 6.

Standard coagulation test Impact of rivaroxaban

Inhibitors of CYP3A4 and/or P-gp

Itraconazole It is not recommended to co-administer these drugs with

Clarithromycin (500mg BID) Strong Moderate 1.5 1.4

4. How to manage bleeding complications under

The pharmacodynamic profile of rivaroxaban is important for the management of bleeding

Hemostatic agent Recommendations

Figure 13: Additional measures are added stepwise depending on the

5. What in case of an overdose without bleeding?

Due to limited absorption of rivaroxaban at higher concentrations, a ceiling effect with no

6. Patients undergoing an intervention or surgery

To decide what to do with rivaroxaban treatment in case of surgical procedures, both