Pharmacology: Pharmacodynamics: Mechanism of Action:
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability.
Activation of Factor X to Factor Xa (FXa) via the intrinsic and extrinsic pathway plays a central role in the cascade of blood coagulation.
Dose-dependent inhibition of Factor Xa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations (r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. The readout for PT is to be done in seconds, because the INR (International Normalized Ratio) 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 hours after tablet intake (i.e. at the time of maximum effect) ranged from 13 to 25 sec.
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dosedependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. Anti-Factor Xa 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 Xarelto.
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 Xarelto for the prevention of venous thromboembolic events (VTE), i.e. proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing major orthopedic surgery of the lower limbs. Over 9,500 patients (7,050 in total hip replacement surgery - 2,531 in total knee replacement surgery) were studied in controlled randomized double-blind phase III clinical studies, the RECORD-program.
Xarelto 10mg once daily started not earlier than 6 hours postoperatively was compared with enoxaparin 40 mg once daily started 12 hours preoperatively.
In all three phase III studies (see Table 1) 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 and VTE-related death), the pre-specified primary and major secondary efficacy endpoints. Furthermore in all three studies the rate of symptomatic VTE (symptomatic DVT, non-fatal PE, VTE-related death) was lower in Xarelto treated patients compared to patients treated with enoxaparin.
The main safety endpoint, major bleeding, showed comparable rates for patients treatedwith Xarelto 10mg compared to enoxaparin 40 mg.
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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 Xarelto 10mg once daily compared to enoxaparin 40 mg once daily.
Ethnic Differences: See Pharmacokinetics as follows.
Elderly/Gender: See Pharmacokinetics as follows.
Different Weight Categories: See Pharmacokinetics as follows.
Hepatic Impairment: See Pharmacokinetics as follows.
Renal Impairment: See Pharmacokinetics as follows.
Pharmacokinetics: Absorption and Bioavailability:
Xarelto is rapidly absorbed with maximum concentrations (Cmax
) appearing 2-4 hours after tablet intake.
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80-100%) for the 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect rivaroxaban AUC or Cmax
at the 10 mg dose. Xarelto 10 mg tablets can be taken with or without food (see Dosage & Administration).
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 30% to 40%.
Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.
Bioavailability (AUC and Cmax
) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce, or suspended in water and administered via a gastric tube followed by a liquid meal, compared to a whole tablet. Given, the predictable, dose-proportional pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable to lower rivaroxaban doses.
Plasma protein binding in humans is high at approximately 92% to 95%, with serum albumin being the main binding component. The volume of distribution is moderate with Vss
being approximately 50 L.
Metabolism and Elimination:
Of the administered rivaroxaban dose, approximately 2
undergoes metabolic degradation, with half then eliminated renally and the other half eliminated by 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-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
Unchanged rivaroxaban is the most important compound in human plasma with no major or active circulating metabolites being present. With a systemic clearance of about 10 l/hr rivaroxaban can be classified as low-clearance drug. Elimination of rivaroxaban from plasma occurred with terminal half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly.
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).
Extremes in body weight (<50 kg vs >120 kg) had only a small influence on rivaroxaban plasma concentrations (less than 25%) (see Dosage & Administration).
Children (From Birth to 16 or 18 Years Depending on Local Law):
Safety and efficacy have not been established for children and adolescents below 18 years (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 one of the five 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.
Xarelto 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 Factor Xa 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 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 measurements.
In individuals with mild (CrCl ≤80-50 mL/min), moderate (CrCl <50-30 mL/min) or severe (CrCl <30-15 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 Precautions).
In individuals with mild, moderate or severe renal impairment the overall inhibition of factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4, respectively.
There are no data in patients with CrCl <15 mL/min.
Use is not recommended in patients with creatinine clearance <15 ml/min. Xarelto is to be used with caution in patients with severe renal impairment creatinine clearance 15-30 ml/min (see Dosage & Administration and Precautions).
Preclinical Safety Data:
The non-clinical safety evaluation in the data from conventional and appropriate studies of safety pharmacology, single and repeat-dose toxicity, genotoxicity, phototoxicity, and carcinogenicity and toxicity to reproduction reveal no special hazard for humans.
No organ-specific toxicity of rivaroxaban was observed up to the highest doses tested (150 mg/kg in all non-rodent studies).