1 Introduction
2 Preclinical Pharmacology
2.1 Chemical and Physicochemical Properties
2.2 Mode of Action
3 Pharmacokinetic Properties
3.1 Absorption, Bioavailability, and Biopharmaceutical Profile
Parameter | Fasted | Fed | ||||
---|---|---|---|---|---|---|
2.5 mg tablet | 5 mg tablet | 10 mg tablet | 10 mg tablet | 15 mg tablet | 20 mg tablet | |
AUC (μg · h/L) | 321 (28.8) [165.4–551.9] | 626 (18.8) [422.6–851.4] | 1,114 (25.2) [685.3–1,842] | 1,201 (21.3) [621.5–1,798] | 1,801 (22.2) [952.1–2,870] | 2,294 (19.0) [1,464–3,227] |
C
max (μg/L) | 52.0 (28.1) [28.6–103.0] | 90.6 (24.0) [56.2–145.0] | 138.4 (29.7) [77.4–251.0] | 161.7 (17.2) [127.3–235.4] | 234.2 (17.4) [170.8–347.1] | 294.4 (15.0) [225.4–360.6] |
t
max (h)a
| 2.00 [0.75–4.00] | 1.50 [0.75–6.00] | 2.50 [1.00–4.00] | 3.00 [0.50–6.00] | 3.50 [1.00–6.00] | 3.00 [0.50–6.00] |
t
½ (h) | 4.99 (28.8) [2.33–7.39] | 6.79 (33.4) [3.62–13.34] | 10.77 (28.3) [5.63–17.34] | 10.98 (44.7) [4.72–21.75] | 11.10 (62.1) [5.11–33.76] | 12.08 (60.8) [4.79–36.43] |
3.2 Protein Binding and Distribution
3.3 Metabolism and Elimination
4 Pharmacokinetic Properties in Selected Special Populations
4.1 Age
4.2 Sex and Body Weight
4.3 Ethnicity
4.4 Renal Impairment
Indication | Recommended dosea
|
---|---|
VTE prevention after elective hip or knee replacement surgery | |
5 weeks (elective hip replacement surgery) | 10 mg od |
2 weeks (elective knee replacement surgery) | 10 mg od |
Treatment of DVT and PE and prevention of recurrent VTE | |
First 21 days | 15 mg bid |
From day 22 onwards | 20 mg od |
Stroke prevention in patients with non-valvular AFb
| |
Patients with CLCR ≥50 mL/min | 20 mg od |
Patients with CLCR 15–49 mL/min | 15 mg od |
Prevention of atherothrombotic events after ACS in patients with elevated cardiac biomarkersc
| 2.5 mg bid |
4.5 Hepatic Impairment
4.6 Pediatric Population
5 Pharmacokinetics in Patient Populations
5.1 Prevention of Venous Thromboembolism after Hip or Knee Replacement Surgery
Patient population/clinical setting | Rivaroxaban dose | AUC24 (μg · h/L) |
C
trough (μg/L)a
|
C
max (μg/L)b
|
---|---|---|---|---|
VTE prevention after total hip replacement surgery | 10 mg od | 1,170 (772–2,118)c
| 9 (1–38)c
| 125 (91–196)c
|
DVT treatment (continued treatment) | 20 mg od | 2,814 (1,702–4,773)d
| 26 (6–87)d
| 270 (189–419)d
|
Stroke prevention in patients with AF (CLCR ≥50 mL/min) | 20 mg od | 3,164 (1,860–5,434)e
| 44 (12–137)e
| 249 (184–343)e
|
Stroke prevention in patients with AF (CLCR 30–49 mL/min) | 15 mg od | 3,249 (1,929–5,311)e
| 57 (18–136)e
| 229 (178–313)e
|
Secondary prevention in patients with ACS | 2.5 mg bid | 376 (213–641)f
| 17 (6–37)f
| 46 (28–70)f
|
5.2 Treatment of Deep Vein Thrombosis and Pulmonary Embolism
5.3 Stroke Prevention in Patients with Non-valvular Atrial Fibrillation
5.4 Secondary Prevention in Patients with Acute Coronary Syndrome
5.5 Use in Patients with Chronic Heart Failure
5.6 Prevention of Venous Thromboembolism in Acutely Ill, Hospitalized Patients
6 Pharmacodynamics and Pharmacokinetic/Pharmacodynamic Relationships
6.1 Healthy Volunteers
6.2 Patient Populations
7 Drug Interactions
7.1 Effects of Other Drugs on the Pharmacokinetics of Rivaroxaban
Concomitant drug | Effect on rivaroxaban concentrationa
| Comments/recommendationsb
|
---|---|---|
Azole-antimycotics | ||
Ketoconazole [38] | Increase | Co-administration of rivaroxaban with the azole-antimycotic ketoconazole (400 mg od) led to a 2.6-fold increase in mean rivaroxaban steady-state AUC and a 1.7-fold increase in mean C
max, with significant increases in its pharmacodynamic effects that may lead to an increased risk of bleeding. Rivaroxaban is not recommended in patients receiving concomitant systemic treatment with ketoconazole, itraconazole, voriconazole, or posaconazole. These active substances are strong inhibitors of both CYP3A4 and P-gp |
Fluconazole [38] | Increase | Co-administration of the moderate CYP3A4 inhibitor fluconazole (400 mg od) led to a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean C
max. This increase is not considered clinically relevant |
HIV protease inhibitors | ||
Ritonavir [38] | Increase | Co-administration of rivaroxaban with the HIV protease inhibitor ritonavir (600 mg bid) led to a 2.5-fold increase in mean rivaroxaban AUC and a 1.6-fold increase in mean C
max, with significant increases in its pharmacodynamic effects that may lead to an increased risk of bleeding. The use of rivaroxaban is not recommended in patients receiving systemic treatment with ritonavir or other HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4 and P-gp |
Anti-infectives | ||
Erythromycin [38] | Increase | Co-administration of erythromycin (500 mg tid), which inhibits CYP3A4 and P-gp moderately, led to a 1.3-fold increase in mean rivaroxaban AUC and C
max. This increase is not considered clinically relevant |
Clarithromycin [38] | Increase | Co-administration of clarithromycin (500 mg bid), considered a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in C
max. This increase is not considered clinically relevant |
Rifampicin [3] | Decrease | Rifampicin is a strong inducer of CYP3A4. Co-administration of rivaroxaban with rifampicin led to an approximate 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. Strong CYP3A4 inducers [e.g. rifampicin, phenytoin, carbamazepine, phenobarbital, or St John’s wort (Hypericum perforatum)] should be administered with caution in combination with rivaroxaban |
Anticoagulants | ||
Enoxaparin [68] | No effect | After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose), an additive effect on anti-Factor Xa activity was observed, without additional effects on prolongation of PT. Enoxaparin did not affect the pharmacokinetics of rivaroxaban. Because of the increased risk of bleeding, care is to be taken if patients are treated concomitantly with any other anticoagulants |
Warfarin [69] | No effect | Converting patients from the vitamin K antagonist warfarin (INR 2.0–3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0–3.0) increased PT/INR (Neoplastin) more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition of Factor Xa activity, and ETP were additive |
If it is necessary to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-Factor Xa activity, PiCT, and Heptest can be used because these tests were not affected by warfarin. On the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of Factor Xa activity, and ETP) reflected only the effect of rivaroxaban | ||
If it is necessary to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the C
trough of rivaroxaban (24 h after the previous intake of rivaroxaban) because INR is minimally affected by rivaroxaban at this time point. No pharmacokinetic interaction was observed between warfarin and rivaroxaban | ||
Non-steroidal anti-inflammatory drugs | ||
Naproxen [65] | No effect | Co-administration with naproxen did not affect rivaroxaban pharmacokinetics. No clinically relevant prolongation of bleeding time was observed after concomitant administration of rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more pronounced pharmacodynamic response. Care is to be taken if patients are treated concomitantly with NSAIDs (including aspirin) because these medicinal products typically increase the risk of bleeding |
Aspirin [66] | No effect | No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg aspirin. Care is to be taken if patients are treated concomitantly with NSAIDs (including aspirin) because these medicinal products typically increase the risk of bleeding |
Antiplatelet drugs | ||
Clopidogrel [67] | No effect | Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not affect the pharmacokinetics of rivaroxaban (15 mg), but a relevant increase in bleeding time was observed in a subset of patients that was not correlated with platelet aggregation, P-selectin, or GPIIb/IIIa receptor levels. Care is to be taken if patients are treated concomitantly with platelet aggregation inhibitors because these medicinal products typically increase the risk of bleeding |