REZALTO 10 mg Film-coated tablet Ref.[115242] Active ingredients: Rivaroxaban

Absorption

The absolute bioavailability of rivaroxaban is approximately 100% for the 10 mg dose. Rivaroxaban is rapidly absorbed with maximum concentrations (C_max) appearing 2-4 hours after tablet intake. Administration of rivaroxaban tablets with food (high-calorie/high-fat meal) showed no significant food effects. Rivaroxaban 10 mg dose can be taken with or without food (see section 4.2).

Rivaroxaban pharmacokinetics is linear with no relevant undue accumulation beyond steady-state after multiple doses. Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 30% to 40%.

Distribution

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 litres.

Biotransformation and elimination

Of the administered rivaroxaban dose, approximately ⅔ undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated by the faecal route. The final ⅓ of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion. Approximately 66% of rivaroxaban dose is eliminated via the kidneys, with 30-40% excreted as unchanged medicine in the urine via both glomerular filtration and 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. 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/h, rivaroxaban can be classified as a low-clearance substance. After intravenous administration of a 1 mg dose 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 approximately 1,5 fold 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 (less than 25%). 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 (1,2 fold increase in rivaroxaban AUC on average), nearly comparable to their matched healthy control group. 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. Unbound AUC was increased 2,6 fold. 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 by a factor of 2,6 in patients with moderate hepatic impairment 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.

REZALTO 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 section 4.3).

Renal impairment

There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via creatinine clearance measurements. In individuals 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 1,4; 1,5 and 1,6 fold respectively. 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 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 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. REZALTO is to be used with caution in patients with creatinine clearance 15-29 mL/min (see section 4.4).

Paediatric population

Safety and efficacy have not been established for children and adolescents up to 18 years.