Pharmacology: Mechanism of Action:
Rivaroxaban is a highly selective direct factor Xa (FXa) inhibitor with oral bioavailability. Activation of factor X to FXa via the intrinsic and extrinsic pathway plays a central role in the cascade of blood coagulation.
Dose-dependent inhibition of FXa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose-dependent way with a close correlation to plasma concentrations (r value=0.98) if Neoplastin is used for the assay. Other reagents would provide different results. The readout for PT is to be done in seconds, because the International Normalized Ratio (INR) is only calibrated and validated for coumarins and cannot be used for any other anticoagulant. In patients undergoing major orthopedic surgery, the 5/95 percentiles for PT (Neoplastin) 2-4 hrs after tablet intake (ie, at the time of maximum effect) ranged from 13-25 sec.
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose dependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. Anti-FXa activity is also influenced by rivaroxaban; however, no standard for calibration is available.
There is no need for monitoring of coagulation parameters during treatment with rivaroxaban.
Clinical Efficacy and Safety:
Prevention of venous thromboembolic events (VTE) in patients undergoing major orthopedic surgery of the lower limbs.
The rivaroxaban clinical program was designed to demonstrate the efficacy of rivaroxaban for the prevention of VTE ie, proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing major orthopedic surgery of the lower limbs. Over 9500 patients (7050 in total hip replacement surgery, 2531 in total knee replacement surgery) were studied in controlled randomized double-blind phase III clinical studies, known as the RECORD-program.
Rivaroxaban 10 mg once daily started not earlier than 6 hrs postoperatively was compared with enoxaparin 40 mg once daily started 12 hrs preoperatively.
In all three Phase III studies rivaroxaban significantly reduced the rate of total VTE (any venographically detected or symptomatic DVT, non-fatal PE or death) and major VTE (proximal DVT, non-fatal PE or VTE-related death), the prespecified primary and major secondary efficacy endpoints. Furthermore in all 3 studies, the rate of symptomatic VTE (symptomatic DVT, non-fatal PE, VTE-related death) was lower in rivaroxaban-treated patients compared to patients treated with enoxaparin.
The main safety endpoint, major bleeding, showed comparable rates for patients treated with rivaroxaban 10 mg compared to enoxaparin 40 mg. (See table.)
Click on icon to see table/diagram/image
The analysis of the pooled results of the phase III trials corroborated the data obtained in the individual studies regarding reduction of total VTE, major VTE and symptomatic VTE with rivaroxaban 10 mg once daily compared to enoxaparin 40 mg once daily.
Special Patient Populations:
Ethnic Differeces, Elderly/Gender, Different Weight Categories, Hepatic Impairment, Renal Impairment: See Pharmacokinetics.
Pharmacokinetics: Absorption and Bioavailability:
The absolute bioavailability of rivaroxaban is high (80-100%) for the 10-mg dose. Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax
) appearing 2-4 hrs after tablet intake.
Intake with food does not affect rivaroxaban AUC or Cmax
at the 10-mg dose. Rivaroxaban 10-mg dose can be taken with or without food (see Dosage & Administration).
Variability in rivaroxaban pharmacokinetics is moderate with interindividual variability (CV%) ranging from 30-40%, apart from the day of surgery and the following day when variability in exposure is high (70%).
Plasma protein-binding in humans is high at approximately 92-95%, with serum albumin being the main binding component. The volume of distribution is moderate with Vss
being approximately 50 L.
Metabolism and Elimination:
Of the administered rivaroxaban dose, approximately 2
undergoes metabolic degradation, with ½ then eliminated renally and the other ½ eliminated via the fecal route. The other 1
of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion.
Rivaroxaban is metabolized via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of biotransformation. Based on in vitro
investigations, rivaroxaban is a substrate of the transporter proteins P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp).
Unchanged rivaroxaban is the most important compound in human plasma with no major or active circulating metabolites being present. With a systemic clearance of about 10 L/hr, rivaroxaban can be classified as a low-clearance drug. Elimination of rivaroxaban from plasma occurred with terminal half-lives of 5-9 hrs in young individuals, and with terminal half-lives of 11-13 hrs in the elderly.
Gender/Elderly (>65 years):
Elderly patients exhibited higher plasma concentrations than younger patients with mean AUC values being approximately 1.5-fold higher, mainly due to reduced (apparent) total and renal clearance (see Dosage & Administration).
There were no clinically relevant differences in pharmacokinetics between male and female patients (see Dosage & Administration).
Different Weight Categories:
Extremes in body weight (<50 kg vs >120 kg) had only a small influence on rivaroxaban plasma concentrations (<25%) (see Dosage & Administration).
Children (From Birth to 16 or 18 years Depending on Local Law):
No data are available for this patient population (see Dosage & Administration).
No clinically relevant interethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding pharmacokinetics and pharmacodynamics (see Dosage & Administration).
The effect of hepatic impairment on rivaroxaban pharmacokinetics has been studied in subjects categorized according to the Child-Pugh classification, a standard procedure in clinical development. The Child-Pugh classification's original purpose is to assess the prognosis of chronic liver disease, mainly cirrhosis. In patients for whom anticoagulation is intended, the critical aspect of liver impairment is the reduced synthesis of normal coagulation factors in the liver. Since this aspect is captured by only 1 of the 5 clinical/biochemical measurements composing the Child-Pugh classification system, the bleeding risk in patients may not clearly correlate with this classification scheme. The decision to treat patients with an anticoagulant should therefore be made independently of the Child-Pugh classification.
Rivaroxaban is contraindicated in patients with hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk.
Cirrhotic patients with mild hepatic impairment (classified as Child-Pugh A) exhibited only minor changes in rivaroxaban pharmacokinetics (1.2-fold increase in rivaroxaban AUC on average), nearly comparable to their matched healthy control group. No relevant difference in pharmacodynamic properties was observed between these groups.
In cirrhotic patients with moderate hepatic impairment (classified as Child-Pugh B), rivaroxaban mean AUC was significantly increased by 2.3-fold compared to healthy volunteers, due to significantly impaired drug clearance which indicates significant liver disease. Unbound AUC was increased 2.6-fold. There are no data in patients with severe hepatic impairment.
The inhibition of FXa activity was increased by a factor of 2.6 as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper pharmacokinetics/pharmacodynamics (PK/PD) relationship between concentration and PT.
No data are available for Child-Pugh C patients (see Dosage & Administration and Contraindications).
There was an increase in rivaroxaban exposure being inversely correlated to the decrease in renal function, as assessed via creatinine clearance (CrCl) measurements.
In individuals with mild (CrCl 80 to 50 mL/min), moderate (CrCl <50 to 30 mL/min) or severe (CrCl <30 to 15 mL/min) renal impairment, rivaroxaban plasma concentrations (AUC) were 1.4-, 1.5- and 1.6-fold increased, respectively, as compared to healthy volunteers (see Dosage & Administration and Precautions).
Corresponding increases in pharmacodynamic effects were more pronounced (see Dosage & Administration and Precautions).
In individuals with mild, moderate or severe renal impairment, the overall inhibition of FXa activity was increased by a factor of 1.5, 1.9 and 2, respectively, as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4, respectively.
There are no data in patients with CrCl <15 mL/min.
Use is not recommended in patients with CrCl <15 mL/min. Rivaroxaban is to be used with caution in patients with severe renal impairment CrCl 15-30 mL/min (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data:
Except for effects related to an exaggerated pharmacological mode of action (bleedings), preclinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity and genotoxicity.