Xarelto® [Rivaroxaban]

Pharmacological properties

mechanism of action. rivaroxaban is a highly selective direct factor xa inhibitor that has a fairly high bioavailability when taken orally.

The activation of factor X with the formation of factor Xa (FXa) along the internal and external pathways plays a central role in the coagulation cascade.

Pharmacodynamic effects. When using the Neoplastin kit, rivaroxaban exerts a dose-dependent effect on prothrombin time, which significantly correlates with plasma concentration (r = 0.98). Using other tests will result in different results. In patients undergoing extensive orthopedic interventions, the 5/95 percentile for prothrombin 2–4 hours after taking the pill (that is, when the maximum effect is achieved) ranges from 13 to 25 seconds.

Rivaroxaban also dose-dependently increases the activated partial thromboplastin time and the result of HepTest; however, these parameters are not recommended for evaluating the pharmacodynamic effects of rivaroxaban. Rivaroxaban also affects anti-Xa activity.

During the treatment with rivaroxaban, monitoring of blood coagulation parameters is not required.

Clinical efficacy and safety. Prevention of venous thromboembolic events in patients who undergo extensive orthopedic interventions on the lower extremities.

The clinical program for the development of rivaroxaban was planned to demonstrate the effectiveness of rivaroxaban used to prevent venous thromboembolism (VTE), i.e., proximal and distal deep vein thrombosis and pulmonary embolism in patients undergoing extensive orthopedic interventions on the lower limb. The RECORD program, which includes controlled randomized, double-blind, phase III clinical trials, examined more than 9,500 patients (7,050 patients who underwent total hip prosthetics and 2,531 patients who underwent total knee prosthetics).

Pharmacokinetics Absorption and bioavailability. The absolute bioavailability of rivaroxaban after administration at a dose of 10 mg is high and amounts to 80-100%.

Rivaroxaban is rapidly absorbed; C_max achieved 2-4 hours after taking the pill.

The use of rivaroxaban 10 mg tablets with food does not affect AUC and C_max rivaroxabana. Rivaroxaban in a dose of 10 mg can be taken regardless of food intake (see APPLICATION).

The pharmacokinetics of rivaroxaban is characterized by moderate variability; individual variability (variation coefficient) is 30–40%, with the exception of the day of the operation and the next day when the variability is high (70%).

Distribution. In the human body, the majority of rivaroxaban (92–95%) is associated with plasma proteins, the main binding component is plasma albumin. The volume of distribution is average, about 50 liters.

Metabolism and excretion from the body. Rivaroxaban is excreted mainly in the form of metabolites (about ⅔ of the applied dose), with half of them excreted in the urine and the other half in the feces. ¹/₃ the applied dose is subjected to direct renal excretion with urine in the form of an unchanged active substance, mainly by active renal secretion.

Rivaroxaban metabolism is carried out by CYP 3A4, CYP 2J2 isoenzymes, as well as enzymes independent of the cytochrome P450 system. The main participants in biotransformation are the morpholine group, which undergoes oxidative decomposition, and the amide groups, which undergo hydrolysis.

According to in vitro data, rivaroxaban is a substrate for the carrier proteins P-gp (P-glycoprotein) and BCR-P (breast cancer resistance protein).

Unchanged rivaroxaban is the most significant compound in human blood plasma; active circulating metabolites in blood plasma have not been identified. Rivaroxaban, whose systemic clearance is about 10 l / h, can be classified as a low-clearance drug. When removing rivaroxaban from blood plasma, the final T_½ is 5–9 hours in young patients and 11–13 hours in elderly patients.

Gender / old age (over 65 years). In elderly patients, plasma concentrations of rivaroxaban are higher than in young patients, the average AUC value is approximately 1.5 times higher than the corresponding values ​​in young patients, mainly due to reduced total and renal clearance.

In men and women, clinically relevant differences in pharmacokinetics have not been identified (see APPLICATION).

Different weight categories. Too small or large body weight (50 kg and 120 kg) only slightly affects the concentration of rivaroxaban in blood plasma (discrepancy is 25%).

Childhood. Data on this age category are not available.

Interethnic features. No clinically significant relevant differences in pharmacokinetics and pharmacodynamics were found in patients of Caucasian, African American, Latin American, Asian ethnicity (see APPLICATION).

Patients with liver failure. The effect of impaired liver function on the pharmacokinetics of rivaroxaban was studied in subjects that were categorized according to the Child-Pugh classification, according to a standard procedure in clinical development. The primary goal of the Child-Pugh classification is to assess the prognosis of chronic liver disease, mainly cirrhosis. In patients who are prescribed anticoagulants, a critical aspect of impaired liver function is a reduced synthesis of normal coagulation factors in the liver. Since this aspect is covered by only one of the 5 clinical / biochemical definitions included in the Child-Pugh classification system, the risk of bleeding in patients may not clearly correlate with this classification scheme. Given this, the decision to treat patients with anticoagulants should be made regardless of the Child-Pugh classification.

Rivaroxaban is contraindicated in patients with liver disease accompanied by coagulopathy, which causes a clinically significant risk of bleeding.

In patients with cirrhosis of the liver with mild hepatic insufficiency (Child-Pugh class A), the pharmacokinetics of rivaroxaban only slightly differed from those in the control group of healthy volunteers (the average increase in AUC of rivaroxaban was 1.2 times). There were no relevant differences in pharmacodynamic properties between groups.

In patients with cirrhosis of the liver with moderate liver failure (Child-Pugh class B), the average AUC of rivaroxaban was significantly increased (2.3 times) compared with healthy volunteers due to a significant decrease in drug clearance. AUC of unbound substance increased by 2.6 times. No data are available for patients with severely impaired liver function.

Inhibition of factor Xa activity was more pronounced (2.6-fold difference) than in healthy volunteers. Prothrombin time also (2.1 times) exceeded that of healthy volunteers. Patients with moderate hepatic impairment were more sensitive to rivaroxaban, which led to a steeper pharmacokinetic and pharmacodynamic curve between concentration and prothrombin time.

There are no data on patients with child-grade Class C liver failure (see APPLICATION, CONTRAINDICATIONS).

Renal failure.An increase in the exposure of rivaroxaban was noted, which inversely correlates with a decrease in renal function (determined according to creatinine clearance).

In persons with mild (creatinine clearance 80–50 ml / min), moderate (creatinine clearance 50–30 ml / min) or severe (creatinine clearance 30–15 ml / min) impaired renal function, plasma rivaroxaban concentrations in blood (AUC) were 1.4; 1.5 and 1.6 times higher compared to healthy volunteers. Accordingly, an increase in the severity of pharmacodynamic effects was revealed.

In individuals with mild, moderate or severe renal impairment, the total inhibition of factor Xa activity was 1.5; 1.9 and 2.0 times, respectively, compared with healthy volunteers; prothrombin time increased by 1.3; 2.2 and 2.4 times, respectively. Data on patients with creatinine clearance of 15 ml / min are not available.

It is not recommended to use the drug in patients with creatinine clearance of 15 ml / min. Rivaroxaban should be used with caution in patients with severe renal failure with creatinine clearance of 15-30 ml / min (see APPLICATION, SPECIAL INSTRUCTIONS).

Preclinical safety data. Except for the effects associated with the manifestation of a pharmacological action (bleeding), preclinical data do not indicate the existence of a particular risk for people, based on studies of pharmacological safety, toxicity with repeated doses or genotoxicity.

Indications

Prevention of VTE in patients undergoing extensive orthopedic surgery on the lower limb.

Application

It is recommended to prescribe 1 tablet of Xarelto 10 mg once a day, regardless of food intake. the first dose should be taken 6-10 hours after surgery, subject to effective hemostasis.

The duration of treatment is determined by the individual risk of developing VTE for the patient, depending on the type of orthopedic surgery.

If you miss a pill, the patient should take rivaroxaban immediately, and continue treatment the next day: 1 tablet per day, as before skipping a pill.

Patients with impaired renal function. When prescribing rivaroxaban to patients with renal insufficiency, mild or moderate dose adjustment is not required (see Pharmacokinetics).

The limited clinical data obtained in patients with severe renal failure indicate a significant increase in plasma concentrations of rivaroxaban in these patients. In this regard, in the treatment of patients of this category, rivaroxaban should be used with caution.

The use of the drug is not recommended in patients with creatinine clearance of 15 ml / min (see SPECIAL INSTRUCTIONS and Pharmacokinetics).

Patients with impaired liver function. Rivaroxaban is contraindicated in patients with liver disease accompanied by coagulopathy, which leads to an increase in the clinically significant risk of bleeding. Xarelto should be used with caution in patients with liver cirrhosis and moderate liver failure (Child-Pugh class B), not associated with coagulopathy.

Dose adjustment is not required for patients with other liver diseases.

Doses in the treatment of elderly patients (over 65 years). Dose adjustment is not required.

Body mass. No correction is required.

Floor. No correction is required.

Contraindications

Hypersensitivity to rivaroxaban or any components of the drug; clinically significant active bleeding (e.g., intracranial, gastrointestinal); liver diseases accompanied by coagulopathy and a clinically significant risk of bleeding (see pharmacokinetics); period of pregnancy and lactation (see special instructions).

Side effects

Overall, approximately 14% of patients who participated in 3 phase III trials reported adverse reactions.bleeding or anemia occurred in approximately 3.3 and 1% of patients, respectively. other common adverse reactions were nausea, increased GGT (gamma-glutamyl transferase), and increased levels of transaminases.

Given the pharmacological mechanism of action of rivaroxaban, the use of the drug may be accompanied by an increased risk of latent or open bleeding from any tissue and organ, which can lead to posthemorrhagic anemia. Signs, symptoms and severity (including the possibility of death) depend on the location and severity or duration of bleeding. The risk of bleeding may increase in certain groups of patients, for example, with uncontrolled severe hypertension and / or who are simultaneously using drugs that affect hemostasis (see SPECIAL INSTRUCTIONS). Hemorrhagic complications can be manifested by weakness, asthenia, pallor, dizziness, headache or edema of unknown etiology. Therefore, when assessing the condition of a patient receiving anticoagulants, the possibility of hemorrhage should be assessed.

Below, in the table. 1, the listed adverse reactions reported by researchers in 3 phase III trials, classified by organ and system (MedDRA) and frequency.

With Xarelto, menstrual bleeding can become more intense and / or prolonged.

The tables below show the frequency of all side effects that occurred with Xarelto.

The classification according to the frequency of adverse reactions provides for the following categories: often: ≥1% to 10% (from ≥1 / 100 to 1/10); infrequently: from ≥0.1% to 1% (from ≥1 / 1000 to 1/100); rarely: from ≥ 0.01% to 0.1% (≥1 / 10,000 to 1/1000); very rare: 0.01% (1/10 000); frequency is unknown (cannot be estimated based on available data).