Xarelto 2.5 mg instructions for use. Application for violations of kidney function

Mechanism of action

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

Activation of factor X to form factor Xa via the intrinsic and extrinsic coagulation pathways plays a central role in the coagulation cascade. Factor Xa is a component of the emerging prothrombinase complex, the action of which leads to the conversion of prothrombin to thrombin. As a result, these reactions lead to the formation of a fibrin thrombus and activation of platelets by thrombin. One molecule of factor Xa catalyzes the formation of more than 1000 thrombin molecules, which is called the "thrombin explosion". The reaction rate of prothrombinase-bound factor Xa increases by 300,000 times compared to that of free factor Xa, which provides a sharp jump in thrombin levels. Selective factor Xa inhibitors can stop the "thrombin burst". Thus, rivaroxaban affects the results of some specific or general laboratory tests used to evaluate clotting systems. In humans, there is a dose-dependent inhibition of factor Xa activity.

Pharmacodynamic effects

In patients undergoing major orthopedic surgery, the 5/95th percentile for prothrombin time (Neoplastin®) 2-4 hours after taking the tablet (ie, at the maximum effect) varies from 13 to 25 seconds.

Also, rivaroxaban dose-dependently increases the APTT and the result of HepTest ® ; however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban. Rivaroxaban also interferes with anti-factor Xa activity, but calibration standards are not available.

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 QT interval on the ECG under the influence of rivaroxaban was not observed.

Pharmacokinetics

Suction

After oral administration, rivaroxaban is rapidly absorbed; C max is achieved 2-4 hours after taking the pill.

After oral administration, rivaroxaban is rapidly and almost completely absorbed. C max is achieved 2-4 hours after taking the pill. The bioavailability of rivaroxaban when taking 2.5 mg and 10 mg tablets is high (80-100%), regardless of food intake. Eating does not affect AUC and Cmax when taking the drug at a dose of 10 mg. Xarelto ® tablets at a dosage of 2.5 mg and 10 mg can be taken both with food and on an empty stomach.

The pharmacokinetics of rivaroxaban is characterized by moderate interindividual variability, the coefficient of variability Cv% ranges from 30% to 40%.

Distribution

Rivaroxaban has a high degree of binding to plasma proteins - approximately 92-95%, mainly rivaroxaban binds to serum albumin. The drug has an average V d - approximately 50 liters.

Metabolism and excretion

Rivaroxaban is metabolized by CYP3A4, CYP2J2 isoenzymes, as well as by 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 carrier proteins P-gp (P-glycoprotein) and Bsrr (breast cancer resistance protein).

Unchanged rivaroxaban is the only active compound in plasma, with no major or active circulating metabolites found in plasma. Rivaroxaban, with a systemic clearance of approximately 10 L/h, can be classified as a low clearance drug.

breeding

With the removal of rivaroxaban from plasma, the final half-life is 5 to 9 hours in young patients and 11 to 13 hours in elderly patients.

Pharmacokinetics in special clinical situations

Age. In elderly patients over 65 years of age, the plasma concentration of rivaroxaban is 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 an apparent decrease in total and renal clearance.

Floor. In men and women, clinically significant differences in pharmacokinetics were not found.

Body mass. Too little or too much body weight (less than 50 kg and more than 120 kg) only slightly affects the concentration of rivaroxaban in plasma (the difference is less than 25%).

Childhood. Data on pharmacokinetics in children are not available.

Interethnic differences. Clinically significant differences in pharmacokinetics and pharmacodynamics in patients of Caucasian, Negroid, Asian race, as well as Hispanic, Japanese or Chinese ethnicity were not observed.

Liver dysfunction. The effect of hepatic insufficiency on the pharmacokinetics of rivaroxaban was studied in patients divided into classes according to the Child-Pugh classification (according to standard procedures in clinical studies). The Child-Pugh classification makes it possible to assess the prognosis of chronic liver diseases, mainly cirrhosis. In patients who are scheduled for anticoagulant therapy, a particularly important critical moment of liver dysfunction is a decrease in the synthesis of blood coagulation factors in the liver. Because this indicator meets 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. Treatment of such patients with anticoagulants should be considered regardless of Child-Pugh class.

Xarelto ® is contraindicated in patients with liver disease that occurs with coagulopathy, causing 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 (on average, there was an increase in AUC of rivaroxaban by 1.2 times). There were no significant differences in pharmacodynamic properties between groups.

In patients with cirrhosis of the liver and moderate hepatic insufficiency (Child-Pugh class B), the mean AUC of rivaroxaban was significantly increased (2.3-fold) compared with healthy volunteers due to a significantly reduced clearance of the drug substance, indicating a serious liver disease. The suppression of factor Xa activity was more pronounced (2.6 times) than in healthy volunteers. Prothrombin time was also 2.1 times higher than in healthy volunteers. By measuring the prothrombin time, 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 insufficiency are more sensitive to rivaroxaban, which is a consequence of a closer relationship between pharmacodynamic effects and pharmacokinetic parameters, especially between concentration and prothrombin time.

There are no data on the use of the drug in patients with Child-Pugh class C hepatic insufficiency. Therefore, rivaroxaban is contraindicated in patients with cirrhosis of the liver and Child-Pugh B and C hepatic impairment.

Kidney dysfunction. In patients with renal insufficiency, an increase in rivaroxaban exposure was observed, inversely proportional to the degree of decrease in renal function, which was assessed by CC.

In patients with mild renal insufficiency (CC 50-80 ml / min), moderate (CC 30-49 ml / min) or severe (CC 15-29 ml / min) severity, a 1.4-, 1.5- and 1.6-fold increase in rivaroxaban plasma concentrations (AUC), respectively, compared with healthy volunteers. The corresponding increase in pharmacodynamic effects was more pronounced.

In patients with mild, moderate and severe renal insufficiency, the total suppression of factor Xa activity increased by 1.5, 1.9 and 2 times compared with healthy volunteers; prothrombin time due to the action of factor Xa also increased by 1.3, 2.2 and 2.4 times, respectively.

Data on the use of Xarelto ® in patients with CC 15-29 ml / min are limited, and therefore caution should be exercised when using the drug in this category of patients. Data on the use of rivaroxaban in patients with CC<15 мл/мин отсутствуют, в связи с чем не рекомендуется применять препарат у данной категории пациентов.

Release form

Tablets, film-coated, light yellow, round, biconvex; on one side, a triangle with the designation of the dosage "2.5" is applied by extrusion, on the other side, the Bayer logo in the form of a cross; in cross section, the nucleus is white.

	1 tab.
rivaroxaban (micronized)	2.5 mg

Excipients: microcrystalline cellulose - 40 mg, croscarmellose sodium - 3 mg, hypromellose 5cP - 3 mg, lactose monohydrate - 35.7 mg, magnesium stearate - 0.6 mg, sodium lauryl sulfate - 0.2 mg.

The composition of the film shell: iron dye yellow oxide - 0.015 mg, hypromellose 15cP - 1.5 mg, macrogol 3350 - 0.5 mg, titanium dioxide - 0.485 mg.

10 pieces. - blisters (10) - packs of cardboard.
14 pcs. - blisters (1) - packs of cardboard.
14 pcs. - blisters (2) - packs of cardboard.
14 pcs. - blisters (4) - packs of cardboard.
14 pcs. - blisters (7) - packs of cardboard.
14 pcs. - blisters (12) - packs of cardboard.
14 pcs. - blisters (14) - packs of cardboard.

Dosage

Take orally 2.5 mg (1 tab.) 2 times / day, regardless of food intake.

After acute coronary syndrome, the recommended dose of Xarelto ® is 2.5 mg (1 tab.) 2 times / day. Patients also need to take acetylsalicylic acid at a dose of 75-100 mg / day or acetylsalicylic acid at a dose of 75-100 mg / day in combination with clopidogrel at a dose of 75 mg / day or ticlopidine at a standard daily dose.

The ongoing treatment should be regularly evaluated in terms of maintaining a balance between the risk of ischemic events and the risk of bleeding. The duration of treatment is 12 months. Treatment may be extended up to 24 months for selected patients, as there are limited data on treatment for this duration.

Treatment with Xarelto 2.5 mg should be started as soon as possible after the patient has stabilized during the current ACS (including revascularization procedures). Treatment with Xarelto® should begin at least 24 hours after hospitalization. Xarelto 2.5 mg should be started when parenteral anticoagulants are usually discontinued.

If the dose is missed, then you should continue taking the drug at a dose of 2.5 mg at the next scheduled dose.

If the patient is unable to swallow the tablet whole, the Xarelto ® tablet can be crushed or mixed with water or liquid food such as applesauce immediately before taking. The crushed Xarelto ® tablet can be administered through a gastric tube. The position of the probe in the gastrointestinal tract must be additionally 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 it is necessary to introduce a small amount of water in order to wash off the remnants of the drug from the walls of the tube.

Limited clinical data from patients with moderate hepatic impairment (Child-Pugh class B) indicate a significant increase in pharmacological activity. There are no clinical data available for patients with severe hepatic impairment (Child-Pugh class C).

< 15 мл/мин.

Switching from Vitamin K Antagonists (VKAs) to Xarelto®: When patients switch from VKAs to Xarelto®, MHO values will be erroneously high after taking Xarelto®. MHO is not suitable for determining the anticoagulant activity of Xarelto ® , so this indicator is not used for this purpose.

Switching from Xarelto ® therapy to vitamin K antagonist therapy: There is a possibility of insufficient anticoagulant effect when switching from Xarelto ® therapy to VKA therapy. 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 during the transition from Xarelto ® therapy to VKA therapy, Xarelto ® may contribute to an increase in MHO.

In patients switching from Xarelto therapy to VKA therapy, the latter should be taken continuously until the MHO value is ≥2.0. In the first 2 days of the transition period, VKA should be used at standard doses, subsequently adapting the dose of VKA according to the INR value. Because patients during this period receive both the drug Xarelto ® and VKA, MHO should be assessed no earlier than 24 hours (after the first dose, but before the next dose of Xarelto ®). Thus, after discontinuation of Xarelto ® , MHO as a reliable assessment of the therapeutic effect of VKA can be used no earlier than 24 hours after the last dose of Xarelto ® .

Switching from parenteral anticoagulant therapy to Xarelto ® therapy: for patients receiving parenteral anticoagulants, Xarelto ® should be started 0-2 hours before the time of the next planned parenteral administration of the drug (for example, low molecular weight heparin) or at the time of cessation of continuous parenteral administration of the drug ( e.g. intravenous unfractionated heparin).

Switching from Xarelto ® therapy to parenteral anticoagulant therapy: Xarelto ® should be discontinued and the first dose of parenteral anticoagulant administered at the time when the next dose of Xarelto ® should be taken.

The safety and efficacy of the drug in children and adolescents under 18 years of age have not been established.

In elderly patients, dose adjustment is not required.

Dose adjustment of Xarelto ® is not required depending on gender, body weight, ethnicity.

Overdose

Rare cases of overdose have been reported with rivaroxaban up to 600 mg without bleeding or other adverse reactions. Due to limited absorption, a concentration plateau is expected without further increase in the mean plasma concentration of rivaroxaban when used at excessive doses of 50 mg or higher.

Treatment: The specific antidote for rivaroxaban is unknown. In case of an overdose of Xarelto®, activated charcoal can be used to reduce the absorption of rivaroxaban. Due to the significant binding of rivaroxaban to plasma proteins, it is expected that rivaroxaban will not be excreted by hemodialysis.

If a complication occurs in the form of bleeding, the next dose of the drug should be postponed or the treatment should be discontinued altogether. T 1 / 2 rivaroxaban leaves approximately 5-13 hours. Treatment should be selected individually, depending on the severity and location of bleeding.

If necessary, appropriate symptomatic treatment can be performed, such as mechanical compression (for example, for severe nosebleeds), surgical hemostasis with evaluation of its effectiveness (bleeding control), fluid therapy and hemodynamic support, use of blood products (erythrocyte mass or fresh frozen plasma, depending anemia or coagulopathy) or platelets.

If the above measures do not lead to elimination of bleeding, specific reversible procoagulant drugs can be used, such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa. However, there is currently very limited experience with these drugs in patients receiving Xarelto ® .

It is expected that protamine sulfate and vitamin K will not affect the anticoagulant activity of rivaroxaban.

There is no experience with the use of antifibrinolytic drugs (tranexamic acid, aminocaproic acid) in patients receiving Xarelto ® . There is no evidence to support or experience with the systemic haemostatic agents desmopressin and aprotinin in patients receiving Xarelto®.

Interaction

Pharmacokinetic interaction

Elimination of rivaroxaban occurs mainly through hepatic metabolism mediated by CYP3A4, CYP2J2 isoenzymes, as well as through renal excretion of unchanged drug with the participation of P-glycoprotein/Bcrp.

Rivaroxaban does not inhibit or induce the CYP3A4 isoenzyme and any other major isoenzymes of the cytochrome P450 system.

Co-administration of Xarelto® with potent inhibitors of CYP3A4 and P-glycoprotein may result in reduced renal and hepatic clearance and thus significantly increase systemic exposure.

Simultaneous use of the drug Xarelto ® and the azole antifungal drug ketoconazole (400 mg 1 time / day), a powerful inhibitor of CYP3A4 and P-glycoprotein, led to an increase in the average equilibrium 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 enhancing the pharmacodynamic effects of Xarelto ® .

Co-administration of Xarelto with the HIV protease inhibitor ritonavir (600 mg twice daily), which is a strong inhibitor of CYP3A4 and P-glycoprotein, resulted in a 2.5-fold increase in the mean steady-state AUC of rivaroxaban and a 1.6-fold increase in the mean Cmax of rivaroxaban, which was accompanied by a significant increase in the pharmacodynamic effects of the drug.

Other active agents that inhibit at least one of the rivaroxaban elimination pathways mediated by either CYP3A4 or P-gp are likely to increase plasma concentrations of rivaroxaban to a lesser extent.

Clarithromycin (500 mg 2 times / day), a potent inhibitor of the CYP3A4 isoenzyme and a moderate inhibitor of P-glycoprotein, 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 C max and is considered clinically insignificant.

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

Fluconazole (400 mg 1 time / day), 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 C max and is considered clinically insignificant.

Co-administration of Xarelto® and rifampicin, which is a strong inducer of CYP3A4 and P-glycoprotein, resulted in a decrease in the mean AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects. Co-administration of Xarelto with other strong CYP3A4 inducers (eg, phenytoin, carbamazepine, phenobarbital, or St. John's wort) may also result in decreased plasma concentrations of rivaroxaban.

Strong CYP3A4 inducers should be used with caution in post-ACS patients receiving Xarelto 2.5 mg twice daily.

Pharmacodynamic interaction

After the simultaneous use of enoxaparin sodium (40 mg once) and the drug Xarelto ® (10 mg once), a cumulative effect of suppression of anti-factor Xa activity was observed without any additional effect on coagulation parameters (prothrombin time, APTT). Enoxaparin does not affect the pharmacokinetics of rivaroxaban.

There was no pharmacokinetic interaction of clopidogrel (loading dose of 300 mg followed by a maintenance dose of 75 mg) with Xarelto ® (at a dose of 15 mg), however, a significant increase in bleeding time was registered in a subgroup of patients, which did not correlate with the degree of platelet aggregation, the number of receptors to P-selectin or GPIIb/IIIa.

After the simultaneous use of the drug Xarelto ® (15 mg) and naproxen (500 mg), no clinically significant prolongation of bleeding time was observed. However, in some patients, a more pronounced pharmacodynamic response is possible.

Caution should be exercised when co-administering rivaroxaban with dronedarone due to limited clinical data on co-administration.

Due to the increased risk of bleeding, caution is required when co-administered with any other anticoagulant.

Use Xarelto with caution in conjunction with NSAIDs (including acetylsalicylic acid) and antiplatelet agents, since the use of these drugs usually increases the risk of bleeding.

Switching patients from warfarin (MHO 2 to 3) to Xarelto® (20 mg) or Xarelto® (20 mg) to warfarin (MHO 2 to 3) increased prothrombin time/INR (Neoplastin) more than simple summation effects (individual INR values can reach 12), while the effects of changes in APTT, suppression of factor Xa activity and endogenous thrombin potential (EPT) were additive.

If it is necessary to study the pharmacodynamic effects of Xarelto ® during the transition period, anti-factor Xa activity, prothrombinase-induced clotting time and Hep Test ® can be used as necessary tests that are not affected by warfarin. Starting from the 4th day after discontinuation of warfarin, all tests (including prothrombin time, APTT, inhibition of factor Xa activity and on EPT (endogenous thrombin potential)) reflect only the effect of Xarelto ® .

To assess the pharmacodynamic effects of warfarin during the transition period, you can use the MHO indicator measured at the time of reaching Cmax of rivaroxaban (24 hours after taking a dose of rivaroxaban), since at this point in time rivaroxaban has practically no effect on this indicator.

Pharmacokinetic interaction between warfarin and Xarelto ® has not been registered.

No interaction

There is no pharmacokinetic interaction between rivaroxaban and midazolam (CYP3A4 substrate), digoxin (P-glycoprotein substrate), or atorvastatin (CYP3A4 and P-glycoprotein substrate).

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

No clinically significant pharmacokinetic and pharmacodynamic interactions have been identified with the combined use of Xarelto ® and acetylsalicylic acid at a dose of 500 mg.

Impact on laboratory parameters

Xarelto ® affects blood clotting parameters (prothrombin time, APTT, Hep Test ®) due to its mechanism of action.

Side effects

The safety of Xarelto® was assessed in four phase III studies involving 6097 patients undergoing major orthopedic surgery on the lower extremities (total hip replacement or total knee replacement) and 3997 patients hospitalized for medical reasons treated with Xarelto® 10 mg for up to 39 days, as well as in 2 phase III studies in the treatment of venous thromboembolism, which included 2194 patients who received Xarelto ® either 15 mg 2 times / day for 3 weeks, followed by a dose of 20 mg 1 time / day, or 20 mg 1 time / day with a duration of treatment up to 21 months.

In addition, two phase III studies involving 7,750 patients provided safety data for the drug in patients with non-valvular atrial fibrillation who received at least one dose of Xarelto ®, as well as in 10,225 patients with ACS who received, at least one dose of Xarelto ® 2.5 mg (2 times / day) or 5 mg (2 times / day) Xarelto ® in combination with either acetylsalicylic acid or acetylsalicylic acid with clopidogrel or ticlopidine.

Due to the pharmacological mechanism of action, the use of Xarelto ® may be accompanied by an increased risk of occult or overt bleeding from any organs and tissues, which can lead to post-hemorrhagic anemia. The risk of bleeding may increase in patients with severe uncontrolled hypertension and / or when used together with drugs that affect hemostasis.

Signs, symptoms, and severity (including possible death) vary depending on the location, intensity, or duration of bleeding and/or anemia.

Hemorrhagic complications may present with weakness, pallor, dizziness, headache, unexplained edema, dyspnea, or shock that cannot be explained by other causes. In some cases, due to anemia, symptoms of myocardial ischemia developed, such as chest pain and angina pectoris.

When taking Xarelto ®, such well-known complications secondary to severe bleeding, such as prolonged compression syndrome and renal failure due to hypoperfusion, were recorded. Therefore, the possibility of bleeding should be taken into account when assessing the condition of a patient receiving anticoagulants.

Summarized data on the frequency of adverse reactions registered for Xarelto ® are given below. In groups divided by frequency, undesirable effects are presented in decreasing order of their severity, as follows: very often (≥1/10); often (≥1/100 -<1/10); нечасто (≥1/1000 - <1/100); редко (≥1/10 000 - <1/1000).

Table. All treatment-related adverse drug reactions reported in patients in phase III clinical trials (cumulative data from RECORD 1-4, EINSTEIN-DVT (deep vein thrombosis), ROCKET AF, J-ROCKET AF, MAGELLAN, ATLAS and EINSTEIN (DVT/ PE/Extension)

Often	Infrequently	Rarely
From the hematopoietic and lymphatic systems
Anemia (including relevant laboratory values)	Thrombocythemia, including increased platelet count) A
From the side of the cardiovascular system
Pronounced decrease in blood pressure Hematoma	Tachycardia
From the organ of vision
Hemorrhage in the eye (including hemorrhage in the conjunctiva)
From the digestive system
Bleeding gums Gastrointestinal bleeding (including rectal bleeding) Stomach ache Dyspepsia Nausea Constipation A Diarrhea Vomit A	Dry mouth
General disorders
Fever A peripheral edema Decreased overall muscle strength and tone (including weakness and asthenia)	Deterioration in general well-being (including malaise)	local edema
From the side of the liver and biliary tract
	Impaired liver function	Jaundice
From the side of the immune system
	Allergic reaction Allergic dermatitis
Injury, poisoning and complications after manipulation
Bleeding after medical manipulation (including postoperative anemia and bleeding from a postoperative wound) Injury Secretion from wound A		Vascular pseudoaneurysm C
From the side of the results of laboratory and instrumental studies
Increased activity of hepatic transaminases	Increasing the concentration of bilirubin Increased activity of alkaline phosphatase A Increasing activity LDH A Increased activity of lipase A Increased activity of amylase A Increased activity of GGT A	Increase in conjugated bilirubin (with or without a corresponding increase in ALT activity)
From the musculoskeletal system, connective tissue and bones
Pain in limbs A	Hemarthrosis	Hemorrhage into the muscle
From the side of the nervous system
Dizziness Headache	Intracerebral and intracranial hemorrhages Fainting
From the urinary and reproductive system
Bleeding from the urogenital tract (including hematuria and menorrhagia B) Kidney damage (including increased blood creatinine, increased blood urea)
From the side of the respiratory tract
Nose bleed Hemoptysis
From the side of the skin and subcutaneous fat
Skin pruritus (including infrequent cases of generalized pruritus) Rash ecchymosis Skin and subcutaneous hemorrhages	Hives

A - observed mainly after major orthopedic surgeries

B - observed during the treatment of VTE as very frequent in women aged<55 лет

C - observed as infrequent in the prevention of complications in ACS (after percutaneous interventions)

The most common adverse reactions in patients treated with the drug were bleeding. The most common bleeding events (≥4%) were epistaxis (5.9%) and gastrointestinal bleeding (4.2%).

Overall, 67% of patients who received at least one dose of rivaroxaban developed adverse reactions requiring therapy. In approximately 22% of patients, according to the researchers, adverse reactions were associated with the use of the drug. When using the drug Xarelto ® 10 mg in patients undergoing knee or hip arthroplasty, as well as in patients with prolonged immobilization during hospitalization, cases of bleeding were observed in approximately 6.8% and 12.6% of patients, respectively, and cases of anemia in approximately 5.9% and 2.1 % of patients, respectively. In patients treated with Xarelto at a dose of 15 mg 2 times / day and then switched to 20 mg 1 time / day for the treatment of DVT or PE, or 20 mg for the prevention of recurrence of DVT or PE, bleeding was observed in approximately 22.7% of patients, anemia occurred in approximately 2.2% of patients. In patients taking the drug for the prevention of stroke and systemic thromboembolism, the frequency of bleeding of varying severity was 28 per 100 person-years, anemia - 2.5 per 100 person-years. In patients taking the drug to prevent death due to cardiovascular causes of myocardial infarction in patients after ACS, the frequency of bleeding of varying severity was 22 per 100 person-years, anemia occurred in 1.4 per 100 person-years.

As part of post-registration surveillance programs, cases of angioedema and allergic edema have been reported, the development of which had a temporal relationship with the use of Xarelto ® . It is not possible to estimate the frequency of occurrence of such an undesirable effect within the framework of an observational program. As part of a phase III randomized clinical trial, such adverse effects were regarded as infrequent (≥1/1000-≤1/100).

Indications

prevention of death due to cardiovascular causes and myocardial infarction in patients after acute coronary syndrome (ACS), occurring with an increase in cardiospecific biomarkers, in combination therapy with acetylsalicylic acid or acetylsalicylic acid and thienopyridines - clopidogrel or ticlopidine.

Contraindications

hypersensitivity to the components of the drug;
clinically significant active bleeding (eg, intracranial hemorrhage, gastrointestinal bleeding);
liver diseases occurring with coagulopathy, which causes a clinically significant risk of bleeding, incl. cirrhosis of the liver and violations of the liver class B and C according to the Child-Pugh classification;
pregnancy;
lactation period (breastfeeding);
children and adolescents under 18 years of age (efficacy and safety for patients of this age group have not been established);
clinical data on the use of rivaroxaban in patients with severe renal insufficiency (CC<15 мл/мин) отсутствуют, поэтому применение ривароксабана у данной категории пациентов противопоказано;
treatment of ACS with antiplatelet agents in patients who have had a stroke or transient ischemic attack;
concomitant therapy with any other anticoagulants, for example, unfractionated heparin, low molecular weight heparins (including enoxaparin, dalteparin), heparin derivatives (including fondaparinux), oral anticoagulants (including warfarin, apixaban, dabigatran ), except when switching from or to rivaroxaban or when using unfractionated heparin at doses necessary to ensure the functioning of a central venous or arterial catheter;
congenital lactase deficiency, lactose intolerance, malabsorption of glucose-galactose (due to the presence of lactose in the preparation).

The drug should be used with caution:

in the treatment of patients with an increased risk of bleeding (including with congenital or acquired tendency to bleeding, uncontrolled severe arterial hypertension, peptic ulcer of the stomach and duodenum in the acute phase, recent acute peptic ulcer of the stomach and duodenum, vascular retinopathy, recently previous intracranial or intracerebral hemorrhage, with vascular pathology of the spinal cord or brain, after a recent operation on the brain, spinal cord and eyes, bronchiectasis or pulmonary bleeding in history);
in the treatment of patients with moderate renal insufficiency (CC 30-49 ml / min), receiving simultaneously drugs that increase the concentration of rivaroxaban in the blood plasma;
in the treatment of patients with severe renal insufficiency (CC 15-29 ml / min), caution should be exercised, since the concentration of rivaroxaban in the blood plasma in such patients can increase significantly (1.6 times on average) and as a result they have an increased risk of bleeding;
in patients receiving drugs that affect hemostasis (for example, NSAIDs, antiplatelet agents or other antithrombotic agents);
Xarelto is not recommended for use in 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-glycoprotein. As a consequence, these drugs may increase the plasma concentration of rivaroxaban to a clinically significant level (2.6-fold on average), which increases the risk of bleeding. Fluconazole (an antifungal drug of the azole group), a moderate inhibitor of CYP3A4, has a less pronounced effect on the elimination of rivaroxaban and can be used simultaneously;
patients with severe renal insufficiency or an increased risk of bleeding and patients receiving concomitant systemic treatment with azole antifungals or HIV protease inhibitors should be closely monitored after the start of treatment to detect bleeding complications in a timely manner.

Application features

Use during pregnancy and lactation

The efficacy and safety of Xarelto ® in pregnant women has not been established.

Data obtained in experimental animals have shown severe 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 the ability to cross the placental barrier, Xarelto ® is contraindicated in pregnancy.

In women of childbearing age, Xarelto should only be used if effective contraceptive methods are being used.

The efficacy and safety of Xarelto ® in lactating women has not been established. Data obtained in experimental animals show that rivaroxaban is excreted in breast milk. Xarelto ® can only be used after breastfeeding has stopped.

Application for violations of liver function

Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy leading to a clinically significant risk of bleeding. Patients with other liver diseases do not require dose adjustment.

Application for violations of kidney function

In patients with impaired renal function of mild (CC 50-80 ml / min) or moderate (CC 30-49 ml / min) severity, dose adjustment of Xarelto ® is not required.

In patients with severe renal impairment (CC 15-29 ml / min), Xarelto ® should be used with caution, because. limited clinical data indicate that plasma levels of rivaroxaban are significantly elevated in this patient population. The use of Xarelto ® is contraindicated in patients with CC< 15 мл/мин.

Use in children

Contraindication: children and adolescents under 18 years of age (efficacy and safety for patients of this age group have not been established).

Use in elderly patients

Dose adjustment depending on the age of the patient (over 65 years) is not required.

special instructions

The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with azole antifungals (eg ketoconazole) or HIV protease inhibitors (eg ritonavir). These drugs are strong inhibitors of CYP3A4 and P-glycoprotein. Thus, these drugs can increase the plasma concentration of rivaroxaban to clinically significant levels (by an average of 2.6 times), which may lead to an increased risk of bleeding.

However, the azole antifungal drug fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on rivaroxaban exposure and can be co-administered with it.

The effect of the drug Xarelto ® on the duration of the QT c interval was not revealed.

kidney failure

Xarelto should be used with caution in patients with moderate renal impairment (CC 30-49 ml / min) receiving concomitant drugs that can lead to an increase in plasma concentrations of rivaroxaban.

In patients with severe renal impairment (CK<30 мл/мин) концентрация ривароксабана в плазме может быть значительно повышенной (в 1.6 раза в среднем), что может привести к повышенному риску кровотечения. Поэтому, вследствие наличия указанного основного заболевания такие пациенты имеют повышенный риск развития, как кровотечений, так и тромбозов. В связи с ограниченным количеством клинических данных препарат Ксарелто ® следует с осторожностью применять у пациентов с КК 15-29 мл/мин.

Clinical data for patients with severe renal impairment (CK<15 мл/мин) не имеется. Поэтому у данной категории пациентов применение препарата Ксарелто ® противопоказано.

Patients with severe renal impairment or an increased risk of bleeding, as well as patients receiving concomitant systemic treatment with azole antifungals or HIV protease inhibitors, should be carefully monitored for signs of bleeding after initiation of treatment. Monitoring can be carried out by conducting a regular physical examination of patients, careful monitoring of the condition of the drainage of the postoperative wound, and also by periodically determining hemoglobin.

Patients with a history of stroke or transient ischemic attack (TIA)

Taking Xarelto ® at a dose of 2.5 mg 2 times / day is contraindicated in patients with ACS who have a history of stroke or TIA. Only a few patients with ACS with a history of stroke or TIA have been studied, so data on the effectiveness of the drug in these patients is extremely limited.

Risk of bleeding

Xarelto ® , like other antithrombotic agents, should be used with caution in diseases and conditions associated with an increased risk of bleeding, such as:

congenital or acquired coagulation disorders;
uncontrolled severe arterial hypertension;
active gastrointestinal pathology with ulceration;
a recent acute ulcer in the gastrointestinal tract;
vascular retinopathy;
recent intracranial or intracerebral hemorrhage;
intraspinal or intracerebral vascular anomalies;
recent surgery on the brain, spinal cord, or ophthalmic surgery;
bronchiectasis or an episode of pulmonary hemorrhage in history.

Caution should be exercised if the patient is simultaneously receiving drugs that affect hemostasis, such as NSAIDs, platelet aggregation inhibitors, or other antithrombotic drugs.

Patients after ACS receiving Xarelto ® in combination with acetylsalicylic acid or Xarelto ® in combination with acetylsalicylic acid and clopidogrel / ticlopidine, as long-term concomitant treatment, can receive NSAIDs only if the positive effects of treatment justify the existing risk of bleeding.

In patients at risk of developing gastrointestinal ulcers, appropriate prophylactic treatment can be used.

With any unexplained decrease in hemoglobin or blood pressure, the source of bleeding should be identified.

The efficacy and safety of Xarelto® have been studied in combination with the antiplatelet agent acetylsalicylic acid and clopidogrel/ticlopidine. The use in combination therapy with other antiplatelet agents (for example, prasugrel or ticagrelor) has not been studied, therefore it is not recommended for use.

spinal anesthesia

When performing epidural/spinal anesthesia or lumbar puncture in patients receiving inhibitors of platelet aggregation to prevent thromboembolic complications, there is a risk of epidural or spinal hematoma, which can lead to long-term 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 lumbar puncture or re-puncture may also increase the risk. Patients should be monitored for signs or symptoms of neurological disorders (eg, leg numbness or weakness, bowel or bladder dysfunction). If neurological disorders are detected, urgent diagnosis and treatment is necessary. The clinician should weigh the potential benefit against the relative risk before performing a spinal intervention in patients receiving anticoagulants or who are scheduled to receive anticoagulants to prevent thrombosis. The epidural catheter is removed no earlier than 18 hours after the last dose of rivaroxaban. Rivaroxaban should not be given earlier than 6 hours after removal of the epidural catheter. In case of traumatic puncture, the administration of rivaroxaban should be postponed for 24 hours.

Surgical operations and interventions

If an invasive procedure or surgical intervention is necessary, Xarelto 2.5 mg should be discontinued at least 24 hours before the intervention, if possible, and based on the clinical judgment of the physician.

If there is no need for an antiplatelet effect in a patient undergoing elective surgery, the use of platelet aggregation inhibitors should be discontinued, as indicated in the instructions for use of the drug provided by the manufacturer.

If the procedure cannot be delayed, then a comparative assessment of the increased risk of bleeding should be made and the need for urgent intervention should be decided.

Xarelto should be restarted after an invasive procedure or surgery as soon as possible, provided that clinical parameters permit and adequate hemostasis is achieved.

Influence on the ability to drive vehicles and control mechanisms

While taking the drug, the occurrence of fainting and dizziness was noted, which may affect the ability to drive vehicles or other mechanisms. Patients who experience such adverse reactions should not drive vehicles or other mechanisms.

In this article, you can read the instructions for using the drug Xarelto. Reviews of site visitors - consumers of this medicine, as well as opinions of doctors of specialists on the use of Xarelta in their practice are presented. We kindly ask you to actively add your reviews about the drug: the medicine helped or did not help get rid of the disease, what complications and side effects were observed, perhaps not declared by the manufacturer in the annotation. Analogues of Xarelta in the presence of existing structural analogues. Use for the treatment of thrombosis, embolism and the prevention of stroke and heart attack in adults, children, as well as during pregnancy and lactation. The composition of the drug.

Xarelto- selective direct inhibitor of factor 10a for oral administration. Activation of factor 10 to form factor 10a via intrinsic and extrinsic pathways plays a central role in the coagulation cascade.

Rivaroxaban (the active ingredient in Xarelto) has a dose-dependent effect on prothrombin time and is highly correlated with plasma concentrations when analyzed using the Neoplastin kit (results will vary with other reagents).

Also, rivaroxaban dose-dependently increases the APTT and the Heptest result, however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban.

Compound

Rivaroxaban (micronized) + excipients.

Pharmacokinetics

After oral administration at a dose of 10 mg, Xarelto is rapidly absorbed, the absolute bioavailability is high and is 80-100%. Food intake does not affect the AUC and Cmax of rivaroxaban. The pharmacokinetics of rivaroxaban is characterized by moderate variability; individual variability (coefficient of variability) is 30-40%, except for the day of the operation and the next day after surgery, when the variability is high (70%). Plasma protein binding, predominantly to albumin, is 92-95%. Rivaroxaban is excreted predominantly in the form of metabolites (approximately 2/3 of the dose), with half of them excreted by the kidneys and the other half in the feces. 1/3 of the applied dose is exposed to direct excretion by the kidneys in the form of unchanged substance, as it is believed, mainly by active renal secretion. Metabolism of rivaroxaban occurs with the participation of isoenzymes CYP3A4, CYP2J2, as well as enzymes independent of the cytochrome P450 system. The main participants in the biotransformation are the morpholine group, which undergoes oxidative degradation, and the amide groups, which undergo hydrolysis.

Indications

prevention of stroke, heart attack and systemic thromboembolism in patients with atrial fibrillation of non-valvular origin;
treatment of deep vein thrombosis and pulmonary embolism and prevention of their recurrence;
prevention of venous thromboembolism in patients undergoing extensive orthopedic surgery on the lower extremities.

Release form

Film-coated tablets 2.5 mg, 10 mg, 15 mg and 20 mg.

Instructions for use and regimen

Inside, during meals.

If the patient is unable to swallow the tablet whole, the Xarelto tablet may be crushed and mixed with water or liquid food such as applesauce immediately before taking. After taking a crushed Xarelto 15 or 20 mg tablet, a meal should be taken immediately.

The crushed tablet of Xarelto may be administered through a stomach tube. The position of the probe in the gastrointestinal tract must be additionally 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 it is necessary to introduce a small amount of water in order to wash off the remnants of the drug from the walls of the tube. After taking a crushed Xarelto 15 or 20 mg tablet, enteral nutrition should be taken immediately.

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

For patients with impaired renal function (Cl creatinine 49-30 ml / min), the recommended dose is 15 mg 1 time per day.

Duration of treatment

Xarelto therapy should be considered as a long-term treatment for as long as the benefit of the treatment outweighs the risk of possible complications.

Steps to take if you miss a dose

If the next dose is missed, the patient should immediately take Xarelto and the next day continue to take the drug regularly in accordance with the recommended regimen. Do not double the dose taken to compensate for the previously missed one.

Side effect

anemia;
thrombocythemia;
post-procedural hemorrhage (including postoperative anemia and bleeding from the wound);
tachycardia;
arterial hypotension (including hypotension during procedures);
hemorrhage (including hematomas and rare cases of muscle hemorrhage);
gastrointestinal hemorrhages (including gemetemesis, bleeding gums, bleeding from the rectum, hematuria, spotting from the genital tract, nosebleeds);
nausea, vomiting;
constipation, diarrhea;
pain in the abdominal cavity;
feeling of discomfort in the stomach;
dyspeptic phenomena;
dry mouth;
localized or peripheral edema;
fatigue;
weakness;
asthenia;
fever;
urticaria (including cases of generalized urticaria);
allergic dermatitis;
dizziness;
headache;
syncope;
pain in the limbs;
itching (including cases of generalized itching);
skin rashes;
renal failure (increased blood levels of creatinine, urea);
an increase in the level of LDH, an increase in the level of AAT and AAT, an increase in the levels of lipase, amylase, blood bilirubin, and alkaline phosphatase levels.

Contraindications

clinically significant active bleeding (eg, intracranial, gastrointestinal);
liver diseases accompanied by coagulopathy, which increases the risk of clinically significant bleeding;
pregnancy;
hypersensitivity to rivaroxaban.

Use during pregnancy and lactation

Use during pregnancy is contraindicated.

Xarelto should be used with caution in the treatment of patients with moderate renal insufficiency (CC 30-49 ml / min), receiving concomitant therapy with drugs that can cause an increase in the concentration of rivaroxaban in the blood plasma, as well as in patients with CC less than 15-30 ml /min In patients with severe renal insufficiency, the plasma concentration of rivaroxaban may be significantly increased, which may lead to an increased risk of bleeding.

Patients with severe renal insufficiency with an increased risk of bleeding and patients receiving concomitant systemic therapy with azole antifungals or HIV protease inhibitors should be closely monitored after the start of treatment in order to timely detect bleeding complications. Such monitoring may include regular physical examination of the patient, careful monitoring of discharge from the drainage of the surgical wound, and periodic determination of hemoglobin levels.

Rivaroxaban should be used with caution in the treatment of patients with an increased risk of bleeding, incl. if there are congenital or acquired diseases leading to bleeding; uncontrolled severe hypertension; peptic ulcer of the gastrointestinal tract in the acute stage; recent peptic ulcer of the gastrointestinal tract; vascular retinopathy; recent intracranial or intracerebral hemorrhage; intraspinal or intracerebral vascular pathology; recent neurosurgical (surgery on the brain, spinal cord) or ophthalmic intervention.

Caution is required when prescribing rivaroxaban to patients receiving drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors or other antithrombotic agents.

drug interaction

With the simultaneous use of rivaroxaban and strong inhibitors of the isoenzyme CYP3A4 and P-glycoprotein, it can lead to a decrease in renal and hepatic clearance and thus significantly increase the AUC of rivaroxaban.

The combined use of rivaroxaban and the azole antifungal drug ketoconazole (400 mg 1 time per day), which is a strong inhibitor of CYP3A4 and P-glycoprotein, led to a 2.6-fold increase in the mean steady-state AUC of rivaroxaban and a 1.7-fold increase in the mean Cmax of rivaroxaban, which was accompanied by a significant increase pharmacodynamic effects of the drug.

With the simultaneous use of rivaroxaban and the HIV protease inhibitor ritonavir (600 mg 2 times a day), which is a strong inhibitor of CYP3A4 and P-glycoprotein, led to a 2.5-fold increase in the average equilibrium AUC of rivaroxaban and a 1.6-fold increase in the average Cmax of rivaroxaban, which is accompanied by a significant enhancing the pharmacodynamic effects of the drug. Therefore, Xarelto should be used with caution in patients receiving concomitant systemic azole antifungals or HIV protease inhibitors.

Clarithromycin (500 mg twice daily), a potent CYP3A4 inhibitor and moderate P-glycoprotein inhibitor, caused a 1.5-fold increase in mean AUC and a 1.4-fold increase in Cmax of rivaroxaban. This increase in AUC and increase in Cmax fluctuates within the normal range and is considered clinically insignificant.

Erythromycin (500 mg 3 times a day), which moderately inhibits the CYP 3A4 isoenzyme and P-glycoprotein, caused a 1.3-fold increase in the mean steady-state AUC and Cmax of rivaroxaban. This increase in AUC and increase in Cmax fluctuates within the normal range and is considered clinically significant.

The simultaneous administration of rivaroxaban and rifampicin, which is a potent inducer of CYP 3A4 and P-glycoprotein, resulted in an approximately 50% decrease in the mean AUC of rivaroxaban and a parallel decrease in its pharmacodynamic effects. Co-administration of rivaroxaban with other potent CYP3A4 inducers (eg, phenytoin, carbamazepine, phenobarbital, or St. John's wort) may also result in decreased plasma levels of rivaroxaban. The decrease in plasma concentrations of rivaroxaban is considered clinically insignificant.

After the combined use of enoxaparin (in a single dose of 40 mg) and rivaroxaban (in a single dose of 10 mg), an additive effect was observed on the activity of antifactor 10a, which was not accompanied by additional effects on blood coagulation parameters (prothrombin time, APTT).

Enoxaparin did not alter the pharmacokinetics of rivaroxaban.

There was no pharmacokinetic interaction between Xarelto and clopidogrel (loading dose of 300 mg followed by a maintenance dose of 75 mg), but a clinically significant increase in bleeding time was observed in a subgroup of patients, which did not correlate with platelet aggregation and the level of P-selectin or GP2b / 3a receptor .

No clinically relevant prolongation of bleeding time was observed after co-administration of rivaroxaban and naproxen 500 mg. However, in individuals, a more pronounced pharmacodynamic response is possible.

Food interactions: Rivaroxaban 10 mg can be taken with or without food.

Effects on laboratory tests: Effects on blood coagulation parameters (PT, APTT, Heptest) are as expected based on the mechanism of action of rivaroxaban.

Analogues of the drug Xarelto

The drug Xarelto has no structural analogues for the active substance. The drug contains a unique active ingredient.

Analogues for the pharmacological group (drugs for the treatment of thrombosis and embolism):

Avelysin Brown;
Agrenox;
Actilyse;
Angiovit;
Aspisol;
Aspirin Cardio;
Acenocoumarol;
Acetylsalicylic acid;
Brilinta;
Bufferin;
Warfarin Nycomed;
Vinpocetine;
Wobenzym;
Heparin;
Godasal;
Dextran;
Dethromb;
Dipyridamole;
Sylt;
Calciparin;
Cardiomagnyl;
Karinat;
Karinat Forte;
Clexane;
Klivarin;
Clopidex;
Colfarite;
Complamin;
Coplavix;
Xanthinol nicotinate;
Curantyl;
Laspal;
Listab;
Mikristin;
Parsedyl;
Pelentan;
Pentoxifylline;
Plavix;
Plagril;
Plidol;
Pradax;
Ralofect;
Reogluman;
Reopoliglyukin;
Ribasan forte;
Sincumar;
Streptase;
Tagren;
Ticlid;
Tiklo;
Thrombo ASS;
Trombopol;
Troparin;
Ukidan;
Urokinase medak;
Phenylin;
fibrinolysin;
Phlogenzyme;
Cibor;
Egitromb.

In the absence of analogues of the drug for the active substance, you can follow the links below to the diseases that the corresponding drug helps with and see the available analogues for the therapeutic effect.

Composition and form of release

1 film-coated tablet contains:

Active substance:

rivaroxaban micronized - 2.5 mg

Excipients:

microcrystalline cellulose - 40.00 mg,
croscarmellose sodium - 3.00 mg,
hypromellose 5сР -3.00 mg,
lactose monohydrate - 35.70 mg,
magnesium stearate - 0.60 mg,
sodium lauryl sulfate - 0.20 mg;

shell:

iron dye yellow oxide - 0.015 mg,
hypromellose 15cP - 1,500 mg,
macrogol 3350 - 0.500 mg,
titanium dioxide - 0.485 mg.

Round biconvex tablets, film-coated, light yellow. On one side, a triangle with the dosage designation “2.5” is applied by extrusion, on the other side, the Bayer logo in the form of a cross. In cross section, the nucleus is white.

Film-coated tablets 2.5 mg.

14 or 10 tablets in Al/PP or Al/PVC-PVDC blisters. On 1, 2, 4, 7, 12, 14 blisters on 14 tablets or 10 blisters on 10 tablets together with the application instruction in a cardboard box.

pharmachologic effect

Direct acting anticoagulant

Pharmacokinetics

Absorption and bioavailability

Rivaroxaban is rapidly absorbed; the maximum concentration (Cmax) is reached 2-4 hours after taking the tablet.

After oral administration, rivaroxaban is almost completely absorbed and its bioavailability when taking 2.5 mg and 10 mg tablets is high (80-100%), regardless of food intake. Eating does not affect AUC (area under the concentration-time curve) and Cmax when taking a dose of 10 mg. Xarelto tablets at a dosage of 2.5 mg and 10 mg can be taken both with food and on an empty stomach.

The pharmacokinetics of rivaroxaban is characterized by moderate interindividual variability, the coefficient of variability Cv% ranges from 30% to 40%.

Distribution

Rivaroxaban has a high degree of binding to plasma proteins, it is approximately 92 - 95%, mainly rivaroxaban binds to serum albumin. The drug has an average volume of distribution, it is approximately 50 liters.

Metabolism and excretion

When administered orally, approximately 2/3 of the received dose of rivaroxaban is metabolized and half is excreted by the kidneys and the other half through the intestines. The remaining third of the dose received is excreted by direct renal excretion unchanged, mainly due to active renal secretion. Rivaroxaban is metabolized by cytochrome P450 isoenzymes - CYP3A4, CYP2J2, as well as by 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). Unchanged rivaroxaban is the only active compound in plasma, with no major or active circulating metabolites found in plasma.

Rivaroxaban, with a systemic clearance of approximately 10 L/h, can be classified as a low clearance drug. When rivaroxaban is eliminated from plasma, the terminal elimination half-life is 5 to 9 hours in young patients and 11 to 13 hours in elderly patients.

Gender/Old age (over 65)

In elderly patients, plasma concentrations of rivaroxaban are higher than in younger patients; the mean AUC is approximately 1.5 times higher than the corresponding values in young patients, mainly due to the apparent decrease in total and renal clearance.

In men and women, clinically significant differences in pharmacokinetics were not found.

Body mass

Too little or too much body weight (less than 50 kg and more than 120 kg) only slightly affects the concentration of rivaroxaban in blood plasma (the difference is less than 25%).

Childhood

There are no data available for this age group.

Interethnic differences

There were no clinically significant differences in pharmacokinetics and pharmacodynamics in patients of Caucasian, Negroid, Asian race, as well as in representatives of Hispanic, Japanese or Chinese ethnicity.

Impaired liver function

The effect of hepatic insufficiency on the pharmacokinetics of rivaroxaban was studied in patients distributed according to the Child-Pugh classification (according to standard procedures in clinical studies). The Child-Pugh classification provides an estimate of the prognosis for a patient with chronic liver disease, mainly cirrhosis. For patients who are scheduled for anticoagulant therapy, the most important consequence of impaired liver function is a decrease in the synthesis of blood coagulation factors in the liver. Since this indicator meets 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. Treatment of such patients with anticoagulants should be considered regardless of Child-Pugh class.

Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy associated with a clinically significant risk of bleeding. In patients with cirrhosis of the liver and mild hepatic insufficiency (Child-Pugh class A), the pharmacokinetics of rivaroxaban only slightly differed from those in the control group of healthy volunteers (on average, there was an increase in AUC of rivaroxaban by 1.2 times). There were no significant differences in pharmacodynamic properties between groups.

In patients with cirrhosis of the liver and moderate hepatic insufficiency (Child-Pugh class B), the mean AUC of rivaroxaban was significantly increased (2.3-fold) compared with healthy volunteers due to a significantly reduced clearance of the drug substance, which indicates a serious liver disease . The suppression of factor Xa activity was more pronounced (2.6 times) than in healthy volunteers. Prothrombin time was also 2.1 times higher than in healthy volunteers. By measuring the prothrombin time, 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 insufficiency are more sensitive to rivaroxaban, which is a consequence of a closer relationship between pharmacodynamic effects and pharmacokinetic parameters, especially between concentration and prothrombin time.

No data are available for patients with Child-Pugh class C hepatic impairment.

Therefore, rivaroxaban is contraindicated in patients with cirrhosis and Child-Pugh B and C hepatic impairment.

Impaired kidney function

In patients with renal insufficiency, an increase in rivaroxaban exposure was observed, inversely proportional to the degree of decrease in renal function, which was assessed by creatinine clearance.

In patients with mild renal insufficiency (creatinine clearance 50-80 ml / min), moderate (creatinine clearance 30-49 ml / min) or severe (creatinine clearance 15-29 ml / min), 1.4-, 1, A 5- and 1.6-fold increase in rivaroxaban plasma concentrations (AUC), respectively, compared with healthy volunteers.

The corresponding increase in pharmacodynamic effects was more pronounced. In patients with mild, moderate and severe renal insufficiency, the total suppression of factor Xa activity increased by 1.5, 1.9 and 2 times compared with healthy volunteers; prothrombin time due to the action of factor Xa also lengthened by 1.3, 2.2 and 2.4 times, respectively.

Data on the use of Xarelto in patients with a creatinine clearance of 15-29 ml / min are limited, and therefore, caution should be exercised when using the drug in this category of patients. Data on the use of Xarelto in patients with creatinine clearance<15 мл/мин отсутствуют, в связи с чем не рекомендуется применять препарат у данной категории пациентов.

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. Factor Xa is a component of the emerging prothrombinase complex, the action of which leads to the conversion of prothrombin to thrombin. As a result, these reactions lead to the formation of a fibrin thrombus and activation of platelets by thrombin. One molecule of factor Xa catalyzes the formation of more than 1000 thrombin molecules, which is called the "thrombin explosion". The reaction rate of factor Xa bound in prothrombinase is increased by 300,000 times compared to that of free factor Xa, which provides a sharp jump in the level of thrombin. Selective factor Xa inhibitors can stop the "thrombin burst". Thus, rivaroxaban affects the results of some specific or general laboratory tests used to evaluate clotting systems. In humans, there is a dose-dependent inhibition of factor Xa activity.

Pharmacodynamic effects

In humans, dose-dependent inhibition of factor Xa was observed. Rivaroxaban has a dose-dependent effect on the change in prothrombin time, which is closely correlated with the plasma concentration of rivaroxaban (correlation coefficient 0.98) when the Neoplastin kit is used for analysis. Results will vary if other reagents are used. Prothrombin time should be measured in seconds because the INR (International Normalized Ratio) is only calibrated and certified for coumarin derivatives and cannot be used for other anticoagulants. In patients undergoing major orthopedic surgery, the 5/95 percentile values for prothrombin time (Neoplastin) 24 hours after taking the tablet (i.e. at the maximum effect) range from 13 to 25 seconds. Rivaroxaban also dose-dependently increases activated partial thromboplastin time (APTT) and HepTest result; however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban. Rivaroxaban also interferes with anti-factor Xa activity, but calibration standards are not available.

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 QT interval of the electrocardiogram under the influence of rivaroxaban was not observed.

Indications for use

Prevention of death due to cardiovascular causes and myocardial infarction in patients after acute coronary syndrome (ACS), occurring with an increase in cardiospecific biomarkers, in combination therapy with acetylsalicylic acid or acetylsalicylic acid and thienopyridines - clopidogrel or ticlopidine.

Contraindications for use

Hypersensitivity to rivaroxaban or any tablet excipient.
Clinically significant active bleeding (eg, intracranial hemorrhage, gastrointestinal bleeding).
Liver disease with coagulopathy leading to a clinically significant risk of bleeding, including cirrhosis of the liver and Child-Pugh class B and C liver dysfunction.
Pregnancy and lactation (breastfeeding period).
Children under 18 years of age (efficacy and safety for patients of this age group have not been established).
Clinical data on the use of rivaroxaban in patients with severe renal insufficiency (creatinine clearance<15 мл/мин) отсутствуют. Поэтому применение ривароксабана не рекомендуется к применению у данной категории пациентов.
Treatment of ACS with antiplatelet agents in patients with stroke or transient ischemic attack.
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 when switching from or on rivaroxaban (see section "Method of administration and doses") or when using unfractionated heparin in doses necessary to ensure the functioning of a central venous or arterial catheter.
Congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption (due to the presence of lactose).

Carefully

The drug should be used with caution:

In the treatment of patients with an increased risk of bleeding (including those with congenital or acquired tendency to bleeding, uncontrolled severe arterial hypertension, gastric and duodenal ulcers in the acute stage, recent acute gastric and duodenal ulcers, vascular retinopathy, recent intracranial or intracerebral hemorrhage, in the presence of known vascular anomalies of the spinal cord or brain, after recent surgery on the brain, spinal cord or eyes, in the presence of bronchiectasis or pulmonary hemorrhage in anamnesis).
In the treatment of patients with moderate renal insufficiency (3049 ml / min), receiving simultaneously drugs that increase the concentration of rivaroxaban in the blood plasma (see section "Interaction with other drugs").
In the treatment of patients with severe renal insufficiency (creatinine clearance 15-29 ml / min), care should be taken, since the concentration of rivaroxaban in the blood plasma in such patients can increase significantly (by an average of 1.6 times) and therefore they have an increased risk of bleeding .
In patients receiving drugs that affect hemostasis (for example, NSAIDs, antiplatelet agents or other antithrombotic agents).
Xarelto is not recommended for use in patients receiving systemic treatment with azole antifungals (eg, ketoconazole, itraconazole, voriconazole, and posaconazole) or HIV protease inhibitors (eg, ritonavir). These drugs are potent inhibitors of the CYP3A4 isoenzyme and P-glycoprotein. As a consequence, these medicinal products may increase the plasma concentration of rivaroxaban to a clinically significant level (2.6-fold on average), which increases the risk of bleeding. The azole antifungal drug fluconazole, a moderate inhibitor of CYP3A4, has a lesser effect on rivaroxaban exposure and can be co-administered with it (see section "Interaction with other medicinal products").
Patients with severe renal insufficiency 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 to detect bleeding complications in a timely manner.

Use in pregnancy and children

Xarelto in women of childbearing age should only be used in combination with effective contraceptive methods.

The safety and efficacy of Xarelto in pregnant women have not been established. Data obtained in experimental animals have shown severe 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 the ability to cross the placenta, Xarelto is contraindicated in pregnancy.

Data on the use of Xarelto for the treatment of women during lactation are not available. Data obtained in experimental animals show that rivaroxaban is excreted in breast milk. Xarelto can only be used after breastfeeding has stopped.

Side effects

The safety of Xarelto was evaluated in four phase III studies that included 6097 patients taking Xarelto 10 mg who underwent major orthopedic surgery on the lower extremities (total hip arthroplasty or total knee arthroplasty) and 3997 patients hospitalized for medical conditions, treated for a maximum of 39 days, and in three Phase III VTE studies that included 4556 patients who received either Xarelto 15 mg twice daily for 3 weeks followed by 20 mg once daily, or up to 20 mg once daily for up to 21 months.

In addition, the safety of Xarelto was also evaluated in 7750 patients with non-valvular atrial fibrillation in two phase III studies who received at least one dose of Xarelto and in 10225 patients with ACS who received at least one dose of Xarelto of either 2.5 mg (twice a day), or 5 mg (twice a day), in combination with either acetylsalicylic acid or acetylsalicylic acid and clopidogrel or ticlopidine.

Due to the pharmacological mechanism of action, the use of Xarelto may be associated with an increased risk of occult or overt bleeding from any tissues and organs, which can lead to the development of posthemorrhagic anemia. The risk of bleeding may be increased in patient groups such as those with severe uncontrolled hypertension and/or those taking concomitant medications that affect hemostasis.

Signs, symptoms, and severity (including death) will vary depending on the source and degree or severity of bleeding and/or anemia.

Hemorrhagic complications may manifest as weakness, pallor, dizziness, headache, or unexplained edema, dyspnea, or shock that cannot be explained by other causes. In some cases, as a consequence of anemia, there are symptoms of myocardial ischemia, such as chest pain or angina pectoris.

Known complications secondary to severe bleeding, such as long-term compression syndrome and renal failure due to hypoperfusion, have also been reported with Xarelt. Thus, when evaluating the condition of any patient receiving anticoagulants, the possibility of bleeding should be considered.

drug interaction

Pharmacokinetic interactions Excretion of rivaroxaban occurs primarily through hepatic metabolism mediated by the cytochrome P450 (CYP3A4, CYP2J2) system, as well as through renal excretion of unchanged drug using the P-gp/Bcrp (P-glycoprotein/Breast Cancer Resistance Protein) transporter systems. ) (see section "Pharmacokinetics"). Rivaroxaban does not inhibit or induce CYP3A4 isoenzyme and other important cytochrome isoforms. The simultaneous use of rivaroxaban and strong inhibitors of the isoenzyme CYP3A4 and P-glycoprotein can lead to a decrease in renal and hepatic clearance and, thus, a significant increase in systemic exposure. The combined use of rivaroxaban 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-glycoprotein, led to an increase in the average equilibrium 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 effects of the drug. Co-administration of rivaroxaban 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-glycoprotein, led to an increase in the average equilibrium 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 effects of the drug. In this regard, rivaroxaban is not recommended for use in patients receiving systemic treatment with azole antifungals or HIV protease inhibitors (see section "Contraindications", subsection "With caution"). It is expected that other drugs that strongly inhibit only one of the routes of elimination of rivaroxaban - with the participation of CYP3A4 or P-glycoprotein - will increase the plasma concentration of rivaroxaban to less significant values. Clarithromycin (at a dose of 500 mg 2 times a day), which strongly inhibits the CYP3A4 isoenzyme and moderately inhibits P-glycoprotein, 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), moderately suppressing the CYP3A4 isoenzyme and P-glycoprotein, caused an increase in AUC and Cmax of rivaroxaban by 1.3 times. This increase is of the order of normal variability in AUC and Cmax and is considered clinically insignificant. The co-administration of rivaroxaban and rifampicin, which is a strong inducer of CYP3A4 and P-glycoprotein, resulted in a decrease in the mean AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects. Co-administration 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. Pharmacodynamic interactions Following the combined administration of enoxaparin sodium (single dose 40 mg) and rivaroxaban (single dose 10 mg), a cumulative effect on anti-factor Xa activity was observed, without additional cumulative effects on blood clotting tests (PT, APTT). Enoxaparin did not alter the pharmacokinetics of rivaroxaban. After co-administration of rivaroxaban and naproxen at a dose of 500 mg, no clinically significant prolongation of bleeding time was observed. However, a more pronounced pharmacodynamic response is possible in individuals. No pharmacokinetic interaction was found between rivaroxaban and clopidogrel (loading dose of 300 mg followed by maintenance doses of 75 mg), but a significant increase in bleeding time was found in some patients, which did not correlate with platelet aggregation and the content of P-selectin or GPIIb / IIIa receptor . Concomitant use of other medicinal products No clinically significant pharmacokinetic or pharmacodynamic interactions have been observed when rivaroxaban was co-administered with midazolam (CYP3A4 substrate), digoxin (P-gp substrate) or atorvastatin (CYP3A4 and P-gp substrate). There were no clinically significant interactions with food. Incompatibility. Unknown. Effects on Laboratory Parameters Effects on test results on clotting parameters (PT, APTT, HepTest®) are as expected given the mechanism of action of rivaroxaban.

Dosage

After acute coronary syndrome, the recommended dose is one tablet of Xarelto 2.5 mg twice daily. Patients also need to take a daily dose of acetylsalicylic acid 75-100 mg or a daily dose of acetylsalicylic acid 75-100 mg in combination with a daily dose of clopidogrel 75 mg or a standard daily dose of ticlopidine.

The ongoing treatment should be regularly assessed in terms of maintaining a balance between the risk of ischemic events and the risk of bleeding. The duration of treatment is 12 months. Treatment may be extended up to 24 months for selected patients, as there are limited data on treatment for this duration.

Treatment with Xarelto 2.5 mg should be initiated as soon as possible after the patient has stabilized during current ACS (including revascularization procedures).

Treatment with Xarelto should begin at least 24 hours after hospitalization. Xarelto 2.5 mg should be started when parenteral anticoagulants are usually discontinued.

Xarelto 2.5 mg should be taken one tablet twice a day.

Xarelto 2.5 mg should be taken with or without food.

If a dose is missed, the patient should continue taking Xarelto 2.5 mg at the usual dose, i.e. at the next scheduled dose as recommended.

If the patient is unable to swallow the tablet whole, the Xarelto tablet may be crushed or mixed with water or liquid food, such as applesauce, immediately before taking. The crushed tablet of Xarelto may be administered through a stomach tube. The position of the probe in the gastrointestinal tract must be additionally 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 it is necessary to introduce a small amount of water in order to wash off the remnants of the drug from the walls of the tube.

Overdose

Rare cases of overdose up to 600 mg without bleeding or other adverse events have been reported. Due to limited absorption, a concentration plateau is expected without further increase in the mean plasma concentration of rivaroxaban at supratherapeutic doses of 50 mg or higher.

There is no specific antidote that counteracts the pharmacodynamic effects of rivaroxaban. In case of an overdose of Xarelto, activated charcoal can be used to reduce the absorption of the drug. Due to significant plasma protein binding, rivaroxaban is not expected to be eliminated by hemodialysis.

If a bleeding complication occurs in a patient receiving rivaroxaban, the next dose of the drug should be postponed or, if necessary, the treatment with this drug should be stopped altogether. The elimination half-life of rivaroxaban is approximately 5 to 13 hours. Treatment should be individualized depending on the severity and location of bleeding. If necessary, appropriate symptomatic treatment can be used, such as mechanical compression (eg, for severe epistaxis), surgical hemostasis with bleeding control procedures, fluid therapy and hemodynamic support, blood products (packed packed red blood cells or fresh frozen plasma, depending on anemia or coagulopathy) or platelets.

If it is not possible to control bleeding using the above procedures, the administration of specific reversible procoagulant drugs, such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor VIIa, can be used. However, there is currently very limited experience with these drugs in patients receiving Xarelto®. It is expected that protamine sulfate and vitamin K will not affect the anticoagulant activity of rivaroxaban.

There is also no experience with antifibrinolytic drugs (tranexamic acid, aminocaproic acid) in patients receiving Xarelto. There is also no scientific rationale for the use of the systemic hemostatic agents, desmopressin and aprotinin, in patients receiving Xarelto, and no experience with these drugs in this group.

Active substance

Rivaroxaban

Dosage form

film-coated tablets

Description

Tablets 15 mg: round, biconvex, pink-brown, film-coated tablets; engraved by extrusion: on one side - a triangle with the designation of the dosage "15", on the other - a branded Bayer cross. Type of tablet on a break: a homogeneous mass of white color, surrounded by a shell of pink-brown color.

Tablets 20 mg: round, biconvex, red-brown, film-coated tablets; engraved by extrusion: on one side - a triangle with the designation of the dosage "20", on the other - a branded Bayer cross. Type of tablet on a break: a homogeneous mass of white color, surrounded by a shell of red-brown color.

Pharmacotherapeutic group

Direct factor Xa inhibitors

B.01.A.F Direct factor Xa inhibitors

B.01.A.F.01 Rivaroxaban

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 prothrombin time and correlates well with plasma concentrations (r=0.98) when the Neoplastin® kit is used for analysis. Results will vary if other reagents are used. Prothrombin time should be measured in seconds because the INR (International Normalized Ratio) is only calibrated and certified for coumarin derivatives and cannot be used for other anticoagulants.

In patients with non-valvular atrial fibrillation taking rivaroxaban for the prevention of stroke and systemic thromboembolism, the 5/95th percentiles for prothrombin time (Neoplastin®) 1-4 hours after taking the pill (i.e. at the maximum effect) range from 14 to 40 seconds in patients taking 20 mg once a day, and 10 to 50 seconds in patients with renal insufficiency (creatinine clearance 49-30 ml/min) taking 15 mg once a day.

In patients receiving rivaroxaban for the treatment and prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE), the 5/95th percentile for prothrombin time (Neoplastin®) 2-4 hours after taking the tablet (i.e. at maximum effect) range from 17 to 32 seconds in patients taking 15 mg twice a day, and from 15 to 30 seconds in patients taking 20 mg once a day.

Also, rivaroxaban dose-dependently increases the activated partial thromboplastin time (APTT) and HepTest® result; however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban. Also, if there is a clinical justification for this, the concentration of rivaroxaban 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 QT interval of the electrocardiogram under the influence of rivaroxaban was not observed.

Pharmacokinetics

Absorption and bioavailability

The absolute bioavailability of rivaroxaban after a dose of 10 mg is high (80-100%).

Rivaroxaban is rapidly absorbed; the maximum concentration (Cmax) is reached 2-4 hours after taking the tablet.

When taking rivaroxaban at a dose of 10 mg with food, there was no change in AUC (area under the concentration-time curve) and Cmax (maximum concentration). 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, when taking 20 mg on an empty stomach, a bioavailability of 66% was observed. When taking Xarelto® 20 mg with meals, there was an increase in mean AUC of 39% compared with fasting, showing almost complete absorption and high bioavailability.

Absorption of rivaroxaban depends on the site of release in the gastrointestinal tract (GIT). A decrease of 29% and 56% in AUC and Cmax, respectively, compared with taking the whole tablet, was observed when rivaroxaban granulate was released in the distal small intestine or ascending colon. The introduction of rivaroxaban into the gastrointestinal tract distal to the stomach should be avoided, as this may lead to a decrease in absorption and, accordingly, exposure of the drug.

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

Distribution

In humans, most of rivaroxaban (92-95%) binds to plasma proteins, the main binding component is serum albumin. The volume of distribution is moderate, Vss is approximately 50 liters.

Metabolism and excretion

When administered orally, approximately 2/3 of the prescribed dose of rivaroxaban are metabolized and subsequently excreted in equal parts in the urine and through the intestines. The remaining 1/3 of the dose is excreted by direct renal excretion unchanged, mainly due to active renal secretion.

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

Unchanged rivaroxaban is the only active compound in human plasma, with no major or active circulating metabolites found in plasma. Rivaroxaban, with a systemic clearance of approximately 10 L/h, can be classified as a low clearance drug. When rivaroxaban is eliminated from plasma, the terminal elimination half-life is 5 to 9 hours in young patients and 11 to 13 hours in elderly patients.

Gender/Old age (over 65)

In men and women, clinically significant differences in pharmacokinetics were not found.

Body mass

Too little or too much body weight (less than 50 kg and more than 120 kg) only slightly affects the concentration of rivaroxaban in blood plasma (the difference is less than 25%).

Childhood

There are no data available for this age group.

Interethnic differences

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

Impaired liver function

The effect of hepatic insufficiency on the pharmacokinetics of rivaroxaban was studied in patients distributed according to the Child-Pugh classification (according to standard procedures in clinical studies). The Child-Pugh classification makes it possible to assess the prognosis of chronic liver diseases, mainly cirrhosis. In patients who are scheduled for anticoagulant therapy, the most important consequence of impaired liver function is a decrease in the synthesis of blood coagulation factors in the liver. Since this indicator meets 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. Treatment of such patients with anticoagulants should be considered regardless of Child-Pugh class.

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

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

In patients with cirrhosis of the liver and moderate hepatic insufficiency (Child-Pugh class B), the mean AUC of rivaroxaban was significantly increased (2.3-fold) compared with healthy volunteers due to a significantly reduced clearance of the drug substance, which indicates a serious liver disease . The suppression of factor Xa activity was more pronounced (2.6 times) than in healthy volunteers. Prothrombin time was also 2.1 times higher than in healthy volunteers. By measuring the prothrombin time, 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 insufficiency are more sensitive to rivaroxaban, which is a consequence of a closer relationship between pharmacodynamic effects and pharmacokinetic parameters, especially between concentration and prothrombin time.

No data are available for patients with Child-Pugh class C hepatic impairment.

Impaired kidney function

In patients with renal insufficiency, an increase in rivaroxaban exposure was observed, inversely proportional to the degree of decrease in renal function, which was assessed by creatinine clearance.

In patients with renal insufficiency with a creatinine clearance of 80-50 ml / min, a creatinine clearance of 49-30 ml / min and a creatinine clearance of 29-15 ml / min, a 1.4-, 1.5- and 1.6-fold increase in concentrations was observed rivaroxaban plasma levels (AUC), respectively, compared with healthy volunteers.

The corresponding increase in pharmacodynamic effects was more pronounced.

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

Data on the use of Xarelto® in patients with a creatinine clearance of 29-15 ml / min are limited, and therefore caution should be exercised when using the drug in this category of patients. Data on the use of Xarelto® in patients with creatinine clearance< 15 мл/мин отсутствуют, в связи с чем не рекомендуется применять препарат у данной категории пациентов.

Indications

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

- treatment of deep vein thrombosis and pulmonary embolism and prevention of recurrence of DVT and PE.

Contraindications

- Hypersensitivity to rivaroxaban or any excipients contained in the tablet;

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

- an injury or condition associated with an increased risk of major bleeding, such as an existing or recent gastrointestinal ulcer, the presence of malignant tumors with a high risk of bleeding, recent trauma to the brain or spinal cord, surgery to the brain, spinal cord or eyes, intracranial hemorrhage , diagnosed or suspected varicose veins of the esophagus, arteriovenous malformations, vascular aneurysms or pathology of the vessels 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 switching from or to rivaroxaban or when using unfractionated heparin in doses necessary to ensure the functioning of a central venous or arterial catheter;

- liver disease with coagulopathy, which causes a clinically significant risk of bleeding;

- pregnancy and breastfeeding period;

- children and adolescents under 18 years of age (efficacy and safety in patients of this age group have not been established);

- kidney failure (creatinine clearance< 15 мл/мин) (клинические данные о применении ривароксабана у данной категории пациентов отсутствуют);

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

Carefully

The drug should be used with caution:

In the treatment of patients with an increased risk of bleeding (including those with congenital or acquired tendency to bleeding, uncontrolled severe arterial hypertension, gastric and duodenal ulcers in the acute stage, recent gastric and duodenal ulcers, vascular retinopathy, bronchiectasis, or history of pulmonary hemorrhage);

In the treatment of patients with renal insufficiency (creatinine clearance 49-30 ml / min), receiving concomitant drugs that increase the concentration of rivaroxaban in plasma ;

In the treatment of patients with renal insufficiency (creatinine clearance 29-15 ml / min), care should be taken, since the concentration of rivaroxaban in the blood plasma in such patients can increase significantly (by an average of 1.6 times), and as a result they are prone to increased the risk of bleeding;

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

Xarelto® is not recommended for use in 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-glycoprotein. As a consequence, these drugs may increase the plasma concentration of rivaroxaban to a clinically significant level (2.6-fold on average), which increases the risk of bleeding. The azole antifungal drug fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on rivaroxaban exposure and can be co-administered with it (see section "Interaction with other medicinal products and other forms of interaction").

Patients with renal insufficiency (creatinine clearance 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 to detect complications in the form of bleeding.

Pregnancy and lactation

Pregnancy

Due to the possible risk of bleeding and the ability to cross the placenta, Xarelto® is contraindicated in pregnancy (see section "Contraindications").

Women of childbearing potential should use effective contraception while taking Xarelto®.

Breast-feeding

Data on the use of Xarelto® for the treatment of women during breastfeeding are not available. Data obtained in experimental animals show that rivaroxaban is excreted in breast milk. Xarelto® can only be used after breastfeeding has been discontinued (see section "Contraindications").

Fertility

Studies have shown that rivaroxaban does not affect male and female fertility in rats. No human fertility studies have been conducted with rivaroxaban.

Side effects

The safety of Xarelto® was evaluated in four phase III studies involving 6097 patients undergoing major orthopedic surgery on the lower extremities (total knee or hip arthroplasty) and 3997 patients hospitalized for medical reasons treated with Xarelto® 10 mg for up to 39 days, and also in three phase III studies of venous thromboembolism, including 4556 patients who received either Xarelto 15 mg twice daily for 3 weeks followed by 20 mg once daily or 20 mg once daily until 21 months.

In addition, two phase III studies involving 7750 patients provided safety data for the drug in patients with non-valvular atrial fibrillation who received at least one dose of Xarelto® for up to 41 months, as well as in 10225 patients with ACS, who received at least one dose of Xarelto® 2.5 mg (twice daily) or 5 mg (twice daily) in addition to therapy with acetylsalicylic acid or acetylsalicylic acid with clopidogrel or ticlopidine, duration of treatment up to 31 months.

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

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

Summarized data on the frequency of adverse reactions recorded for Xarelto® are given below. In groups divided by frequency, adverse effects are presented in order of decreasing severity, as follows:

Common: ≥1% to<10% (от ≥1/100 до <1/10),

Uncommon: ≥0.1% to<1% (от ≥1/1000 до <1/100),

Rare: ≥0.01% to<0,1% (от ≥1/10000 до <1/1000),

Very rarely:<0,01% (<1/10000).

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

Circulatory and lymphatic system disorders

Often: anemia (including relevant laboratory parameters)

Infrequently: thrombocythemia (including elevated platelets)*

Heart disorders

Infrequently: tachycardia

Violations of the organ of vision

Often: hemorrhage in the eye (including hemorrhage in the conjunctiva)

Digestive system disorders

Often: bleeding gums, gastrointestinal bleeding (including rectal bleeding), gastrointestinal pain, dyspepsia, nausea, constipation*, diarrhea, vomiting*

Infrequently: dry mouth

Systemic disorders and reactions at the injection site

Often: fever*, peripheral edema, decreased overall muscle strength and tone (including weakness, asthenia)

Infrequently: deterioration in general well-being (including malaise)

Rarely: local edema*

Liver disorders

Infrequently: liver dysfunction

Rarely: jaundice

Immune System Disorders

Infrequently: allergic reaction, allergic dermatitis

Injury, poisoning and procedural complications

Often: hemorrhage after procedures (including postoperative anemia and bleeding from the wound), excessive hematoma with contusion

Infrequently: discharge from the wound*

Rarely: vascular pseudoaneurysm***

Research results

Often: increased activity of "liver" transaminases

Infrequently: increased bilirubin concentration, increased alkaline phosphatase*, increased LDH*, increased lipase*, increased amylase*, increased GGT*

Rarely: an increase in the concentration of conjugated bilirubin (with or without a concomitant increase in ALT activity)

Musculoskeletal and connective tissue disorders

Often: pain in limbs*

Infrequently: hemarthrosis

Rarely: hemorrhage in the muscles

Nervous System Disorders

Often: dizziness, headache

Infrequently: intracerebral and intracranial hemorrhages, short-term syncope

Renal and urinary tract disorders

Often: bleeding from the urogenital tract (including hematuria and menorrhagia**), renal failure (including increased creatinine, increased urea)*

Respiratory disorders

Often: nosebleeds, hemoptysis

Skin and subcutaneous tissue disorders

Often: pruritus (including infrequent cases of generalized pruritus), rash, ecchymosis, skin and subcutaneous hemorrhages

Infrequently: hives

Vascular disorders

Often: pronounced decrease in blood pressure, hematoma

*registered after major orthopedic surgery

** reported in VTE treatment as very common in women< 55 лет

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

When conducting post-registration monitoring, cases of the following adverse reactions were reported, the development of which had a temporal relationship with taking Xarelto®. It is not possible to estimate the frequency of occurrence of such adverse reactions in the framework of post-registration monitoring.

Immune system disorders: angioedema, allergic edema. In a phase III RCT, these adverse events were assessed as infrequent (>1/1000 to<1/100) .

Liver disorders: cholestasis, hepatitis (including hepatocellular damage). In a phase III RCT, these adverse events were assessed as rare (>1/10000 to<1/1000) .

Circulatory and lymphatic system disorders: thrombocytopenia. In a phase III RCT, these adverse events were assessed as infrequent (>1/1000 to<1/100) .

Musculoskeletal and connective tissue disorders: frequency unknown- syndrome of increased subfascial pressure (compartment syndrome) due to hemorrhage in the muscles.

Renal and urinary tract disorders: frequency unknown - renal failure / acute renal failure due to bleeding leading to renal hypoperfusion.

Overdose

Rare cases of overdose have been reported with rivaroxaban up to 600 mg without bleeding or other adverse reactions. Due to limited absorption, the development of a low-level plateau in the concentration of the drug is expected without a further increase in its average concentration in the blood plasma when using doses exceeding therapeutic, equal to 50 mg and above.

The specific antidote for rivaroxaban is unknown. In case of overdose, activated charcoal can be used to reduce the absorption of rivaroxaban. Given the high plasma protein binding, rivaroxaban is not expected to be removed by dialysis.

Treatment of bleeding

If a bleeding complication occurs in a patient receiving rivaroxaban, the next dose of the drug should be postponed or, if necessary, treatment with this drug should be canceled. The elimination half-life of rivaroxaban is approximately 5-13 hours. Treatment should be individualized depending on the severity and location of bleeding. If necessary, appropriate symptomatic treatment can be used, such as mechanical compression (for example, for severe nosebleeds), surgical hemostasis with evaluation of its effectiveness, fluid therapy and hemodynamic support, use of blood products (packed red blood cells or fresh frozen plasma, depending on whether anemia or coagulopathy) or platelets.

If the above measures do not lead to elimination of bleeding, specific reverse-acting procoagulant drugs may be prescribed, such as coagulation factors II, VII, IX and X in combination [Prothrombin complex], anti-inhibitor coagulant complex or eptacog alfa [activated]. However, there is currently very limited experience with these drugs in patients receiving Xarelto®.

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.

There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in patients receiving Xarelto®. There is no evidence to support or experience the use of the systemic haemostatic drug desmopressin in patients receiving Xarelto®.

Interaction

Pharmacokinetic interactions

Rivaroxaban is eliminated primarily through hepatic metabolism mediated by the cytochrome P450 (CYP3A4, CYP2J2) system, as well as through renal excretion of unchanged drug using the P-gp/Bcrp (P-glycoprotein/breast cancer resistance protein) transporter systems. .

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

Co-administration of Xarelto and potent CYP3A4 and P-glycoprotein inhibitors may result in decreased renal and hepatic clearance of rivaroxaban and thus significantly increase its systemic exposure.

The combined use of Xarelto® and the azole antifungal agent ketoconazole (400 mg 1 time per day), which is a potent inhibitor of CYP3A4 and P-glycoprotein, led to an increase in the average equilibrium 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 action of the drug.

The co-administration of Xarelto® and the HIV protease inhibitor ritonavir (600 mg 2 times a day), which is a potent inhibitor of CYP3A4 and P-glycoprotein, led to an increase in the average equilibrium 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 action of the drug. Therefore, Xarelto is not recommended for use in patients receiving systemic treatment with azole antifungals or HIV protease inhibitors. (See "With caution" section).

Clarithromycin (500 mg twice daily), a potent inhibitor of CYP3A4 and a moderate inhibitor of P-glycoprotein, caused a 1.5-fold increase in AUC and a 1.4-fold increase in Cmax of rivaroxaban. This increase is of the order of normal variability in AUC and Cmax and is considered clinically insignificant.

Erythromycin (500 mg 3 times a day), a moderate inhibitor of the CYP3A4 isoenzyme and P-glycoprotein, caused an increase in AUC and Cmax 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 insufficiency (creatinine clearance ≤80-50 ml / min), erythromycin (500 mg 3 times a day) caused an increase in rivaroxaban AUC values by 1.8 times and Cmax by 1.6 times compared with patients with normal renal function not receiving concomitant therapy. In patients with renal insufficiency (creatinine clearance 49-30 ml / min), erythromycin caused an increase in rivaroxaban AUC values by 2.0 times and Cmax by 1.6 times compared with patients with normal renal function who did not receive concomitant therapy (See "With caution" section).

Fluconazole (400 mg once daily), a moderate CYP3A4 inhibitor, caused a 1.4-fold increase in mean rivaroxaban AUC and a 1.3-fold increase in mean Cmax. This increase is of the order of normal variability in AUC and Cmax and is considered clinically insignificant.

Co-administration of rivaroxaban with dronedarone should be avoided due to limited clinical data on co-administration.

The combined use of Xarelto® and rifampicin, which is a strong inducer of CYP3A4 and P-glycoprotein, led to a decrease in the average AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects. Co-administration of rivaroxaban with other strong CYP3A4 inducers (eg, 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 Interactions

Co-administration of enoxaparin sodium (single dose 40 mg) and Xarelto® (single dose 10 mg) resulted in a cumulative effect on anti-factor Xa activity, with no additional cumulative effects on coagulation tests (prothrombin time, APTT). Enoxaparin sodium did not change the pharmacokinetics of rivaroxaban (See "With caution" section).

Due to the increased risk of bleeding, caution should be exercised when co-administered with any other anticoagulant. (see sections "Contraindications", "With caution" and "Special instructions").

No pharmacokinetic interaction was found between Xarelto® (15 mg) and clopidogrel (loading dose of 300 mg followed by a maintenance dose of 75 mg), but a significant increase in bleeding time was found in a subgroup of patients, which did not correlate with the degree of platelet aggregation and the content of P-selectin or GPIIb /IIIa-receptor (See "With caution" section).

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

Caution must be exercised when co-administering Xarelto with NSAIDs (including acetylsalicylic acid) and inhibitors of platelet aggregation, since the use of these drugs usually increases the risk of bleeding.

Switching patients from warfarin (INR 2.0 to 3.0) to Xarelto® (20 mg) or from Xarelto® (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin ) to a greater extent than would be expected from a simple summation of effects (individual INR values can be as high as 12), while the effect on aPTT, suppression of factor Xa activity and endogenous thrombin potential was 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. From the 4th day after the cessation of warfarin, all test results (including PT, APTT, inhibition of factor Xa activity and on EPT (endogenous thrombin potential)) reflect only the effect of Xarelto® (see section "Method of administration and dosage").

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

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

Drug interactions between Xarelto® and the vitamin K antagonist (VKA) phenindione have not been studied. It is recommended to avoid switching patients from Xarelto therapy to VKA therapy with phenindione, and vice versa, whenever possible.

There is limited experience of switching patients from VKA therapy with acenocoumarol to Xarelto®.

If it becomes necessary to transfer a patient from Xarelto therapy to VKA therapy with phenindione or acenocoumarol, then special care should be taken, daily monitoring of the pharmacodynamic action of drugs (INR, prothrombin time) should be carried out immediately before taking the next dose of Xarelto®.

If it becomes necessary to transfer a patient from VKA therapy with phenindione or acenocoumarol to Xarelto® therapy, then special care should be taken, control of the pharmacodynamic action of the drugs is not required.

Incompatibility

Unknown.

No interactions found

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

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

No clinically significant pharmacokinetic or pharmacodynamic interactions have been observed with the co-administration of Xarelto® and 500 mg acetylsalicylic acid.

Impact on laboratory parameters

Xarelto® has an effect on blood coagulation parameters (PT, APTT, HepTest®) due to its mechanism of action.

special instructions

The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with azole antifungals (eg ketoconazole) or HIV protease inhibitors (eg ritonavir). These drugs are strong inhibitors of CYP3A4 and P-glycoprotein. Thus, these drugs can increase the plasma concentration of rivaroxaban to clinically significant levels (2.6 times on average), which may lead to an increased risk of bleeding.

However, the azole antifungal drug fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on rivaroxaban exposure and can be co-administered with it. (see section "Interaction with other medicinal products and other forms of interaction").

Xarelto® should be used with caution in patients with moderate renal impairment (CC 49-30 ml/min) receiving concomitant medications that may lead to increased plasma concentrations of rivaroxaban (see section "Interaction with other medicinal products and other forms of interaction").

In patients with severe renal impairment (CK<30 мл/мин) концентрация ривароксабана в плазме может быть значительно повышенной (в 1,6 раза в среднем), что может привести к повышенному риску кровотечения. Поэтому, вследствие наличия указанного основного заболевания такие пациенты имеют повышенный риск развития как кровотечений, так и тромбозов. В связи с ограниченным количеством клинических данных препарат Ксарелто® должен применяться с осторожностью у пациентов с КК 29-15 мл/мин.

Clinical data on the use of rivaroxaban in patients with severe renal impairment (CK<15 мл/мин) отсутствуют. Поэтому применение препарата Ксарелто® не рекомендуется у таких пациентов (see section "Method of administration and doses", "Pharmacokinetics", "Pharmacodynamics").

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

Patients with congenital or acquired tendency to bleeding;

Patients with uncontrolled severe arterial hypertension;

Patients with peptic ulcer of the stomach and duodenum in the acute stage;

Patients who have recently undergone peptic ulcer of the stomach and 12 duodenal ulcer;

patients with vascular retinopathy;

Patients who have recently had an intracranial or intracerebral hemorrhage;

Patients with pathology of 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 simultaneously receiving drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or other antithrombotic drugs.

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

With an inexplicable decrease in hemoglobin or blood pressure, it is necessary to look for the source of bleeding.

The safety and efficacy of Xarelto® in patients with prosthetic heart valves have not been studied, therefore, there is no evidence that the use of Xarelto® 20 mg (15 mg in patients with creatinine clearance 49-15 ml / min) provides a sufficient anticoagulant effect in this patient. categories of patients.

Xarelto 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, as the safety and efficacy of Xarelto in these clinical situations has not been established.

If an invasive procedure or surgical intervention is necessary, Xarelto® should be discontinued at least 24 hours before the intervention and based on the judgment of the physician.

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 there are appropriate clinical signs and adequate hemostasis (See section "Pharmacological properties / Metabolism and excretion").

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

The clinician should balance the potential benefit against the relative risk before performing a spinal intervention in patients receiving anticoagulants or who are scheduled to receive anticoagulants to prevent thrombosis. Experience with the clinical use of rivaroxaban at dosages of 15 mg and 20 mg in the situations described is lacking.

In order to reduce the potential risk of bleeding associated with the simultaneous use of rivaroxaban and epidural / spinal anesthesia or spinal puncture, the pharmacokinetic profile of rivaroxaban should be considered. Placement or removal of an epidural catheter or lumbar puncture is best done when the anticoagulant effect of rivaroxaban is considered 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-fold elimination half-life, i.e. not earlier than 18 hours after the last dose of Xarelto® for young patients and not earlier than 26 hours for elderly patients. Xarelto® should be administered 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.

Safety data from preclinical studies

With the exception of effects associated with increased pharmacological action (bleeding), when analyzing preclinical data obtained in studies on pharmacological safety, no specific hazard to humans was found.

Influence on the ability to drive transport. cf. and fur.

When using Xarelto®, there were cases of fainting and dizziness (see section "Side effect"). Patients experiencing these adverse reactions should not drive or operate machinery.

Storage conditions

At a temperature not higher than 30 C.

Keep out of the reach of children.

Terms of dispensing from pharmacies

film-coated tablets

Owner/Registrar

BAYER PHARMA, AG

International Classification of Diseases (ICD-10)

I20.0 Unstable angina I21 Acute myocardial infarction

Pharmacological group

Direct acting anticoagulant - selective inhibitor of factor Xa

pharmachologic effect

Mechanism of action

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

Pharmacodynamic effects

Also, rivaroxaban dose-dependently increases the APTT and the result of HepTest ® ; however, these parameters are not recommended for assessing the pharmacodynamic effects of rivaroxaban.

During treatment with Xarelto ®, monitoring of blood coagulation parameters is not required. However, if there is a clinical justification for this, rivaroxaban concentration can be measured using a calibrated quantitative anti-factor Xa test.

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

Pharmacokinetics

Suction

After oral administration, rivaroxaban is rapidly and almost completely absorbed. C max is achieved 2-4 hours after taking the pill. The bioavailability of rivaroxaban when taking 2.5 mg tablets is high (80-100%), regardless of food intake. Eating does not affect AUC and Cmax when taking the drug at a dose of 10 mg. Xarelto ® 2.5 mg tablets can be taken with food or on an empty stomach.

The pharmacokinetics of rivaroxaban is characterized by moderate interindividual variability, the coefficient of variability ranges from 30% to 40%.

Distribution

Rivaroxaban has a high degree of binding to plasma proteins - approximately 92-95%, mainly rivaroxaban binds to serum albumin. The drug has an average V d - approximately 50 liters.

Metabolism

When administered orally, approximately 2/3 of the received dose of rivaroxaban is metabolized and excreted by the kidneys and through the intestines in equal proportions. The remaining 1/3 of the dose received is excreted by direct renal excretion unchanged, mainly due to active renal secretion.

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

Unchanged rivaroxaban is the only active compound in plasma, with no major or active circulating metabolites found in plasma.

breeding

Rivaroxaban, with a systemic clearance of approximately 10 L/h, can be classified as a low clearance drug. With the removal of rivaroxaban from plasma, the final half-life is from 5 hours to 9 hours in young patients.

Pharmacokinetics in special clinical situations

In elderly patients over 65 years of age, the plasma concentration of rivaroxaban is 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 an apparent decrease in total and renal clearance. With the removal of rivaroxaban from plasma, the final half-life in elderly patients ranges from 11 hours to 13 hours.

In men and women, clinically significant differences in pharmacokinetics were not found.

Too little or too much body weight (less than 50 kg and more than 120 kg) only slightly affects the concentration of rivaroxaban in plasma (the difference is less than 25%).

Data on pharmacokinetics in children are not available.

Clinically significant differences in pharmacokinetics and pharmacodynamics in patients of Caucasian, Negroid, Asian race, as well as Hispanic, Japanese or Chinese ethnicity were not observed.

The effect of hepatic insufficiency on the pharmacokinetics of rivaroxaban was studied in patients divided into classes according to the Child-Pugh classification (according to standard procedures in clinical studies). The Child-Pugh classification makes it possible to assess the prognosis of chronic liver diseases, mainly cirrhosis. In patients who are scheduled for anticoagulant therapy, a particularly important critical moment of liver dysfunction is a decrease in the synthesis of blood coagulation factors in the liver. Because this indicator meets 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. Treatment of such patients with anticoagulants should be considered regardless of Child-Pugh class.

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

In patients with renal insufficiency, an increase in rivaroxaban exposure was observed, inversely proportional to the degree of decrease in renal function, which was assessed by CC.

Data on the use of the drug Xarelto ® in patients with CC 15-29 ml / min are limited, and therefore caution should be exercised when using the drug in this category of patients. Data on the use of rivaroxaban in patients with CC<15 мл/мин отсутствуют, в связи с чем не рекомендуется применять препарат у данной категории пациентов.

Prevention of death due to cardiovascular causes and myocardial infarction in patients after acute coronary syndrome (ACS), which proceeded with an increase in cardiospecific biomarkers, in combination therapy with acetylsalicylic acid or acetylsalicylic acid and thienopyridines - clopidogrel or ticlopidine.

Hypersensitivity to rivaroxaban or any auxiliary component of the drug;

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

Liver diseases that occur with coagulopathy, which causes a clinically significant risk of bleeding, incl. cirrhosis of the liver and violations of the liver class B and C according to the Child-Pugh classification;

Severe renal failure with CC<15 мл/мин (клинические данные о применении ривароксабана у пациентов отсутствуют);

Treatment of ACS with antiplatelet agents in patients who have had a stroke or transient ischemic attack;

Concomitant therapy with any other anticoagulants, for example, unfractionated heparin, low molecular weight heparins (including enoxaparin, dalteparin), heparin derivatives (including fondaparinux), oral anticoagulants (including warfarin, apixaban, dabigatran ), except when switching from or to rivaroxaban or when using unfractionated heparin at doses necessary to ensure the functioning of a central venous or arterial catheter;

Pregnancy;

lactation period (breastfeeding);

Children and adolescents under 18 years of age (efficacy and safety for patients in this age group have not been established);

Congenital lactase deficiency, lactose intolerance, malabsorption of glucose-galactose (due to the presence of lactose in the preparation).

WITH caution drug should be used:

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

In the treatment of patients with moderate renal insufficiency (CC 30-49 ml / min), receiving simultaneously drugs that increase the concentration of rivaroxaban in the blood plasma;

In the treatment of patients with severe renal insufficiency (CC 15-29 ml / min), caution should be exercised, since the concentration of rivaroxaban in the blood plasma in such patients can increase significantly (1.6 times on average) and as a result they have an increased risk of bleeding;

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

Xarelto is not recommended for use in patients receiving systemic treatment with azole antifungals (eg ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (eg ritonavir). These drugs are strong inhibitors of the CYP3A4 isoenzyme and P-glycoprotein. As a consequence, these drugs may increase the plasma concentration of rivaroxaban to a clinically significant level (2.6-fold on average), which increases the risk of bleeding. Fluconazole (an antifungal drug of the azole group), a moderate inhibitor of CYP3A4, has a less pronounced effect on the elimination of rivaroxaban and can be used simultaneously;

Patients with severe renal insufficiency 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 to detect bleeding complications in a timely manner.

The safety of Xarelto® was assessed in four phase III studies involving 6097 patients undergoing major orthopedic surgery on the lower extremities (total hip replacement or total knee replacement) and 3997 patients hospitalized for medical conditions treated for a maximum of 39 days, and in three Phase III studies of venous thromboembolism (VTE) that included 4556 patients who received either Xarelto 15 mg twice daily for 3 weeks followed by 20 mg once daily or 20 mg once daily. times / day with a duration of treatment up to 21 months.

In addition, the safety of Xarelto® was also evaluated in 7,750 patients with non-valvular atrial fibrillation in two phase III studies who received at least one dose of Xarelto®, and in 10,225 patients with ACS who received at least one dose of Xarelto. ® 2.5 mg (2 times / day) or 5 mg (2 times / day) Xarelto ® in combination with either acetylsalicylic acid or acetylsalicylic acid with clopidogrel or ticlopidine.

Due to the pharmacological mechanism of action, the use of Xarelto ® may be accompanied by an increased risk of occult or overt bleeding from any organs and tissues, which can lead to post-hemorrhagic anemia. The risk of bleeding may be increased in patient groups such as those with severe uncontrolled hypertension and/or those taking concomitant medications that affect hemostasis.

Signs, symptoms, and severity (including death) will vary depending on the source and degree or severity of bleeding and/or anemia.

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

The frequency of occurrence of ADRs (adverse drug reactions) with the use of the drug Xarelto ® is given below. Within each frequency group, adverse events are presented in order of decreasing severity. The frequency of occurrence is defined as follows: very often (≥1/10), often (≥1/100–<1/10), нечасто (≥1/1000–<1/100), редко (≥1/10 000–<1/1000).

All treatment-related adverse drug reactions reported in patients in phase III trials (cumulative data from RECORD1-4, EINSTEIN-DVT (deep vein thrombosis), ROCKET AF, J-ROCKET AF, MAGELLAN, ATLAS and EINSTEIN (DVT/PE/Extension)

often - anemia (including relevant laboratory parameters); infrequently - thrombocythemia (including an increase in the number of platelets) *.

From the side of the cardiovascular system: often - a pronounced decrease in blood pressure, hematoma; infrequently - tachycardia.

From the side of 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 *; infrequently - dry mouth.

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

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

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

From the genitourinary system: often - bleeding from the urogenital tract (including hematuria and menorrhagia **), renal failure (including increased creatinine concentration, increased urea concentration) *.

From the respiratory system: often - nosebleeds, hemoptysis.

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

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

often - pain in the limbs *; infrequently - hemarthrosis; rarely - hemorrhage in the muscles.

From the body as a whole: often - fever *, peripheral edema, deterioration in overall muscle strength and tone (including weakness, asthenia); infrequently - deterioration in general well-being (including malaise); rarely - local edema *.

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

* - registered after major orthopedic surgery.

** - were recorded in the treatment of VTE as very frequent in women< 55 лет.

*** - registered as infrequent in the prevention of complications in ACS (after percutaneous interventions).

The most common ADRs in patients treated with the drug were bleeding. The most common bleeding events (≥4%) were epistaxis (5.9%) and gastrointestinal bleeding (4.2%).

Overall, 67% of patients who received at least one dose of rivaroxaban developed adverse reactions requiring therapy. Approximately 22% of patients, according to the researchers, adverse reactions were associated with the use of the drug. When using the drug Xarelto ® at a dose of 10 mg in patients undergoing knee or hip arthroplasty, as well as in patients with prolonged immobilization during hospitalization, bleeding events were observed in approximately 6.8% and 12.6% of patients, respectively, and cases of anemia in approximately 5.9% and 2.1% of patients, respectively. In patients treated with Xarelto 15 mg twice daily and then switched to 20 mg once daily for the treatment of DVT or PE, or 20 mg for the prevention of recurrent DVT or PE, bleeding was observed in approximately 22.7% of patients, anemia occurred in approximately 2.2% of patients. In patients taking the drug for the prevention of stroke and systemic thromboembolism, the frequency of bleeding of varying severity was 28 per 100 person-years, anemia - 2.5 per 100 person-years. In patients taking the drug to prevent death due to cardiovascular causes and myocardial infarction after ACS, the frequency of bleeding of varying severity was 22 per 100 person-years, anemia occurred in 1.4 per 100 person-years.

When conducting post-registration monitoring, cases of the following adverse reactions were reported, the development of which had a temporal relationship with taking Xarelto ® . It is not possible to estimate the frequency of occurrence of such adverse reactions in the framework of post-registration monitoring.

From the immune system: angioedema, allergic edema. In phase III registration clinical trials (RCTs), these adverse reactions were regarded as infrequent (>1/1000 to<1/100).

From the side of the liver: cholestasis, hepatitis (including hepatocellular damage). In a Phase III RCT, these adverse reactions were considered rare (>1/10,000 to<1/1000).

From the hematopoietic system: thrombocytopenia. In a Phase III RCT, these adverse reactions were considered infrequent (>1/1000 to<1/100).

From the musculoskeletal system: the frequency is unknown - a syndrome of increased subfascial pressure (compartment syndrome) due to bleeding.

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

Overdose

Treatment

The specific antidote for rivaroxaban is unknown. In the event of an overdose of Xarelto®, activated charcoal may be used to reduce the absorption of rivaroxaban. Due to the significant binding of rivaroxaban to plasma proteins, it is expected that rivaroxaban will not be excreted by hemodialysis.

If a complication occurs in the form of bleeding, the next dose of the drug should be postponed or treatment with the drug should be canceled. T 1 / 2 rivaroxaban leaves approximately 5-13 hours. Treatment should be selected individually, depending on the severity and location of bleeding.

It is expected that protamine sulfate and vitamin K will not affect the anticoagulant activity of rivaroxaban.

There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in patients receiving Xarelto®. There is no evidence to support or experience with the systemic hemostatic drug desmopressin in patients receiving Xarelto®.

special instructions

The use of concomitant drugs

However, the azole antifungal fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on rivaroxaban exposure and can be co-administered with it.

kidney failure

Xarelto should be used with caution in patients with moderate renal impairment (CC 30-49 ml / min) receiving concomitant drugs that can lead to an increase in plasma concentrations of rivaroxaban.

Clinical data on the use of rivaroxaban in patients with severe renal impairment (CK<15 мл/мин) отсутствуют. Поэтому у данной категории пациентов применение препарата Ксарелто ® не рекомендуется.

Patients with severe renal impairment or an increased risk of bleeding, as well as patients receiving concomitant systemic treatment with azole antifungals or HIV protease inhibitors, should be closely monitored for signs of bleeding after initiation of treatment. Monitoring can be carried out by conducting a regular physical examination of patients, carefully monitoring the condition of the drainage of the postoperative wound, and also by periodically determining hemoglobin.

Patients with a history of stroke or transient ischemic attack (TIA)

The use of Xarelto ® at a dose of 2.5 mg 2 times / day is contraindicated in patients with ACS who have a history of stroke or TIA. Only a few patients with ACS with a history of stroke or TIA have been studied, so data on the effectiveness of the drug in these patients is extremely limited.

Risk of bleeding

Xarelto ® , like other antithrombotic agents, should be used with caution in diseases and conditions associated with an increased risk of bleeding, such as:

Congenital or acquired clotting disorders;

Uncontrolled severe arterial hypertension;

Active gastrointestinal pathology with ulceration;

A recent acute ulcer in the gastrointestinal tract;

Vascular retinopathy;

Recent intracranial or intracerebral hemorrhage;

Intraspinal or intracerebral vascular anomalies;

recent surgery on the brain, spinal cord, or ophthalmic surgery;

Bronchiectasis or an episode of pulmonary hemorrhage in history.

Caution should be exercised if the patient is simultaneously receiving drugs that affect hemostasis, such as NSAIDs, platelet aggregation inhibitors, or other antithrombotic drugs.

In patients at risk of developing gastrointestinal ulcers, appropriate prophylactic treatment can be used.

With any unexplained decrease in hemoglobin or blood pressure, the source of bleeding should be identified.

spinal anesthesia

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 lumbar puncture or re-puncture may also increase the risk. Patients should be monitored for signs or symptoms of neurological disorders (eg, leg numbness or weakness, bowel or bladder dysfunction). If neurological disorders are detected, urgent diagnosis and treatment is necessary. The clinician should weigh the potential benefit against the relative risk before performing a spinal intervention in patients receiving anticoagulants or who are scheduled to receive anticoagulants to prevent thrombosis. There is no clinical experience with rivaroxaban at a dose of 2.5 mg with acetylsalicylic acid or with acetylsalicylic acid and clopidogrel or ticlopidine in the situations described.

Attention should be paid to the simultaneous use of inhibitors of platelet aggregation and, if necessary, discontinue their use.

Surgical operations and interventions

If an invasive procedure or surgery is required, Xarelto 2.5 mg should be discontinued at least 12 hours before the intervention, if possible, and based on the physician's clinical judgement.

If there is no need for an antiplatelet effect in a patient with ACS who is undergoing elective surgery, the use of platelet aggregation inhibitors should be discontinued, as indicated in the instructions for use of the drug provided by the manufacturer.

If the procedure cannot be delayed, then a comparative assessment of the increased risk of bleeding should be made and the need for urgent intervention should be decided.

Xarelto should be restarted after an invasive procedure or surgery as soon as possible, provided that clinical parameters permit and adequate hemostasis is achieved.

Prolongation of the corrected QT interval

The effect of the drug Xarelto ® on the duration of the QT interval has not been identified.

Influence on the ability to drive vehicles and control mechanisms

Against the background of the use of the drug, the occurrence of fainting and dizziness was noted, which may affect the ability to drive vehicles or other mechanisms. . Patients who experience such adverse reactions should not drive vehicles or other mechanisms.

With kidney failure

The use of the drug is contraindicated in severe renal failure with CC<15 мл/мин (clinical data on the use of rivaroxaban in patients of this category are not available).

WITH caution should be used in the treatment patients with severe renal failure (CC 30-15 ml / min) because, due to the underlying disease, such patients are at increased risk of both bleeding and thrombosis; patients with moderate renal failure (CC 50-30 ml / min), concomitantly receiving drugs that increase the concentration of rivaroxaban in the blood plasma.

In violation of the functions of the liver

Xarelto ® is contraindicated . dose adjustment is not required .

No clinical data available .

Elderly

Dose adjustment depending on age of the patient (over 65 years old) not required.

Use during pregnancy and lactation

The efficacy and safety of Xarelto ® in pregnant women has not been established.

Data received in in animals have shown severe maternal toxicity of rivaroxaban associated with the pharmacological action of the drug (eg, complications in the form of hemorrhages) and leading to reproductive toxicity.

Due to the possible risk of bleeding and the ability to cross the placental barrier, Xarelto ® is contraindicated in pregnancy.

At women of childbearing age Xarelto ® should only be used if effective contraceptive methods are being used.

Data on the use of Xarelto ® for the treatment of women during lactation are not available. Data received in experimental studies in animals show that rivaroxaban is excreted in breast milk. Xarelto ® can only be used after breastfeeding has stopped.

drug interaction

Pharmacokinetic interaction

Excretion of rivaroxaban is carried out mainly through hepatic metabolism mediated by CYP3A4, CYP2J2 isoenzymes, as well as through renal excretion of unchanged drug with the participation of P-glycoprotein / Bcrp.

Rivaroxaban does not inhibit or induce the CYP3A4 isoenzyme and any other major isoforms of CYP.

Co-administration of Xarelto® with potent inhibitors of CYP3A4 and P-glycoprotein may result in reduced renal and hepatic clearance and thus significantly increase systemic exposure.

Simultaneous use of the drug Xarelto ® and the antifungal drug of the azole group ketoconazole (400 mg 1 time / day), a powerful inhibitor of CYP3A4 and P-glycoprotein, led to an increase in the average equilibrium 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 effects of the drug.

Other active agents that inhibit at least one of the rivaroxaban elimination pathways mediated by either CYP3A4 or P-gp are likely to increase plasma concentrations of rivaroxaban to a lesser extent.

In patients with renal insufficiency (CC ≤ 80-50 ml / min), erythromycin (500 mg 3 times / day) caused an increase in the AUC of rivaroxaban by 1.8 times and C max by 1.6 times compared with patients with normal renal function who did not receive concomitant therapy. In patients with renal insufficiency (CC 50-30 ml / min), erythromycin caused an increase in the AUC of rivaroxaban by 2 times and C max by 1.6 times compared with patients with normal renal function who did not receive concomitant therapy.

Co-administration of Xarelto® and rifampicin, which is a strong inducer of CYP3A4 and P-glycoprotein, resulted in a decrease in the AUC of rivaroxaban by an average of approximately 50% and a parallel decrease in its pharmacodynamic effects. Co-administration of Xarelto with other strong CYP3A4 inducers (eg, phenytoin, carbamazepine, phenobarbital, or St. John's wort) may also result in decreased plasma concentrations of rivaroxaban.

Strong CYP3A4 inducers should be used with caution in post-ACS patients receiving Xarelto 2.5 mg twice daily.

Pharmacodynamic interaction

Clopidogrel (loading dose of 300 mg followed by a maintenance dose of 75 mg) showed no pharmacokinetic interaction (with Xarelto ® at a dose of 15 mg), however, a significant increase in bleeding time was recorded in a subgroup of patients, which did not correlate with the degree of platelet aggregation, number receptors for P-selectin or GP IIb/IIIa.

No clinically significant increase in bleeding time was observed after co-administration of Xarelto ® 15 mg with naproxen 500 mg. However, there may be patients with a more pronounced pharmacodynamic response.

Caution should be exercised when co-administering rivaroxaban with dronedarone due to limited clinical data on co-administration.

Due to the increased risk of bleeding, caution is required when co-administered with any other anticoagulant.

Xarelto should be used with caution in conjunction with NSAIDs (including acetylsalicylic acid) and antiplatelet agents, since the use of these drugs usually increases the risk of bleeding.

If it is necessary to study the pharmacodynamic effects of Xarelto ® during the transition period, anti-factor Xa activity, prothrombinase-induced clotting time and HepTest ® can be used as necessary tests that are not affected by warfarin. Starting from the 4th day after discontinuation of warfarin, all tests (including prothrombin time, APTT, inhibition of factor Xa activity and on EPT (endogenous thrombin potential)) reflect only the effect of Xarelto ® .

To assess the pharmacodynamic effects of warfarin during the transition period, you can use the MHO indicator measured at the time of reaching C trough of rivaroxaban (24 hours after taking a dose of rivaroxaban), since at this point in time rivaroxaban has practically no effect on this indicator.

Pharmacokinetic interaction between warfarin and Xarelto ® has not been registered.

Food and dairy products

Xarelto ® can be taken with or without food.

No interaction

There is no pharmacokinetic interaction between rivaroxaban and midazolam (CYP3A4 substrate), digoxin (P-glycoprotein substrate), or atorvastatin (CYP3A4 and P-glycoprotein substrate).

No clinically significant pharmacokinetic and pharmacodynamic interactions have been identified with the combined use of Xarelto ® and acetylsalicylic acid at a dose of 500 mg.

Impact on laboratory parameters

Xarelto ® affects blood clotting parameters (prothrombin time, APTT, HepTest ®) due to its mechanism of action.

Take orally 2.5 mg (1 tab.) 2 times / day, regardless of food intake.

After acute coronary syndrome the recommended dose of Xarelto ® is 2.5 mg (1 tab.) 2 times / day. Patients also need to take acetylsalicylic acid at a dose of 75-100 mg / day or acetylsalicylic acid at a dose of 75-100 mg / day in combination with clopidogrel at a dose of 75 mg / day or ticlopidine at a standard daily dose.

If the dose is missed, then you should continue taking the drug at a dose of 2.5 mg at the next scheduled dose.

Xarelto ® is contraindicated patients with liver disease, occurring with coagulopathy, leading to a clinically significant risk of bleeding . Patients with other liver diseases dose adjustment is not required . Limited clinical data from patients with moderate hepatic impairment (Child-Pugh class B), indicate a significant increase in pharmacological activity. For patients with severe liver dysfunction (Child-Pugh class C) no clinical data available.

At patients with impaired renal function of mild (CC 50-80 ml / min) or moderate (CC 30-49 ml / min) severity dose adjustment of Xarelto ® is not required. The limited clinical data available from patients with renal insufficiency (CC 29-15 ml / min), show a significant increase in rivaroxaban concentrations in these patients. For the treatment of this category of patients, rivaroxaban should be used with caution. The use of Xarelto ® in patients with CC<15 мл/мин not recommended.

At elderly patients dose adjustment is not required.

The safety and efficacy of the drug in children and adolescents under the age of 18 not installed.

Dose adjustment of Xarelto ® is not required depending on gender, body weight, ethnicity.

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

When switching patients from VKA to Xarelto ® , MHO values will be falsely elevated after taking Xarelto ® . Therefore, the MHO should not be used to monitor the anticoagulant effect of Xarelto ® .

Switching patients from Xarelto ® to VKA

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 during the transition from therapy with Xarelto ® to VKA therapy, Xarelto ® may contribute to an increase in MHO. When switching a patient from Xarelto to VKA, both drugs should be given simultaneously until the MHO reaches ≥2. During the first two days of the transition period, the standard dose of VKA should be used, and then the INR value should be followed. During the 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 stopping the use of Xarelto ®, the MHO value can be reliably determined 24 hours after the last dose.

Transfer of patients from parenteral anticoagulants to Xarelto ®

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

Switching patients from Xarelto ® to parenteral anticoagulants

Xarelto ® should be discontinued and the first dose of parenteral anticoagulant administered at the time of the next dose of Xarelto ® expected.

Storage conditions and shelf life

The drug should be stored out of the reach of children at a temperature not exceeding 30 ° C. Shelf life - 3 years.