Xarelto, 28 pcs., 20 mg, film-coated tablets

Compound

Description of the dosage form

Film-coated tablets, 15 mg: round, biconvex, pink-brown; An engraving is applied using the extrusion method: on one side there is a triangle with the dosage designation (15), on the other there is a branded Bayer cross.

The appearance of the tablet at the break: a homogeneous white mass surrounded by a pink-brown shell.

Film-coated tablets, 20 mg: round, biconvex, red-brown; An engraving is applied by extrusion: on one side there is a triangle with the dosage designation (20), on the other there is a branded Bayer cross.

Broken appearance of the tablet: a homogeneous white mass surrounded by a red-brown shell.

Pharmacodynamics

Mechanism of action. Rivaroxaban is a highly selective direct factor Xa inhibitor with high oral bioavailability.

Activation of factor X to form factor Xa through the intrinsic and extrinsic coagulation pathways plays a central role in the coagulation cascade.

Pharmacodynamic effects. In humans, dose-dependent inhibition of factor Xa was observed. Rivaroxaban has a dose-dependent effect on PT, the values ​​of which correlate well with plasma concentrations of the drug (r = 0.98), if the Neoplastin® kit is used for analysis. Results will vary if other reagents are used. PT should be measured in seconds because MHO is calibrated and certified only for coumarin derivatives and cannot be used for other anticoagulants.

In patients with nonvalvular atrial fibrillation taking rivaroxaban for the prevention of stroke and systemic thromboembolism, the 5/95th percentile for PT (Neoplastin®) 1 to 4 hours after tablet dosing (i.e., at maximum effect) ranges from 14 to 40 s in patients taking 20 mg once daily, and from 10 to 50 s in patients with renal failure (Cl creatinine 49–30 ml/min) taking 15 mg once daily.

In patients receiving rivaroxaban for the treatment and prevention of recurrent deep vein thrombosis (DVT) and PE, the 5/95th percentile for PT (Neoplastin®) 2 to 4 hours after tablet dosing (i.e., at maximum effect) ranges from 17 up to 32 s in patients taking 15 mg twice daily, and 15 to 30 s in patients taking 20 mg once daily.

Also, rivaroxaban dose-dependently increases APTT and HepTest® result; however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban. Also, if clinically warranted, rivaroxaban concentrations can be measured using a calibrated quantitative anti-factor Xa test.

During treatment with Xarelto®, monitoring of blood coagulation parameters is not required.

In healthy men and women over 50 years of age, prolongation of the ECG QT interval under the influence of rivaroxaban was not observed.

Instructions for use XARELTO® (XARELTO)

Xarelto® 15 mg and 20 mg should be taken with food.

Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation

The recommended dose is 20 mg 1 time/day, daily. For patients with moderate renal failure (creatinine clearance <50-30 ml/min)

The recommended dose of the drug is 15 mg 1 time/day, daily.

Treatment should be continued as long as the risk factors for stroke and systemic thromboembolism persist.

If a dose is missed, the patient should immediately take Xarelto® and continue taking the drug regularly the next day in accordance with the recommended regimen. You should not double the dose you take to compensate for a previously missed dose.

The recommended maximum daily dose of the drug is 20 mg.

Treatment of deep vein thrombosis and prevention of recurrent DVT and pulmonary embolism (PE)

The recommended initial dose of the drug is 15 mg 2 times a day for the first 3 weeks, followed by Xarelto 20 mg 1 time a day for long-term therapy and prevention of recurrent DVT or PE.

Treatment should be continued as long as risk factors for venous thromboembolism persist.

It is recommended to adhere to a regular regimen of taking the drug. If a dose is missed while taking a dose of 15 mg 2 times a day, the patient should immediately take Xarelto® in order to ensure the delivery of the daily dose of 30 mg. To do this, you can take 2 tablets at the same time. (15 mg each). The next day, you should continue taking the drug regularly at a dose of 15 mg 2 times a day in accordance with the recommended regimen.

If a dose is missed while taking the 20 mg dose, the patient should immediately take Xarelto® to ensure the daily dose of 20 mg is supplied. The next day, you should continue taking the drug regularly at a dose of 20 mg 1 time / day in accordance with the recommended regimen.

The recommended maximum daily dose of the drug is 30 mg during the first 3 weeks of treatment.

In the subsequent treatment phase, the recommended maximum dose of the drug is 20 mg.

Additional information on specific patient groups

Patients with liver dysfunction

Xarelto® is contraindicated in patients with liver disease

accompanied by coagulopathy, which causes a clinically significant risk of bleeding.
Patients with other liver diseases do not require dosage changes. Available limited clinical data obtained for patients with moderate hepatic impairment (class B according to the Child-Pugh classification)
indicate a significant increase in the pharmacological activity of the drug.
For patients with severe hepatic impairment (Child-Pugh class C),
clinical data are not available.

Patients with impaired renal function

For the prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation

When prescribing Xarelto® to patients with mild renal failure (creatinine clearance <80-50 ml/min)

no dose adjustment is required.
For patients with moderate renal failure (creatinine clearance <50-30 ml/min)
, the recommended dose is 15 mg 1 time/day.
The limited clinical data available in patients with severe renal impairment (creatinine clearance < 30-15 ml/min)
demonstrate a significant increase in rivaroxaban concentrations in these patients.
For the treatment of this category of patients, Xarelto® 15 mg should be used with caution. The use of Xarelto® is not recommended in patients with CC < 15 ml/min
.

In patients for the treatment of deep vein thrombosis and prevention of recurrent DVT and PE

When prescribing Xarelto® to patients with mild renal failure (creatinine clearance < 80-50 ml/min) or moderate renal failure (creatinine clearance < 50-30 ml/min)

no dose adjustment is required.
The limited clinical data available in patients with severe renal impairment (creatinine clearance < 30-15 ml/min)
demonstrate a significant increase in rivaroxaban concentrations in these patients.
To treat this category of patients, Xarelto® should be used with caution. The use of Xarelto® is not recommended in patients with CC <15 ml/min
.

Switching from vitamin K antagonists (VKAs) to Xarelto® for the prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation

If MHO≤3, treatment with VKA should be stopped and treatment with Xarelto® should be started. When switching patients from VKA to Xarelto®, MHO values ​​will be erroneously elevated after taking Xarelto®. MHO is not suitable for determining the anticoagulant activity of Xarelto® and should therefore not be used for this purpose.

Switching from vitamin K antagonists to Xarelto® in patients for the treatment of DVT and prevention of recurrent DVT and PE

If MHO≤2.5, treatment with VKA should be stopped and treatment with Xarelto® should be started. When switching patients from VKA to Xarelto®, MHO values ​​will be erroneously elevated after taking Xarelto®. MHO is not suitable for determining the anticoagulant activity of Xarelto® and should therefore not be used for this purpose.

Switching from Xarelto® to vitamin K antagonists

There is a possibility of insufficient anticoagulant effect when switching from Xarelto® to VKA. In this regard, it is necessary to ensure a continuous sufficient anticoagulant effect during such a transition using alternative anticoagulants. It should be noted that Xarelto® may help increase MHO.

When switching from Xarelto® to VKA, VKA should be taken concomitantly until MHO reaches ≥2. During the first two days of the transition period, a standard dose of VKA should be used, followed by a dose of VKA depending on the results of the MHO determination. While taking Xarelto® and VKA, MHO should be determined no earlier than 24 hours after taking the previous dose, but before taking the next dose of Xarelto®.

A reliable determination of MHO can be carried out 24 hours after stopping the use of Xarelto® and taking the last dose of the drug.

Switching from parenteral anticoagulants to Xarelto®

For patients receiving parenteral anticoagulants, the use of Xarelto should be started 0-2 hours before the time of the next scheduled parenteral administration of the drug (for example, low molecular weight heparin) or at the time of discontinuation of continuous parenteral administration of the drug (for example, intravenous administration of unfractionated heparin).

Switching from Xarelto® to parenteral anticoagulants

Discontinue Xarelto® and administer the first dose of the parenteral anticoagulant at the time the next dose of Xarelto® is due.

Childhood

Safety and effectiveness in children and adolescents under 18 years of age

not installed.

Elderly patients, gender, weight or ethnicity

No dose adjustment is required in these categories of patients.

Pharmacokinetics

Absorption and bioavailability. The absolute bioavailability of rivaroxaban after taking a dose of 10 mg is high (80–100%). Rivaroxaban is rapidly absorbed; Cmax is reached 2–4 hours after taking the tablet.

When taking rivaroxaban at a dose of 10 mg with food, no changes in AUC and Cmax were observed. Rivaroxaban 10 mg can be given with or without food.

The pharmacokinetics of rivaroxaban is characterized by moderate individual variability; individual variability (variation coefficient) ranges from 30 to 40%.

Due to the reduced degree of absorption, a bioavailability of 66% was observed when taking 20 mg on an empty stomach. When Xarelto®, 20 mg was taken with food, there was a 39% increase in mean AUC compared to fasting, indicating almost complete absorption and high bioavailability.

The absorption of rivaroxaban depends on the site of its release in the gastrointestinal tract. A 29% and 56% reduction in AUC and Cmax, respectively, compared to the whole tablet, was observed when rivaroxaban granules were released in the distal small intestine or ascending colon. Administration of rivaroxaban into the gastrointestinal tract distal to the stomach should be avoided, as this may result in decreased absorption and, accordingly, decreased exposure of the drug.

The study assessed the bioavailability (AUC and Cmax) of 20 mg rivaroxaban taken orally as a crushed tablet mixed with applesauce or suspended in water, or given by gastric tube followed by a liquid meal, compared with administration of a whole tablet. The results demonstrated a predictable dose-dependent pharmacokinetic profile for rivaroxaban, with bioavailability at the above dosing levels consistent with lower doses of rivaroxaban.

Distribution. In the human body, the majority of rivaroxaban (92–95%) is bound to plasma proteins, the main binding component being serum albumin. Vd - moderate. Vss is approximately 50 l.

Metabolism and excretion. When taken orally, approximately 2/3 of the prescribed dose of rivaroxaban is metabolized and subsequently excreted in equal parts in urine and feces. The remaining third of the dose is eliminated unchanged by direct renal excretion, mainly due to active renal secretion.

Rivaroxaban is metabolized through isoenzymes CYP3A4, CYP2J2, as well as through mechanisms independent of the cytochrome system. The main sites of biotransformation are the oxidation of the morpholine group and the hydrolysis of amide bonds.

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

Unmodified rivaroxaban is the only active compound in human plasma; no high concentration metabolites or active circulating metabolites have been detected in plasma. Rivaroxaban, whose systemic clearance is approximately 10 L/h, can be classified as a drug with a low clearance rate. When rivaroxaban is eliminated from plasma, the final T1/2 ranges from 5 to 9 hours in young patients and from 11 to 13 hours in elderly patients.

Gender/old age (over 65 years old). In elderly patients, plasma concentrations of rivaroxaban are higher than in younger patients, with a mean AUC value approximately 1.5 times higher than in younger patients, mainly due to an apparent decrease in total and renal clearance. No clinically significant differences in pharmacokinetics were found in men and women.

Body mass. Too little or too much body weight (less than 50 and more than 120 kg) has only a small effect on the plasma concentration of rivaroxaban (the difference is less than 25%).

Childhood. There are no data available for this age category.

Interethnic differences. No clinically significant differences in pharmacokinetics and pharmacodynamics were observed in patients of Caucasian, African American, Hispanic, Japanese or Chinese ethnicity.

Liver dysfunction. The effect of hepatic impairment on the pharmacokinetics of rivaroxaban was studied in patients classified according to the Child-Pugh classification (according to standard procedures in clinical trials). The Child-Pugh classification allows you to assess the prognosis of chronic liver diseases, mainly cirrhosis. In patients undergoing anticoagulant therapy, a particularly important critical point in liver dysfunction is the decrease in the synthesis of coagulation factors in the liver. Since this indicator corresponds to only one of the five clinical/biochemical criteria that make up the Child-Pugh classification, the risk of bleeding does not clearly correlate with this classification. The question of treating such patients with anticoagulants should be decided regardless of the Child-Pugh class.

Xarelto® is contraindicated in patients with liver disease associated with coagulopathy causing a clinically significant risk of bleeding.

In patients with liver cirrhosis with mild liver failure (Child-Pugh class A), the pharmacokinetics of rivaroxaban differed only slightly from the corresponding indicators in the control group of healthy subjects (on average, there was an increase in the AUC of rivaroxaban by 1.2 times). There were no significant differences in pharmacodynamic properties between groups.

In patients with cirrhosis and moderate hepatic impairment (Child-Pugh class B), the mean AUC of rivaroxaban was significantly increased (2.3-fold) compared with healthy volunteers due to significantly reduced drug clearance, indicating significant liver disease. The suppression of factor Xa activity was more pronounced (2.6 times) than in healthy volunteers. PT was also 2.1 times higher than in healthy volunteers. By measuring PT, the extrinsic coagulation pathway is assessed, including coagulation factors VII, X, V, II and I, which are synthesized in the liver. Patients with moderate hepatic impairment are more sensitive to rivaroxaban, which is a consequence of a closer relationship between pharmacodynamic effects and pharmacokinetic parameters, especially between concentration and PT.

There are no data available for patients with Child-Pugh Class C hepatic impairment.

Renal dysfunction. In patients with renal failure, an increase in rivaroxaban plasma concentrations was observed, inversely proportional to the decrease in renal function assessed by creatinine clearance.

In patients with renal impairment, rivaroxaban plasma concentrations (AUC) of 1.4-, 1.5-, and 1.6-fold increased in rivaroxaban plasma concentrations (AUC) of 80–50, 49–30, and 29–15 mL/min, respectively, compared with healthy volunteers. The corresponding increase in pharmacodynamic effects was more pronounced.

In patients with creatinine Cl 80–50, 49–30 and 29–15 ml/min, the total suppression of factor Xa activity increased by 1.5, 1.9 and 2 times compared with healthy volunteers; PT - due to changes in factor Xa activity also increased by 1.3, 2.2 and 2.4 times, respectively.

Data on the use of Xarelto® in patients with creatinine Cl 29–15 ml/min are limited, and therefore caution should be exercised when using the drug in this category of patients. There are no data on the use of Xarelto® in patients with creatinine Cl <15 ml/min, and therefore it is not recommended to use the drug in this category of patients.

Xarelto®

Inside. Xarelto® 15 mg and 20 mg should be taken with food.

If the patient is unable to swallow the tablet whole, the Xarelto® tablet may be crushed and mixed with water or a liquid meal, such as applesauce, immediately before dosing. After taking crushed Xarelto® 15 mg or 20 mg tablets, you should immediately eat. A crushed Xarelto® tablet can be given through a gastric tube. The position of the probe in the gastrointestinal tract must be further agreed with the doctor before taking Xarelto®. The crushed tablet should be administered through a gastric tube in a small amount of water, after which a small amount of water must be introduced in order to wash off any remaining drug from the walls of the tube. After taking crushed Xarelto® 15 mg or 20 mg tablets, enteral nutrition must be taken immediately.

Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation

The recommended dose is 20 mg 1 time / day.

For patients with impaired renal function (creatinine clearance 49-30 ml/min)

The recommended dose is 15 mg 1 time / day. The recommended maximum daily dose is 20 mg. Duration of treatment: Xarelto® therapy should be considered as a long-term treatment, continued as long as the benefit of treatment outweighs the risk of possible complications.

What to do if you miss a dose

If a dose is missed, the patient should immediately take Xarelto® and continue taking the drug regularly the next day in accordance with the recommended regimen.

You should not double the dose you take to compensate for a previously missed dose.

Treatment of DVT and PE and prevention of recurrence of DVT and PE

The recommended initial dose for the treatment of acute DVT or PE is 15 mg 2 times / day for the first 3 weeks, followed by a transition to a dose of 20 mg 1 time / day for further treatment and prevention of recurrent DVT and PE.

The maximum daily dose is 30 mg during the first 3 weeks of treatment and 20 mg during further treatment. The duration of treatment is determined individually after carefully weighing the benefits of treatment against the risk of bleeding. .

The minimum duration of treatment (at least 3 months) should be based on an assessment regarding reversible risk factors (ie, previous surgery, trauma, period of immobilization). The decision to extend the course of treatment for a longer period is based on an assessment regarding persistent risk factors or in the event of the development of idiopathic DVT or PE.

What to do if you miss a dose

It is important to adhere to the established dosage regimen.

If the next dose is missed during the dosing regimen of 15 mg 2 times / day, the patient should immediately take Xarelto® to achieve the daily dose of 30 mg. Thus, two 15 mg tablets can be taken at one time. The next day, the patient should continue taking the drug regularly in accordance with the recommended regimen. If the next dose is missed with a dosing regimen of 20 mg 1 time / day, the patient should immediately take Xarelto® and continue taking the drug regularly the next day in accordance with the recommended regimen.

Selected patient groups

Dose adjustment depending on patient age (over 65 years), gender, body weight or ethnicity

not required.

Xarelto® is contraindicated in patients with liver disease

accompanied by coagulopathy, which causes a clinically significant risk of bleeding.
Patients with other liver diseases do not require dose changes. Available limited clinical data obtained in patients with moderate hepatic impairment (class B according to the Child-Pugh classification)
indicate a significant increase in the pharmacological activity of the drug.
For patients with severe hepatic impairment (Child-Pugh class C),
clinical data are not available.

When prescribing Xarelto® to patients
with renal failure (creatinine clearance 80-50 ml/min),
no dose adjustment is required.

For the prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation with renal failure (creatinine clearance 49-30 ml/min)

The recommended dose is 15 mg 1 time / day.

In the treatment of DVT and PE and the prevention of recurrence of DVT and PE in patients with renal failure (creatinine clearance 49-30 ml/min)

no dose adjustment is required.

Available limited clinical data obtained in patients with renal failure (creatinine clearance 29-15 ml/min),

demonstrate a significant increase in rivaroxaban concentrations in these patients. To treat this category of patients, Xarelto® should be used with caution.

The use of Xarelto® is not recommended in patients with creatinine clearance <15 ml/min.

.

Switching patients from vitamin K antagonists (VKA) to Xarelto®

When preventing stroke and systemic thromboembolism, treatment with VKA should be stopped and treatment with Xarelto® should be started when MHO is ≤3.

In case of DVT and PE, treatment with VKA should be discontinued and treatment with Xarelto® should be started if MHO is ≤2.5.

When switching patients from VKA to Xarelto®, MHO values ​​will be erroneously elevated after taking Xarelto®. The MHO value is not suitable for determining the anticoagulant activity of Xarelto® and should therefore not be used for this purpose.

Switching from Xarelto® to vitamin K antagonists (VKAs)

There is a possibility of insufficient anticoagulant effect when switching from Xarelto® to VKA. In this regard, it is necessary to ensure a continuous sufficient anticoagulant effect during such a transition using alternative anticoagulants. It should be noted that Xarelto® may help increase MHO. Patients switching from Xarelto® to a VKA should take a VKA concomitantly until the MHO reaches ≥2. During the first two days of the transition period, a standard dose of VKA should be used, followed by a dose of VKA determined depending on the MHO value. Thus, during simultaneous use of Xarelto® and VKA, MHO should be determined no earlier than 24 hours after the previous dose, but before taking the next dose of Xarelto®. After discontinuation of Xarelto®, the MHO value can be reliably determined 24 hours after the last dose.

Switching from parenteral anticoagulants to Xarelto®

For patients receiving parenteral anticoagulants, the use of Xarelto should be started 0-2 hours before the time of the next scheduled parenteral administration of the drug (for example, low molecular weight heparin) or at the time of discontinuation of continuous parenteral administration of the drug (for example, intravenous administration of unfractionated heparin).

Switching from Xarelto® to parenteral anticoagulants

Discontinue Xarelto® and administer the first dose of the parenteral anticoagulant at the time the next dose of Xarelto® is due.

Contraindications

hypersensitivity to rivaroxaban or any excipients contained in the tablet;

clinically significant active bleeding (eg, intracranial hemorrhage, gastrointestinal bleeding);

injury or condition associated with an increased risk of major bleeding, such as a current or recent gastrointestinal ulcer, presence of malignancies with a high risk of bleeding, recent brain or spinal cord injury, brain, spinal cord or eye surgery, intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous malformations, vascular aneurysms, or vascular pathology of the brain or spinal cord;

concomitant therapy with any other anticoagulants, for example, unfractionated heparin, low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran, etc.), except in cases of transition from or on rivaroxaban (see “Dosage and Administration”) or when using unfractionated heparin in doses necessary to ensure the functioning of a central venous or arterial catheter;

liver diseases occurring with coagulopathy, which causes a clinically significant risk of bleeding;

renal failure (Cl creatinine <15 ml/min) (clinical data on the use of rivaroxaban in this category of patients are absent);

congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption (due to the presence of lactose);

pregnancy and breastfeeding;

children and adolescents up to 18 years of age (efficacy and safety in patients in this age group have not been established).

CAREFULLY:

treatment of patients with an increased risk of bleeding (including congenital or acquired tendency to bleeding, uncontrolled severe arterial hypertension, peptic ulcer of the stomach and duodenum in the acute stage, recently suffered peptic ulcer of the stomach and duodenum, vascular retinopathy, recently suffered intracranial or intracerebral hemorrhage, vascular pathology of the spinal cord or brain, after recent surgery on the brain, spinal cord or eyes, a history of bronchiectasis or pulmonary hemorrhage);

treatment of patients with renal failure (Cl creatinine 49–30 ml/min) who are simultaneously receiving drugs that increase the level of rivaroxaban in the blood plasma (see “Interaction”);

treatment of patients with renal failure (Cl creatinine 29–15 ml/min) - caution should be exercised, since the concentration of rivaroxaban in the blood plasma in such patients may increase significantly (on average 1.6 times) and as a result they are at increased risk of bleeding;

patients receiving medications that affect hemostasis (for example, NSAIDs, antiplatelet agents or other antithrombotic agents);

patients receiving systemic treatment with azole antifungals (eg ketoconazole) or HIV protease inhibitors (eg ritonavir). These drugs are strong inhibitors of the CYP3A4 isoenzyme and P-gp. As a consequence, these drugs may increase plasma concentrations of rivaroxaban to clinically significant levels (on average 2.6-fold), which increases the risk of bleeding. The azole antifungal drug fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on the exposure of rivaroxaban and can be used concomitantly with it (see Interactions);

Patients with renal impairment (Cl creatinine 29–15 ml/min) or an increased risk of bleeding and patients receiving concomitant systemic treatment with azole antifungals or HIV protease inhibitors should be closely monitored after initiation of treatment for timely detection of bleeding complications.

Xarelto, 28 pcs., 20 mg, film-coated tablets

Pharmacokinetic interaction

Elimination of rivaroxaban occurs primarily through hepatic metabolism mediated by the cytochrome P450 system (CYP3A4, CYP2J2) and via renal excretion of unchanged drug using the P-gp/BCRP transporter systems.

Rivaroxaban does not suppress or induce the CYP3A4 isoenzyme and other important cytochrome isoforms.

Concomitant use of Xarelto and strong CYP3A4 and P-gp inhibitors may result in decreased renal and hepatic clearance and thus significantly increase systemic exposure.

The combined use of Xarelto® and the azole antifungal agent ketoconazole (at a dose of 400 mg 1 time per day), which is a strong inhibitor of CYP3A4 and P-gp, led to an increase in the average steady-state AUC of rivaroxaban by 2.6 times and an increase in the average Cmax of rivaroxaban by 1.7 times, which was accompanied by a significant increase in the pharmacodynamic effect of the drug.

Co-administration of Xarelto® and the HIV protease inhibitor ritonavir (at a dose of 600 mg 2 times a day), which is a strong inhibitor of CYP3A4 and P-gp, led to an increase in the average steady-state AUC of rivaroxaban by 2.5 times and an increase in the average Cmax of rivaroxaban by 1.6 times, which was accompanied by a significant increase in the pharmacodynamic effect of the drug. In this regard, Xarelto® is not recommended for use by patients receiving systemic treatment with azole antifungals or HIV protease inhibitors (see “Contraindications”, subsection WITH CAUTION).

Clarithromycin (at a dose of 500 mg 2 times a day), a strong inhibitor of the CYP3A4 isoenzyme and a moderate inhibitor of P-gp, caused an increase in AUC values ​​by 1.5 times and Cmax of rivaroxaban by 1.4 times. This increase is of the order of normal variability in AUC and Cmax and is considered clinically insignificant.

Erythromycin (at a dose of 500 mg 3 times a day), a moderate inhibitor of the CYP3A4 isoenzyme and P-gp, caused an increase in the AUC and Cmax values ​​of rivaroxaban by 1.3 times. This increase is of the order of normal variability in AUC and Cmax and is considered clinically insignificant.

In patients with renal impairment (creatinine clearance <80–50 mL/min), erythromycin (500 mg three times daily) increased rivaroxaban AUC by 1.8-fold and Cmax by 1.6-fold compared with patients with normal renal function. who did not receive concomitant therapy. In patients with renal insufficiency (Cl creatinine 49–30 ml/min), erythromycin caused an increase in rivaroxaban AUC values ​​by 2 times and Cmax by 1.6 times compared with patients with normal renal function who did not receive concomitant therapy (see “Contraindications” , subsection WITH CAUTION).

Fluconazole (at a dose of 400 mg once daily), a moderate inhibitor of the CYP3A4 isoenzyme, caused an increase in the average AUC of rivaroxaban by 1.4 times and an increase in the average Cmax by 1.3 times. This increase is of the order of normal variability in AUC and Cmax and is considered clinically insignificant.

Concomitant use of rivaroxaban with dronedarone should be avoided due to limited clinical data on coadministration.

Co-administration of Xarelto® and rifampicin, which is a strong inducer of CYP3A4 and P-gp, led to a decrease in the mean AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects.

Concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's wort) may also result in decreased plasma concentrations of rivaroxaban. The decrease in plasma concentrations of rivaroxaban was considered clinically insignificant. Strong CYP3A4 inducers should be used with caution.

Pharmacodynamic interaction

After simultaneous use of enoxaparin sodium (single dose 40 mg) and Xarelto® (single dose 10 mg), there was a summation of their effects on anti-Factor Xa activity, which was not accompanied by an additional summation effect on blood clotting tests (PT, APTT). Enoxaparin did not change the pharmacokinetics of rivaroxaban (see “Contraindications”, subsection CAUTIONS).

Due to the increased risk of bleeding, caution should be exercised when used together with any other anticoagulants (see "Contraindications", "CAUTIONS" and "Special Instructions").

No pharmacokinetic interaction was found between Xarelto® (at a dose of 15 mg) and clopidogrel (loading dose - 300 mg followed by a maintenance dose of 75 mg), but in a subgroup of patients a significant increase in bleeding time was found, which did not correlate with the degree of platelet aggregation and P content -selectin or GPIIb/IIIa receptor (see “Contraindications”, subsection WITH CAUTION).

After co-administration of Xarelto® (at a dose of 15 mg) and naproxen at a dose of 500 mg, no clinically significant increase in bleeding time was observed. However, a more pronounced pharmacodynamic response is possible in some individuals.

Caution should be exercised when using Xarelto® together with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors, since the use of these drugs usually increases the risk of bleeding.

Switching patients from warfarin (IHO 2 to 3) to Xarelto® (20 mg) or from Xarelto® (20 mg) to warfarin (MHO 2 to 3) increased PT/INR (Neoplastin®) more than expected would be expected by simple summation of the effects (individual MHO values ​​can be as high as 12), whereas the effects on aPTT, factor Xa suppression, and endogenous thrombin potential were additive.

If it is necessary to study the pharmacodynamic effects of Xarelto® during the transition period, anti-Xa activity, PiCT and HepTest® can be used as necessary tests that are not affected by warfarin. Starting from the 4th day after stopping the use of warfarin, all test results (including PT, aPTT, inhibition of factor Xa activity and effects on EPT - endogenous thrombin potential) reflect only the effect of Xarelto® (see "Dosage and Administration" ).

If it is necessary to study the pharmacodynamic effects of warfarin during the transition period, measuring the INR value at Spromezhat can be used. rivaroxaban (24 hours after the previous dose of rivaroxaban), since rivaroxaban has minimal effect on this indicator during this period.

No pharmacokinetic interactions have been reported between warfarin and Xarelto®.

The drug interaction of Xarelto® with VKA phenindione has not been studied. It is recommended, whenever possible, to avoid transferring patients from Xarelto® therapy to VKA phenindione therapy and vice versa.

There is limited experience converting patients from VKA acenocoumarol therapy to Xarelto®.

If there is a need to transfer a patient from Xarelto® therapy to VKA therapy with phenindione or acenocoumarol, special care should be taken; daily monitoring of the pharmacodynamic effects of the drugs (MHO, PT) should be carried out immediately before taking the next dose of Xarelto®.

If there is a need to transfer a patient from VKA therapy with phenindione or acenocoumarol to Xarelto® therapy, special care should be taken; monitoring of the pharmacodynamic effect of the drugs is not required.

Incompatibility. Unknown.

No interaction detected

No pharmacokinetic interactions have been identified between rivaroxaban and midazolam (CYP3A4 substrate), digoxin (P-gp substrate) or atorvastatin (CYP3A4 and P-gp substrate).

Co-administration with the proton pump inhibitor omeprazole, the H2 receptor antagonist ranitidine, the antacid aluminum/magnesium hydroxide, naproxen, clopidogrel or enoxaparin does not affect the bioavailability and pharmacokinetics of rivaroxaban.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with the combined use of Xarelto® and acetylsalicylic acid at a dose of 500 mg.

Effect on laboratory parameters. Xarelto® affects blood clotting parameters (PT, APTT, HepTest®) due to its mechanism of action.

Use during pregnancy and breastfeeding

The effectiveness and safety of Xarelto® in pregnant women have not been established.

Data obtained in experimental animals have shown pronounced maternal toxicity of rivaroxaban, associated with the pharmacological action of the drug (for example, complications in the form of hemorrhages) and leading to reproductive toxicity.

Due to the possible risk of bleeding and ability to cross the placenta, rivaroxaban is contraindicated during pregnancy.

Women with preserved reproductive capacity should use effective methods of contraception during treatment with Xarelto®.

There are no data on the use of Xarelto® for the treatment of women during breastfeeding. Data obtained in experimental animals show that rivaroxaban is excreted in breast milk. Rivaroxaban can be used only after breastfeeding has been stopped (see “Contraindications”).

Fertility. Studies have shown that rivaroxaban does not affect male or female fertility in rats. No studies have been conducted on the effects of rivaroxaban on fertility in humans.

Side effects

The safety of Xarelto® was assessed in four phase III studies involving 6097 patients undergoing major lower extremity orthopedic surgery (total knee or total hip replacement) and 3997 medically hospitalized patients treated with Xarelto® 10 mg for up to 39 days. and in three phase III studies for the treatment of VTE, including 4566 patients who received either 15 mg Xarelto® twice daily for 3 weeks, followed by 20 mg once daily, or 20 mg once daily before 21 months

In addition, two phase III studies, including 7,750 patients, provided safety data in patients with non-valvular atrial fibrillation who received at least one dose of Xarelto® for up to 41 months, as well as 10,225 patients with acute coronary artery disease. syndrome, receiving at least one dose of 2.5 mg (2 times a day) or 5 mg (2 times a day) Xarelto® in addition to therapy with acetylsalicylic acid or acetylsalicylic acid with clopidogrel or ticlopidine, treatment duration up to 31 months.

Given the mechanism of action, the use of Xarelto may be accompanied by an increased risk of latent or overt bleeding from any organs and tissues, which can lead to posthemorrhagic anemia. The risk of bleeding may increase in patients with uncontrolled arterial hypertension and/or when used together with drugs that affect hemostasis (see "Contraindications", subsection WITH CAUTION). Signs, symptoms, and severity (including possible death) vary depending on the location, intensity, or duration of bleeding and/or anemia (see Overdose). Hemorrhagic complications can manifest as weakness, pallor, dizziness, headache, shortness of breath, as well as enlargement of the limb or shock, which cannot be explained by other reasons. In some cases, symptoms of myocardial ischemia, such as chest pain and angina, developed as a result of anemia.

Known complications secondary to severe bleeding, such as compartment syndrome and renal failure due to hypoperfusion, have also been reported with the use of Xarelto®. Therefore, the possibility of bleeding should be considered when assessing any patient receiving anticoagulants.

A summary of the incidence of adverse reactions reported for Xarelto® is provided below. In groups divided by frequency, adverse effects are presented in order of decreasing severity as follows: often - from ≥1 to <10% (from ≥1/100 to <1/10); uncommon - from ≥0.1 to <1% (from ≥1/1000 to <1/100); rarely - from ≥0.01 to <0.1% (from ≥1/10000 to <1/1000); very rarely - <0.01% (<1/10000).

All adverse reactions that occurred during treatment in patients participating in phase III clinical trials

From the circulatory and lymphatic system: often - anemia (including relevant laboratory parameters); uncommon - thrombocythemia (including elevated platelet counts)*.

From the heart: infrequently - tachycardia.

From the organ of vision: often - hemorrhage in the eye (including hemorrhage in the conjunctiva).

From the digestive system: often - bleeding gums, gastrointestinal bleeding (including rectal bleeding), pain in the gastrointestinal tract, dyspepsia, nausea, constipation*, diarrhea, vomiting*; Uncommon: dry mouth.

Systemic disorders and reactions at the site of drug administration: often - fever*, peripheral edema, deterioration in general health (including weakness, asthenia); uncommon - malaise (including anxiety); rarely - local swelling*.

From the liver: infrequently - impaired liver function; rarely - jaundice.

From the immune system: rarely - allergic reactions, allergic dermatitis.

Injuries, poisoning and procedural complications: often - hemorrhages after procedures (including postoperative anemia and bleeding from a wound), excessive hematoma from a bruise; infrequently - discharge from the wound*; rarely - vascular pseudoaneurysm***.

Research results: often - increased activity of liver transaminases; infrequently - increased bilirubin concentration, increased alkaline phosphatase activity*, increased LDH activity*, increased lipase activity*, increased amylase activity*, increased GGT activity*; rarely - an increase in the concentration of conjugated bilirubin (with or without a concomitant increase in ALT activity).

From the musculoskeletal system and connective tissue: often - pain in the extremities*; infrequently - hemarthrosis; rarely - hemorrhage into the muscles.

From the nervous system: often - dizziness, headache; infrequently - intracerebral and intracranial hemorrhages, short-term fainting.

From the kidneys and urinary tract: often - bleeding from the urogenital tract (including hematuria and menorrhagia**), renal failure (including increased levels of creatinine, urea)*.

From the respiratory tract: often - nosebleeds, hemoptysis.

From the skin and subcutaneous tissues: often - itching (including rare cases of generalized itching), rash, ecchymosis, skin and subcutaneous hemorrhages; infrequently - urticaria.

Vascular disorders: often - marked decrease in blood pressure, hematoma.

*Registered after major orthopedic operations.

**Recorded as very common in the treatment of VTE in women <55 years of age.

***Recorded as uncommon in the prevention of sudden death and myocardial infarction in patients after acute coronary syndrome (after percutaneous interventions).

During post-marketing monitoring, cases of the following adverse reactions, the development of which had a temporary relationship with taking Xarelto, were reported. It is not possible to assess the frequency of occurrence of such adverse reactions within the framework of post-registration monitoring.

From the immune system: angioedema, allergic edema. In phase III randomized clinical trials (RCTs), such adverse events were considered uncommon (>1/1000 to <1/100).

From the liver: cholestasis, hepatitis (including hepatocellular damage). In the phase III RCT, such adverse events were considered rare (>1/10,000 to <1/1,000).

From the circulatory and lymphatic system: thrombocytopenia. In the phase III RCT, such adverse events were considered infrequent (>1/1000 to <1/100).

From the musculoskeletal system and connective tissue: frequency unknown - increased subfascial pressure syndrome (compartment syndrome) due to hemorrhage into the muscles.

From the kidneys and urinary tract: frequency unknown - renal failure/acute renal failure due to bleeding leading to renal hypoperfusion.

Xarelto®

Use of Concomitant Medications
The use of rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole antifungals (eg, ketoconazole) or HIV protease inhibitors (eg, ritonavir). These drugs are potent inhibitors of CYP3A4 and P-glycoprotein. Thus, these drugs may increase the plasma concentration of rivaroxaban to clinically significant levels (2.6-fold on average), which may lead to an increased risk of bleeding (see sections "Precautions", "Interactions with other drugs") .

However, the azole antifungal drug fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on the exposure of rivaroxaban and can be used concomitantly with it (see section "Interactions with other drugs").

Renal dysfunction

Rivaroxaban should be used with caution in patients with moderate renal impairment (CrCl 30-49 ml/min) receiving concomitant medications that may lead to increased plasma concentrations of rivaroxaban (see sections “With caution”, “Interaction with other drugs”). means").

In patients with severe renal impairment (CrCl < 30 ml/min), plasma concentrations of rivaroxaban may be significantly increased (1.6 times on average), which may lead to an increased risk of bleeding. Therefore, due to the presence of this underlying disease, such patients have an increased risk of developing both bleeding and thrombosis. Due to limited clinical data, rivaroxaban should be used with caution in patients with CrCl 15-29 ml/min.

There are no clinical data on the use of rivaroxaban in patients with severe renal impairment (CrCl <15 ml/min). Therefore, the use of Xarelto® is not recommended in such patients {see. sections “Contraindications”, “Method of administration and dosage”, “Pharmacological properties”). Patients with severe renal impairment (CrCl 15–29 mL/min), an increased risk of bleeding, or those receiving concomitant systemic treatment with azole antifungals or HIV protease inhibitors should be closely monitored for signs of bleeding after initiation of treatment.

Risk of bleeding

As with other anticoagulants, patients taking Xarelto should be carefully monitored for signs of bleeding.

In case of severe bleeding, Xarelto® should be discontinued.

In clinical studies, mucocutaneous bleeding (namely, bleeding from the nose, gums, gastrointestinal tract, genitourinary tract, including abnormal vaginal or increased menstrual bleeding) and anemia were observed more frequently during long-term treatment with rivaroxaban compared to VKA treatment. Thus, in addition to proper clinical monitoring, laboratory testing of hemoglobin/hematocrit may be useful in identifying occult bleeding and quantifying the clinical significance of overt bleeding that would be considered acceptable.

Xarelto®, like other antithrombotic agents, should be used with caution in patients at increased risk of bleeding, including:

• patients with a congenital or acquired tendency to bleeding;
• patients with uncontrolled severe arterial hypertension;
• patients with gastric and duodenal ulcers in the acute stage;
• patients who have recently suffered from gastric and duodenal ulcers;
• patients with vascular retinopathy;
• patients who have recently suffered intracranial or intracerebral hemorrhage;
• patients with pathology of the blood vessels of the brain or spinal cord;
• patients who have recently undergone surgery on the brain, spinal cord, or eyes;
• patients with a history of bronchiectasis or pulmonary hemorrhage.

Caution should be exercised if the patient is concomitantly receiving medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, other antithrombotics, or selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SNRIs). ) (see section “Interaction with other drugs”).

In patients at risk of developing gastric and duodenal ulcers, appropriate preventive treatment can be prescribed.

If there is an unexplained decrease in hemoglobin or blood pressure, it is necessary to look for the source of bleeding.

Rivaroxaban therapy does not require routine monitoring of its exposure.

However, measuring rivaroxaban concentrations using a calibrated test to quantify anti-Xa activity may be useful in exceptional cases where information about rivaroxaban exposure can be used to make clinically relevant decisions, such as in cases of overdose or emergency surgery.

Patients with artificial heart valves

Based on data from a randomized controlled clinical trial comparing Xarelto® therapy with antiplatelet therapy, Xarelto® is not recommended for the prevention of thrombosis in patients who have undergone recent transcatheter aortic valve replacement. The safety and effectiveness of Xarelto® have not been studied in patients with any other prosthetic heart valves or in patients undergoing other heart valve procedures; therefore, there is no data to support the use of Xarelto® 20 mg (15 mg in patients with moderate and severe renal impairment with ClCr 15-49 ml/min) provides a sufficient anticoagulant effect in these categories of patients.

Patients at high risk of triple positive antiphospholipid syndrome

The use of Xarelto® is not recommended in patients with a history of thrombosis who have been diagnosed with persistent triple positive antiphospholipid syndrome (the presence of lupus anticoagulant, antibodies to cardiolipin and antibodies to beta-2-glycoprotein I), since therapy with rivaroxaban is accompanied by an increased incidence of recurrent thrombotic events compared with vitamin K antagonist (VKA) therapy.

Patients with non-valvular atrial fibrillation who underwent PCI with stenting

There are data from an international clinical trial, the primary purpose of which was to evaluate safety in patients with non-valvular atrial fibrillation who underwent PCI with stenting. Data on effectiveness in this population are limited (see section "Dosage and Administration"). There are no data available for such patients with a history of stroke/transient ischemic attack.

Patients with hemodynamically unstable pulmonary embolism (PE) and patients requiring thrombolysis or thrombectomy

Rivaroxaban is not recommended as an alternative to unfractionated heparin in patients with hemodynamically unstable pulmonary embolism or in patients who may require thrombolysis or thrombectomy, since the safety and effectiveness of Xarelto in these clinical situations has not been established.

Surgical operations and interventions

If an invasive procedure or surgery is necessary, Xarelto® should be discontinued at least 24 hours before the procedure and based on the doctor's opinion.

If the procedure cannot be delayed, the increased risk of bleeding should be weighed against the need for urgent intervention.

Xarelto® should be restarted after an invasive procedure or surgery, provided that appropriate clinical indicators and adequate hemostasis are present (see section "Pharmacological properties").

Spinal anesthesia

When performing epidural/spinal anesthesia or spinal puncture in patients receiving platelet aggregation inhibitors to prevent thromboembolic complications, there is a risk of developing an epidural or spinal hematoma, which can lead to prolonged paralysis. The risk of these events is further increased by the use of an indwelling epidural catheter or concomitant therapy with drugs that affect hemostasis. Traumatic epidural or spinal puncture or repeat puncture may also increase the risk.

Patients should be monitored for signs and symptoms of neurological impairment (eg, numbness or weakness of the legs, bowel or bladder dysfunction). If neurological disorders are detected, urgent diagnosis and treatment are necessary.

The physician should weigh the potential benefit against the relative risk before performing spinal surgery in patients receiving anticoagulants or who are scheduled to receive anticoagulants for the purpose of preventing thrombosis. There is no clinical experience with the use of rivaroxaban in dosages of 15 mg and 20 mg in the situations described.

To reduce the potential risk of bleeding associated with concomitant use of rivaroxaban and epidural/spinal anesthesia or spinal puncture, the pharmacokinetic profile of rivaroxaban should be considered. Insertion or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is assessed as weak.

However, the exact time to achieve a sufficiently low anticoagulant effect in each patient is unknown. Based on general pharmacokinetic characteristics, the epidural catheter is removed after at least 2 times the elimination half-life, i.e. no earlier than 18 hours after the last dose of Xarelto® for young patients and no earlier than 26 hours for older patients. Xarelto® should be prescribed no earlier than 6 hours after removal of the epidural catheter.

In the event of a traumatic puncture, the administration of Xarelto® should be postponed for 24 hours.

Skin reactions

Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported during post-marketing surveillance. At the first appearance of a severe skin rash (eg, if it spreads, intensifies and/or blisters), or if other mucosal hypersensitivity symptoms occur, Xarelto therapy should be discontinued.

Women of reproductive age

Xarelto® should only be used by women of childbearing age if they are using effective contraception.

Corrected QT interval prolongation

There was no effect of Xarelto® on the duration of the QT interval.

Safety data obtained from nonclinical studies

With the exception of effects associated with enhanced pharmacological action (bleeding), analysis of preclinical data obtained in pharmacological safety studies did not reveal any specific hazard to humans.