Rivaxored Mechanism of Action

Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors. ATC code: B01AF01.
Pharmacology: Pharmacodynamics: Mechanism of action: Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated factor II) and no effects on platelets have been demonstrated.
Pharmacodynamic effects: 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 is only calibrated and validated for coumarins and cannot be used for any other anticoagulant.
The 3-factor PCC reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation than the 4-factor PCC (see Overdosage).
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. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-factor Xa tests (see Pharmacokinetics as follows).
10 mg: In patients undergoing major orthopaedic 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 s (baseline values before surgery 12 to 15 s).
15 mg and 20 mg: In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95 percentiles for PT (Neoplastin) 2-4 hours after tablet intake (i.e. at the time of maximum effect) for 15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15 to 30 s. At trough (8-16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from 14 to 24 s and for 20 mg once daily (18-30 h after tablet intake) from 13 to 20 s.
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1-4 hours after tablet intake (i.e. at the time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough (16-36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 to 26 s.
Paediatric population: The European Medicines Agency has deferred the obligation to submit the data with Rivaroxaban in one or more subsets of the paediatric population in the treatment of thromboembolic events. The European Medicines Agency has waived the obligation to submit data or the results of studies with Rivaroxaban in all subsets of the paediatric population in the prevention of thromboembolic events (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Absorption: Rivaroxaban 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 for the 2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect rivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose.
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily (in fasting state for 15 mg and 20 mg). Under fed conditions Rivaxored 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and decreased absorption rate with increased dose. This is more marked in fasting state than in fed state (for 10 mg).
Variability in rivaroxaban pharmacokinetics is moderate, (with apart from on the day of surgery and the following day when variability in exposure is high for 10 mg only).
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the stomach should be avoided since this can result in reduced absorption and related rivaroxaban exposure.
Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushed tablet mixed in apple puree, 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 data/results are likely applicable to lower rivaroxaban doses.
10 mg: Rivaroxaban 10 mg tablets can be taken with or without food.
15 mg and 20 mg: Due to a reduced extent of absorption an oral bioavailability was determined for the 20 mg tablet under fasting conditions. When Rivaxored 20 mg tablets are taken together with food increases in mean AUC were observed when compared to tablet intake under fasting conditions, indicating almost complete absorption and high oral bioavailability. Rivaxored 15 mg and 20 mg are to be taken with food (see Dosage & Administration).
Distribution: Plasma protein binding in humans is high, with serum albumin being the main binding component. The volume of distribution is moderate with Vss being approximately 50 litres.
Biotransformation and elimination: Of the administered rivaroxaban dose, approximately ²/₃ undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated by the faecal route. The final ¹/₃ of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion.
Rivaroxaban is metabolised 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. 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/h, rivaroxaban can be classified as a low-clearance substance. The elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption rate limited. Elimination of rivaroxaban from plasma occurs 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.
Special populations: Gender: There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between male and female patients.
Elderly population: Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values being higher, mainly due to reduced (apparent) total and renal clearance. No dose adjustment is necessary.
Different weight categories: Extremes in body weight (<50 kg or >120 kg) had only a small influence on rivaroxaban plasma concentrations. No dose adjustment is necessary.
Inter-ethnic differences: No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and pharmacodynamics.
Hepatic impairment: Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor changes in rivaroxaban pharmacokinetics (increase in rivaroxaban AUC on average), nearly comparable to their matched healthy patients. In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased compared to healthy patients. Unbound AUC was increased. These patients also had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. There are no data in patients with severe hepatic impairment.
The inhibition of factor Xa activity was increased in patients with moderate hepatic impairment as compared to healthy patients; prolongation of PT was similarly increased. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between concentration and PT.
Rivaxored is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see Contraindications).
Renal impairment: There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via creatinine clearance measurements. In patients with mild (creatinine clearance 50-80 ml/min), moderate (creatinine clearance 30-49 ml/min) and severe (creatinine clearance 15-29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased. Corresponding increases in pharmacodynamic effects were more pronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa activity was increased respectively as compared to healthy patients; prolongation of PT was similarly increased. There are no data in patients with creatinine clearance <15 ml/min.
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.
Use is not recommended in patients with creatinine clearance <15 ml/min. Rivaxored is to be used with caution in patients with creatinine clearance 15-29 ml/min (see Precautions).
Pharmacokinetic/pharmacodynamic relationship: The relationship between rivaroxaban concentration and factor Xa activity is best described by an Emax model. For PT, the linear intercept model generally described the data better. Depending on the different PT reagents used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and the slope was around 3 to 4 s/(100 mcg/l). The results of the PK/PD analyses were consistent with the data established in healthy patients.
10 mg: In patients, baseline factor Xa and PT were influenced by the surgery resulting in a difference in the concentration-PT slope between the day post- surgery and steady state.
15 mg and 20 mg: The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated after administration of a wide range of doses (5-30 mg twice a day).
Paediatric population: Safety and efficacy have not been established for children and adolescents up to 18 years.