Rivaroxaban: A Practical Guide V1.0 6 July 2012 RIVAROXABAN

Transcription

1 RIVAROXABAN A Practical Guide V July

2 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

3 Table of Contents Writing and Review Committee... 2 List of Figures... 5 List of Tables... 6 List of Abbreviations... 7 Disclaimer... 9 Preamble Guide to treatment with rivaroxaban How to initiate and follow-up patients on rivaroxaban? Dosing schemes in the different indications How to switch between different anticoagulant therapies? Switch from another anti-thrombotic agent to rivaroxaban Vitamin K antagonist to rivaroxaban Low molecular weight heparin to rivaroxaban Intravenous unfractioned heparin to rivaroxaban Dabigatran to rivaroxaban Low dose acetylsalicylic acid to rivaroxaban Switch from rivaroxaban to another anti-thrombotic agent Rivaroxaban to vitamin K antagonist Rivaroxaban to low molecular weight heparin Rivaroxaban to intravenous unfractioned heparin Rivaroxaban to dabigatran Summary switching schemes Is there a need for biological measurement of the anticoagulant effect of rivaroxaban? Is routine laboratory monitoring required for rivaroxaban? Performing point measurements in specific clinical situations Prothrombin time and international normalized ratio Anti-Factor Xa chromogenic assays Summary on the impact of rivaroxaban on standard coagulation tests Drug-drug interactions

4 4. How to manage bleeding complications under rivaroxaban? What in case of an overdose without bleeding? Patients undergoing an intervention or surgery Elective procedures Minor interventions without significant bleeding risk When to interrupt rivaroxaban? When to restart rivaroxaban? Interventions with increased bleeding risk When to interrupt rivaroxaban therapy? When to restart rivaroxaban? Urgent surgical interventions Specific situations Neuraxial (spinal/epidural) anaesthesia Patients with atrial fibrillation and coronary heart disease Acute management of acute coronary syndrome Long-term treatment after acute coronary syndrome Cardioversion in a rivaroxaban treated patient Patients presenting with non-hemorrhagic stroke while on rivaroxaban Acute phase Post-acute phase Initiation of rivaroxaban following an ischaemic stroke or transient ischemic attack Renal and hepatic (dys)function Renal (dys)function Hepatic (dys)function Patient education References

5 List of Figures FIGURE 1: HOW TO SWITCH FROM VKA TO RIVAROXABAN? FIGURE 2: HOW TO SWITCH FROM LMWH TO RIVAROXABAN? FIGURE 3: HOW TO SWITCH FROM INTRAVENOUS UFH TO RIVAROXABAN? 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? FIGURE 6: HOW TO SWITCH FROM RIVAROXABAN TO LMWH? FIGURE 7: HOW TO SWITCH FROM RIVAROXABAN TO INTRAVENOUS UFH? FIGURE 8: HOW TO SWITCH FROM RIVAROXABAN TO DABIGATRAN? FIGURE 9: PHARMACOKINETIC PROFILE RIVAROXABAN: INHIBITION OF FXA ACTIVITY IS DOSE DEPENDENT FIGURE 10: INFLUENCE OF RIVAROXABAN ON PROTHROMBIN TIME FIGURE 11: RELATIONSHIP BETWEEN THE RIVAROXABAN PLASMA CONCENTRATION AND THE TIME AFTER ADMINISTRATION FIGURE 12: PHARMACODYNAMIC PROFILE OF RIVAROXABAN IN A ONE AND TWICE DAILY DOSING REGIMEN RESPECTIVELY IN THE LOWER AND UPPER PICTURES FIGURE 13: ADDITIONAL MEASURES ARE ADDED STEPWISE DEPENDING ON THE SEVERITY OF BLEEDING FIGURE 14: INTERRUPTING RIVAROXABAN FOR INTERVENTIONS WITH A BLEEDING RISK

6 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

7 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 CT creatinine clearance computed tomography CYP3A4 cytochrome P450 3A4 DVT DRVVT deep vein thrombosis dilute Russell s viper venom EMA European Medicines Agency G gram H hour H 2 O water ICH INR IV kg l LMWH mg min ml MRI ng NOAC NSAIDs OAC od PCC PCI PD PE P-gp PK POC PT intracranial hemorrhage international normalized ratio intravenous kilogram liter low molecular weight heparin milligram minute milliliter magnetic resonance image nanogram new oral anticoagulant non-steroidal anti-inflammatory drugs oral anticoagulant omne in die (once daily) prothrombin complex concentrate percutaneous coronary intervention pharmacodynamic pulmonary embolism P-glycoprotein pharmacokinetic point-of-care prothrombin time 7

8 RBPA sec SmPC SPAF T 1/2 TEE TGA TIA T max U UFH VKA VTE red blood loss per anum seconds summary of product characteristics stroke prevention in atrial fibrillation half-life transesophagal echocardiogram thrombin generation assay transient ischemic attack time to reach maximum (peak) plasma concentration Units unfractionated heparin vitamin K antagonist venous thromboembolism 8

9 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

10 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 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 DVT 1. 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 preferred 2. Rivaroxaban is rapidly absorbed with maximum concentrations appearing 2 to 4 hours after oral intake 3. The half-life (T ½ ) of rivaroxaban is 5 to 13 hours 3, 8. Parameter Rivaroxaban Mode of action Inhibition of free, prothombinase bound and clot-associated Factor Xa 4 Type of inhibition Direct, selective, competitive and reversible 5 Oral bioavailability % Plasma protein binding 92 95% T ½ (h) Renal clearance 33% 7 T max (h) 2 4 3, (young healthy) (elderly) 6 Table 1: Pharmacokinetic and pharmacodynamic characteristics of rivaroxaban 9 About one-third of the drug is excreted unchanged in the urine while the remaining twothirds are metabolized to inactive metabolites in the liver which then become eliminated via the kidney or the colon in an approximate 50% ratio 9. Rivaroxaban has a low propensity for drug-drug interactions with the frequently used medications (table 1) 9. 10

11 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 hip replacement surgery Prevention of VTE after elective knee replacement surgery 10 mg od 5 weeks* 10 mg od 2 weeks* Acute treatment of proximal DVT Continued treatment and prevention of recurrent DVT and PE Intensified regimen of 15 mg bid 20 mg od 15 mg od for patients with moderate to severe renal impairment** 3 weeks At least 3 months 3 months of therapy for VTE caused by transient risk factors (recent surgery, trauma, immobilization, ) or in case of increased bleeding risk Prevention of stroke and systemic embolism in patients with non-valvular AF 20 mg od 15 mg od for patients with moderate to severe renal impairment** For idiopathic VTE or when permanent risk factors are present, the risks and benefits of continued anticoagulant treatment need to be evaluated Clinical judgment applies: rivaroxaban is recommended for long term use, provided the benefit of prevention of stroke and 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: ml/min, Severe renal impairment: CrCl: ml/min, see further considerations in section 11. Table 2: Dosing schemes in the different indications of rivaroxaban 9 11

12 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) 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 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). INR < 2 INR INR > 2.5 Start rivaroxaban immediately Start rivaroxaban the next day Switching recommendations Repeat the INR measurement after stopping VKA for 1 to 3 days, taking into account the INR and the half-life of the VKA acenocoumarol (Sintrom ): warfarin (Marevan ): phenprocoumon (Marcoumar ) : 8-14 hours hours hours Table 3: Relation between INR measures under VKA treatment and initiation of rivaroxaban 12

13 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

14 Intravenous unfractioned heparin to rivaroxaban Following the short half-life of intravenous unfractioned heparin (IV UFH) (T ½ 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 hours while for patients with a creatinine clearance of 30 to 50ml/min the T ½ increases to approximately 18 hours 10. 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

15 * 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) 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

16 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

17 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

18 FROM RIVAROXABANN FROM Rivaroxaban: A Practical Guide V1.0 6 July Summary switching schemes TO RIVAROXABAN Rivaroxaban can be initiated once the INR is lower than 2.5 VKA INR < 2.0 INR INR > 2.5 Start rivaroxaban immediately Start rivaroxaban the next day Repeat INR after 1-3 days, considering VKA half-life LMWH IV UFH Start rivaroxaban at planned next administration of LMWH Start rivaroxaban immediately after stopping IV UFH When switching from rivaroxaban to dabigatran the renal function is an important parameter Dabigatran 50ml/min CrCL 30-50ml/min CrCL 15-29ml/min CrCL start rivaroxaban 20mg od hours after last dabigatran intake start rivaroxaban 15mg od hours after last dabigatran intake start rivaroxaban 15mg od at the earliest 48 hours after last dabigatran intake ASA In the absence of a specific indication for continuing ASA, ASA should no longer be administered after initiating rivaroxaban TO VKA LMWH DABIGATRAN IV UFH Rivaroxaban and the VKA should be administered concomitantly until the INR exceeds 2.0 Important! INR testing to be performed just before the next Initiate LMWH at the time the next rivaroxaban would have been taken Initiate dabigatran at the time the next rivaroxaban would have been taken Initiate IV UFH at the time the next rivaroxaban would have been taken intake of rivaroxaban) Table 4: Summary switching scheme between the different anticoagulants 18

19 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) 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. T max at 2 to 4 hours post-dose and the T 1/2 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 (T max ) 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 is dose dependent 8 19

20 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 manner 11, 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 the slope of the linear regression) depends on the reagent used 11, 12. 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

21 (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 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)

22 Figure 11: Relationship between the rivaroxaban plasma concentration and the time after administration 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 PT Impact of rivaroxaban aptt Time prolonged + PT-based coagulation factors (II, V, VII, X) Limited decrease - aptt-based coagulation factors (VIII, IX, XI) POC test for INR measurement aptt Thrombin Generation Assay Activated Clotting Time Thrombo-elastogram Fibrinogen (Clauss method) D-Dimer Thrombin time Ecarin clotting time Lupus anticoagulants (DRVVT) Antithrombin anti-xa based Antithrombin anti-iia based Time prolonged ++ (may vary depending on the reagents used) Limited decrease - Unpredictable Decreased/Influenced (depending on the parameter used) Unpredictable In vitro data only, all parameters influenced (R, K, Angle, MA) Not influenced Not influenced Not influenced Not influenced False positive results expected Increase with appr.10%/100µg/l rivaroxaban Not affected 11, 13, 14 Table 6: Impact of rivaroxaban on the different standard coagulation tests 22

23 3. Drug-drug interactions Rivaroxaban is metabolized via CYP3A4 and is a substrate of the transporter proteins P-gp (Pglycoprotein). 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

24 Concomitant Medications CYP 3A4 interaction Rivaroxaban: A Practical Guide V1.0 6 July 2012 P-gp interaction Mean X-fold change in AUC Mean X-fold change in Cmax Recommendation Inhibitors of CYP3A4 and/or P-gp Azole-antimycotics Ketoconazole (400mg OD) Itraconazole Voriconazole Posaconazole Strong Strong It is not recommended to co-administer these drugs with rivaroxaban due to significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Fluconazole (400mg OD) Moderate HIV protease inhibitors Ritonavir (600mg BID) Strong Strong Macrolide antibiotics Fluconazole is expected to have a weak increase of rivaroxaban exposure. This increase is not considered clinically relevant. It is not recommended to co-administer these drugs with rivaroxaban due to an increased bleeding risk. Clarithromycin (500mg BID) Strong Moderate Erythromycin (500mg TID) Moderate Moderate No clinically relevant interactions have been noted and rivaroxaban can be used in patients taking these medications 4. Nevertheless, caution should be exercised 10 Inducers of CYP3A4 Rifampicin Phenytoin Carbamazepine Phenobarbital St. John s Wort Strong Strong 0,5 NA Medications in this class should be co-administered with caution. 24

25 Concomitant Medications Recommendation Antithrombotic agents NSAID Acetylsalicylic acid Clopidogrel Enoxaparin Warfarin Acenocoumarol NSAIDs Acetylsalicylic acid (500mg) Other commonly used medications Midazolam Digoxin Atorvastatin Dronedarone Anti-acids (Aluminium-magnesium hydroxide) (Maalox ) Ranitidin Care is to be taken, due to the increased bleeding risk. There may be individuals with a more pronounced pharmacodynamic response. Care is to be taken if patients that are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with rivaroxaban when these drugs were coadministered Given the limited clinical data available with dronedarone, co-adminsitration with rivaroxaban should be avoided The change in gastric ph by pretreatment with ranitidine or Aluminium-magnesium hydroxide had no effect on the plasmaconcentration profiles of rivaroxaban. The absorption of rivaroxaban was unaltered by the concomitant administration of these 2 drugs that alter intestinal ph. Table 7: Drug-drug interactions based on the CYP3A4 and P-gP interactions 2,9 25

26 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 in the lower and upper pictures 3,8 26

27 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 volunteers 15, 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 PPSB S.D. (flacon 20 ml - FIX 400IE) Confidex (flacon 20 ml - FIX 500IE) Octaplex (flacon 20 ml - FIX 400 à 620IE) Desmopressin Minirin Amp (4 µg/ml) for iv. use Tranexamic Acid Exacyl apcc: activated prothrombin concentrate (Feiba S-Tim 4 ) recombinant human FVIIa (Novoseven ) Table 8: Recommended a-specific pro-hemostatic agents The administration of Prothrombin Complex Concentrate (PCC) is suggested in case of life-threatening bleeding. After an initial administration of 25U/kg of the available PCC we recommend to clinically re-evaluate the need for a repeat administration of PCCs*. Desmopressin can be considered in case of associated coagulopathy or thrombopathy**. A standard dose scheme for bleeding disorders is 0,03 µg/kg with a maximum of 20 µg. Tranexamic acid associated to direct anti-xa (antithrombin-independent) oral anticoagulants was effective in reducing postoperative blood loss, improving hemoglobinemia at 5 days and reducing transfusion rates. 21 This writing group does not recommend the use of Feiba S-Tim 4 for life-threatening bleedings in patients treated with rivaroxaban. There is no clinical experience with rhfviia in rivaroxaban treated subjects. Due to the 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. 27

28 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

29 propose to use in this case a suspension of 20g active charcoal / 240 ml H 2 0, 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) Elective procedures 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 interventions 18. 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

30 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 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

31 *Thromboprophylaxis with rivaroxaban low dose (10mg OD) only recommended in case of THR and TKR surgery 9. 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