Instruction for use: Xarelto

Dosage form: film-coated tablets

Active substance: Rivaroxabanum

ATX

B01AF01 Rivaroxaban

Pharmacological group

Direct Factor Xa Inhibitors [Anticoagulants]

The nosological classification (ICD-10)

I26 Pulmonary embolism: Recurrent thromboembolism of the pulmonary artery; Recurrent pulmonary embolism; Thromboembolism of the branches of the pulmonary artery; Thromboembolism of the lungs; Thromboembolism of the pulmonary artery (PE); Thrombosis of the pulmonary artery; Thromboembolism; Thromboembolism of the pulmonary artery; Thromboembolism; Pulmonary embolism; Thromboembolism of the pulmonary artery and its branches; Thromboembolism of pulmonary vessels; Embolism of the lung; Embolism of the pulmonary artery; Acute massive thromboembolism of the pulmonary artery

I48 Atrial fibrillation and flutter: Permanent atrial tachyarrhythmias; Relief frequent ventricular rate during atrial flutter or blink; atrial fibrillation; Paroxysm of atrial fibrillation and flutter; Paroxysm of atrial fibrillation; Paroxysmal atrial fibrillation; Atrial premature beats; Tahiaritmicheskoy atrial fibrillation; Tahisistolicheskoy atrial fibrillation; auricular flutter; Life-threatening ventricular fibrillation; Atrial fibrillation; Chronic atrial fibrillation; supraventricular arrhythmia; Paroxysmal atrial fibrillation and flutter; Paroxysmal fibrilloflutter; Atrial premature beats

I64 Unspecified Stroke as a bleeding or heart attack: Primary stroke; Stroke; Stroke in the course of; microstroke; stroke; The completed stroke

I74 Embolism and arterial thrombosis: Thrombosis of effort (stress); Arterial thrombosis; Arteriothrombosis; Subacute and chronic arterial thrombosis; Subacute thrombosis of peripheral arteries; Postoperative thrombosis; Vascular thrombosis; Vascular embolism; Thrombosis of aortocoronary shunt; Arterial thrombosis; Thrombosis of arteries; Coronary artery thrombosis; Coronary thrombosis; Thrombosis of blood vessels; Thrombosis with ischemic stroke; Thrombosis with general surgical operations; Thrombosis in Oncology Operations; Vascular thrombosis; Thrombus formation in the postoperative period; Thrombotic complications; Thromboembolic diseases; Thromboembolic syndrome; Thromboembolic complication in the postoperative period; Thromboembolism of arteries; Partial vascular thrombosis; Embolism; Embolism of arteries

I82 Embolism and thrombosis of other veins: Recurrent venous thrombosis; Postoperative thrombosis; Venous thrombosis; Acute venous thromboembolism; Recurrent vein thrombosis; Venous thrombosis; Thrombosis of veins of internal organs; Venous thrombosis; Deep vein thrombosis; Thrombosis of blood vessels; Vascular thrombosis; Thrombosis of veins; Deep vein thrombosis; Thromboembolic diseases; Thromboembolism of veins; Severe venous thrombosis; Embolism; Embolism of veins; Thromboembolic complications

Composition

Film-coated tablets 1 tab.

active substance: Rivaroxaban micronized 15 mg; 20 mg

Auxiliary substances: microcrystalline cellulose - 37.5 / 35 mg; Croscarmellose sodium - 3/3 mg; Hypromellose 5cP - 3/3 mg; Lactose monohydrate - 25,4 / 22,9 mg; Magnesium stearate - 0.6 / 0.6 mg; Sodium lauryl sulfate - 0.5 / 0.5 mg

Film membrane: iron oxide red oxide - 0,15 / 0,35 mg; Hypromellose 15 ńĐ - 1,5 / 1,5 mg; Macrogol 3350 - 0.5 / 0.5 mg; Titanium dioxide - 0.35 / 0.15 mg

Description of dosage form

The tablets covered with a film cover, 15 mg: round, biconcave, pink-brown color; The method of extrusion is engraved: on one side - a triangle with a designation of dosage (15), on the other - a firm Bayer's cross.

Type of tablet on the break: a homogeneous mass of white, surrounded by a shell of pink-brown color.

The tablets covered with a film cover, 20 mg: round, biconcave, red-brown color; The method of extrusion is engraved: on one side - a triangle with a designation of dosage (20), on the other - a firm Bayer's cross.

Type of tablet on the break: homogeneous mass of white, surrounded by a shell of red-brown color.

Pharmachologic effect

Mode of action - Anticoagulant, inhibitory factor Xa.

Pharmacodynamics

Mechanism of action. Rivaroxaban is a highly selective direct inhibitor of factor Xa, which has high bioavailability when ingested.

Activation of factor X with the formation of factor Xa through the internal and external ways of coagulation plays a central role in the coagulation cascade.

Pharmacodynamic effects. A dose-dependent inhibition of factor Xa was observed in humans. Rivaroxaban has a dose-dependent effect on PV, the values of which correlate well with the concentrations of the drug in plasma (r = 0.98) if NeoplastinŽ is used for the analysis. If other reagents are used, the results will be different. PV should be measured in seconds, since MHO is calibrated and certified only 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, 5/95 percentile for PV (NeoplastinŽ) 1-4 hours after taking the tablet (ie at the maximum effect) range from 14 to 40 S in patients taking 20 mg once a day and 10 to 50 seconds in patients with renal insufficiency (Cl creatinine 49-30 mL / min) taking 15 mg once a day.

In patients receiving rivaroxaban for the treatment and prevention of relapses of deep vein thrombosis (DVT) and PE, 5/95-percentile for PV (NeoplastinŽ) 2 to 4 hours after taking the pill (i.e., at the maximum effect) range from 17 Up to 32 seconds in patients taking 15 mg twice a day and 15 to 30 seconds in patients taking 20 mg once a day.

Also, rivaroxaban dose-dependently increases the APTT and the HepTestŽ result; However, these parameters are not recommended for evaluating the pharmacodynamic effects of rivaroxaban. Also, if there is a clinical rationale for this, the concentration of rivaroxaban can be measured using a calibrated quantitative anti-factor Xa test.

During the period of XareltoŽ treatment, monitoring of blood coagulation parameters is not required.

In healthy men and women older than 50 years, the elongation of the QT interval of the ECG under the influence of rivaroxaban was not observed.

Pharmacokinetic

Absorption and bioavailability. Absolute bioavailability of rivaroxaban after taking in a dose of 10 mg is high (80-100%). Rivaroxaban is rapidly absorbed; Cmax is achieved 2-4 hours after taking the pill.

When taking rivaroxaban at a dose of 10 mg with food, no changes in AUC and Cmax were noted. Rivaroksaban in a dose of 10 mg can be given for admission during meals or regardless of food intake.

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

In connection with a reduced degree of absorption with admission of 20 mg on an empty stomach, a bioavailability of 66% was observed. When taking the drug XareltoŽ, 20 mg, during meals, the mean AUC was 39% higher than when taken on an empty stomach, showing almost complete absorption and high bioavailability.

Absorption of rivaroxaban depends on the site of its release in the digestive tract. The decrease in AUC and Cmax values by 29 and 56%, respectively, compared to the whole tablet, was observed when the rivaroxaban granulate was released in the distal small intestine or ascending colon. Avoid the introduction of rivaroxaban in the gastrointestinal tract distal to the stomach, as this may lead to a decrease in absorption and, accordingly, exposure of the drug.

The study evaluated the bioavailability (AUC and Cmax) of 20 mg of rivaroxaban taken internally in the form of a crushed tablet mixed with apple puree or suspended in water, as well as injected through a gastric tube, followed by a liquid intake, compared to taking the whole tablet. The results demonstrated a predictable dose-dependent pharmacokinetic profile of rivaroxaban, while bioavailability at the above-mentioned admission was consistent with that given lower doses of rivaroxaban.

Distribution. In the human body, most of the rivaroxaban (92-95%) binds to plasma proteins, the main binding component is serum albumin. Vd - moderate. Vss is approximately 50 liters.

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

Rivaroksaban is metabolized by isozymes CYP3A4, CYP2J2, and also by means of mechanisms independent of the cytochrome system. The main sites of biotransformation are the oxidation of the morpholino group and the hydrolysis of amide bonds.

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

Unchanged rivaroxaban is the only active compound in human plasma, metabolites in high concentrations or active circulating metabolites in plasma are not detected. Rivaroxaban, whose systemic clearance is approximately 10 l / h, can be attributed to drugs with low clearance. With the removal of rivaroxaban from the plasma, the final T1 / 2 is from 5 to 9 hours in young patients and from 11 to 13 hours in elderly patients.

Sex / Old age (over 65 years). In elderly patients, the concentration of rivaroxaban in plasma is higher than in young 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 detected.

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

Childhood. Data on this age category are absent.

Interethnic differences. Clinically significant differences in pharmacokinetics and pharmacodynamics in patients of European, African American, Latin American, Japanese or Chinese ethnicity were not observed.

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 trials). Classification Child-Pugh allows you to assess the prognosis of chronic liver disease, mainly cirrhosis. In patients who are scheduled to undergo anticoagulant therapy, an especially important critical moment of liver dysfunction is a decrease in the synthesis of clotting factors in the liver. Since this indicator corresponds only to one of the five clinical / biochemical criteria that make up the Child-Pugh classification, the risk of bleeding is not clearly correlated with this classification. The treatment of such patients with anticoagulants should be decided independently of the Child-Pugh class.

XareltoŽ is contraindicated in patients with liver diseases that occur with coagulopathy, which causes a clinically significant risk of bleeding.

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

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

Data on patients with hepatic insufficiency of Class C according to the Child-Pugh classification are absent.

Impaired renal function. In patients with renal insufficiency, an increase in the concentration of rivaroxaban in blood plasma was observed, inversely proportional to a decrease in renal function, estimated by the clearance of creatinine.

In patients with renal insufficiency with Cl creatinine 80-50, 49-30 and 29-15 ml / min, there was a 1.4-, 1.5- and 1.6-fold increase in plasma concentrations of rivaroxaban (AUC) Healthy volunteers. The corresponding increase in pharmacodynamic effects was more pronounced.

In patients with Cl creatinine 80-50, 49-30 and 29-15 ml / min, the overall inhibition of factor Xa activity increased 1.5, 1.9 and 2 times compared to healthy volunteers; PV - due to a change in factor Xa activity also increased in 1.3, 2.2 and 2.4 times, respectively.

Data on the use of XareltoŽ in patients with Cl creatinine of 29-15 ml / min are limited, and therefore care should be taken when using the drug in this category of patients. Data on the use of XareltoŽ in patients with Cl creatinine <15 ml / min are absent, and therefore it is not recommended to use the drug in this category of patients.

Indication of the drug Xarelto

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

Treatment of deep vein thrombosis and thromboembolism of the pulmonary artery and prevention of their relapse.

Contraindications

Hypersensitivity to rivaroxaban or any excipients contained in the tablet;

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

Damage 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 on 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 heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran, etc.) Or on rivaroxaban (see "Method of administration and dose") or when unfractionated heparin is used at the doses necessary to ensure the functioning of the central venous or arterial catheter;

Liver diseases that occur with coagulopathy, which causes clinically significant risk of bleeding;

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

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

Pregnancy and the period of breastfeeding;

Children and adolescents under 18 years of age (efficacy and safety in patients of this age group are not established).

CAREFULLY:

Treatment of patients with an increased risk of bleeding (including with a congenital or acquired tendency to bleeding, uncontrolled severe arterial hypertension, gastric ulcer and duodenal ulcer in the acute stage, a recent gastric and duodenal ulcer, vascular retinopathy, recently transferred intracranial Or intracerebral hemorrhage, the pathology of the vessels of the spinal cord or brain, after a recent surgery on the brain, spinal cord or eyes, bronchiectasis, or pulmonary hemorrhage in an anamnesis);

Treatment of patients with renal insufficiency (Cl creatinine 49-30 ml / min), receiving simultaneously drugs that increase the level of rivaroxaban in blood plasma (see "Interaction");

Treatment of patients with renal insufficiency (Cl creatinine 29-15 ml / min) - caution should be used, as the concentration of rivaroxaban in blood plasma in such patients can significantly increase (on average 1.6 times) and therefore they are at increased risk of bleeding;

Patients receiving drugs that affect hemostasis (eg, NSAIDs, antiplatelet agents or other antithrombotic agents);

Patients receiving systemic treatment with antifungal azole agents (eg ketoconazole) or HIV protease inhibitors (eg ritonavir). These drugs are potent inhibitors of the isoenzyme CYP3A4 and P-gp. As a consequence, these drugs can increase the concentration of rivaroxaban in blood plasma to a clinically significant level (an average of 2.6 times), which increases the risk of bleeding. The azole antifungal preparation fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on the exposure of rivaroxaban and can be used with it simultaneously (see "Interaction");

Patients with renal insufficiency (Cl creatinine 29-15 ml / min) or an increased risk of bleeding, and patients receiving concomitant systemic treatment with antifungal azole agents or HIV protease inhibitors should be closely monitored for the timely detection of complications in the form of bleeding.

Pregnancy and breast-feeding

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

Data from experimental animals showed pronounced toxicity of rivaroxaban for the maternal organism due to the pharmacological action of the drug (eg, complications in the form of hemorrhages) and resulting in reproductive toxicity.

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

Women with preserved reproductive capacity should use effective methods of contraception during the treatment of XareltoŽ.

Data on the use of XareltoŽ for the treatment of women during breast-feeding are not available. Data from experimental animals show that rivaroxaban is excreted in breast milk. Rivaroxaban can only be used after breastfeeding has been abolished (see Contraindications).

Fertility. Studies have shown that rivaroxaban does not affect male and female fertility in rats. Studies of the effect of rivaroxaban on fertility in humans have not been conducted.

Side effects

XareltoŽ safety was evaluated in four phase III trials involving 6097 patients undergoing large orthopedic surgery on the lower extremities (total knee or hip joint prosthesis) and 3997 patients hospitalized for medical reasons treated with XareltoŽ 10 mg for up to 39 days, As well as in three studies of phase III treatment of VTE involving 4566 patients who received either 15 mg Xarelto 2 times a day for 3 weeks, followed by a dose of 20 mg once a day, or 20 mg once daily before 21 months

In addition, of the two Phase III trials involving 7750 patients, safety data were obtained in patients with non-valvular atrial fibrillation who received at least one dose of XareltoŽ for up to 41 months and 10225 patients with acute coronary Syndrome, receiving at least one dose of 2.5 mg (2 times a day) or 5 mg (2 times a day) of XareltoŽ in addition to therapy with acetylsalicylic acid or acetylsalicylic acid with clopidogrel or ticlopidine, treatment duration up to 31 months.

Given the mechanism of action, the use of XareltoŽ may be accompanied by an increased risk of latent or obvious bleeding from any organs and tissues that can lead to post-hemorrhagic anemia. The risk of bleeding may increase in patients with uncontrolled hypertension and / or with joint use with drugs that affect hemostasis (see "Contraindications", subsection C CAUTION). Symptoms, symptoms and severity (including possible fatal outcome) vary depending on localization, intensity or duration of bleeding and / or anemia (see "Overdose"). Hemorrhagic complications may manifest as weakness, pallor, dizziness, headache, dyspnea, and an increase in the limb in volume or shock, which cannot be explained by other causes. In some cases, as a result of anemia, the symptoms of myocardial ischemia, such as chest pain and angina pectoris, developed.

With the application of XareltoŽ, such known complications, secondary to severe bleeding, such as compartmentalism and renal failure due to hypoperfusion, were also recorded. Thus, the possibility of bleeding in assessing the condition of any patient receiving anticoagulants should be considered.

The generalized data on the frequency of undesirable reactions recorded for XareltoŽ are given below. In groups divided by frequency, undesirable effects are presented in order of decreasing severity as follows: often - from ≥1 to <10% (from ≥1 / 100 to <1/10); Infrequently - from ≥0.1 to <1% (from ≥1 / 1000 to <1/100); Rarely - from ≥0.01 to <0.1% (from ≥1 / 10000 to <1/1000); Very rarely - <0.01% (<1/10000).

All the undesirable reactions that occurred during the treatment period in patients who participated in phase III clinical trials

From the blood and lymphatic system: often - anemia (including relevant laboratory parameters); Infrequently - thrombocythemia (including increased platelet count) *.

From the heart: infrequently - a 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 *; Infrequent - dry mouth.

Systemic disorders and reactions at the injection site: often - fever *, peripheral edema, deterioration of general health (including weakness, asthenia); Infrequent - malaise (including anxiety); Rarely - local edema *.

From the liver: infrequently - a violation of the liver; Rarely - jaundice.

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

Injuries, poisonings and procedural complications: often - hemorrhages after the procedures (including postoperative anemia and bleeding from the wound), excess hematoma with a bruise; Infrequent - discharge from the wound *; Rarely - vascular pseudoaneurysm ***.

Research results: often - increased activity of hepatic transaminases; Infrequent increase in bilirubin concentration, increased activity of APF *, increased LDH activity *, increased lipase activity *, increased activity of amylase *, increased activity of GGT *; Rarely - an increase in the concentration of conjugated bilirubin (with or without concomitant increase in ALT activity).

From the osteomuscular system and connective tissue: often - pain in the extremities *; Infrequently - a hemarthrosis; Rarely - a hemorrhage in the muscles.

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

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

On the part of the respiratory tract: often - nosebleeds, hemoptysis.

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

From the side of the vessels: often - marked decrease in blood pressure, hematoma.

* Recorded after large orthopedic operations.

** Registered in the treatment of VTE as very frequent in women <55 years.

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

During post-registration monitoring, cases of the undesirable reactions listed below were reported, the development of which had a temporary connection with the XareltoŽ administration. It is not possible to assess the frequency of occurrence of such undesirable reactions within the framework of post-registration monitoring.

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

On the part of the liver: cholestasis, hepatitis (including hepatocellular damage). In the framework of RCT Phase III, such adverse events were regarded as rare (> 1 / 10,000 to <1/1000).

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

From the musculoskeletal system and connective tissue: the frequency is unknown - the syndrome of elevated subfascial pressure (compartmental syndrome) due to hemorrhage into the muscles.

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

Interaction

Pharmacokinetic interaction

The excretion of rivaroxaban is mainly mediated by liver metabolism mediated by the cytochrome P450 system (CYP3A4, CYP2J2), as well as by renal excretion of unchanged drug substance using P-gp / BCRP vector systems.

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

Simultaneous application of XareltoŽ and strong inhibitors of the isoenzyme CYP3A4 and P-gp can lead to a decrease in renal and hepatic clearance and thus significantly increase systemic exposure.

The combined use of XareltoŽ and the azole antifungal agent ketoconazole (400 mg once daily), a potent inhibitor of CYP3A4 and Pgp, resulted in a 2.6-fold increase in the mean equilibrium AUC of rivaroxaban and an increase in the mean Cmax of rivaroxaban in 1.7 Times, which was accompanied by a significant increase in the pharmacodynamic effect of the drug.

The simultaneous administration of XareltoŽ and HIV protease inhibitor ritonavir (600 mg twice daily), which is a potent inhibitor of CYP3A4 and Pgp, led to an increase in the mean equilibrium AUC of rivaroxaban by a factor of 2.5 and an increase in the mean Cmax of rivaroxaban in 1.6 Times, which was accompanied by a significant increase in the pharmacodynamic effect of the drug. In this regard, XareltoŽ is not recommended for use by a patient receiving systemic treatment with antifungal azole agents or HIV protease inhibitors (see "Contraindications", subsection with CAUTION).

Clarithromycin (500 mg twice daily), strongly suppressing the isoenzyme CYP3A4 and moderately suppressing P-gp, caused an increase in AUC values by 1.5 times and Cmax of rivaroxaban by 1.4 times. This increase is of the order of normal variability of AUC and Cmax and is considered clinically insignificant.

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

In patients with renal insufficiency (Cl creatinine <80-50 ml / min) erythromycin (500 mg 3 times a day) caused an increase in the values of AUC of rivaroxaban by 1.8 times and Cmax by 1.6 times compared with patients with normal renal function , Who did not receive concomitant therapy. In patients with renal insufficiency (Cl creatinine 49-30 ml / min), erythromycin caused an increase in the values of AUC of rivaroxaban by a factor of 2 and Cmax by 1.6 times in comparison with patients with normal renal function who did not receive concomitant therapy (see "Contraindications" , Subsection C CAUTION).

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

The simultaneous use of rivaroxaban with dronedarone should be avoided due to the limited clinical data on joint application.

The combined use of XareltoŽ and rifampicin, which is a strong inducer of CYP3A4 and P-gp, led to a decrease in the average AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects.

The combined use of rivaroxaban with other strong inducers of CYP3A4 (eg phenytoin, carbamazepine, phenobarbital or preparations of St. John's wort) can also lead to a decrease in plasma rivaroxaban concentration. Reducing the concentration of rivaroxaban in plasma is clinically insignificant. Strong inductors CYP3A4 should be used with caution.

Pharmacodynamic interaction

After simultaneous use of sodium enoxaparin (single dose 40 mg) and XareltoŽ (single dose 10 mg), their effects on anti-Xa factor activity were observed, not accompanied by an additional summation effect on blood coagulation tests (PT, APTT). Enoxaparin did not alter the pharmacokinetics of rivaroxaban (see "Contraindications", subsection with CAUTION).

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

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

After the co-administration of XareltoŽ (at a dose of 15 mg) and naproxen 500 mg, a clinically significant increase in bleeding time was not observed. Nevertheless, in individuals, a more pronounced pharmacodynamic response is possible.

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

The transition from warfarin (MHO 2 to 3) to XareltoŽ (20 mg) or XareltoŽ (20 mg) to warfarin (MHO 2 to 3) increased MOP / MNO (NeoplastinŽ) to a greater extent than is possible It would be expected with simple summation of effects (individual MHO values can reach 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 XareltoŽ during the transition period as necessary tests that are not affected by warfarin, the activity of anti-Xa, PiCT and HepTestŽ can be used. Starting from the 4th day after discontinuation of the use of warfarin, all test results (including PV, APTT, inhibition of factor Xa activity and action on EPT-endogenous thrombin potential) reflect only the effect of XareltoŽ (see "Method of administration and dose" ).

If it is necessary to study the pharmacodynamic effects of warfarin during the transitional period, a measurement of the INR value at Intermediate may be used. Rivaroxaban (24 hours after the previous administration of rivaroxaban), since rivaroxaban has minimal effect on this indicator in this period.

No pharmacokinetic interactions have been reported between warfarin and XareltoŽ.

The drug interaction of XareltoŽ with AVK phenindione has not been studied. It is recommended that transfer of patients from Xarelto therapy to AVK therapy with phenindione and vice versa is avoided whenever possible.

There is limited experience in transferring patients with AVC therapy with acenocoumarol to XareltoŽ.

If there is a need to transfer the patient from Xarelto therapy to AVK therapy with phenindione or acenocoumarol, special care should be taken, daily monitoring of the pharmacodynamic action of the drugs (MHO, PV) should be performed immediately before the next dose of XareltoŽ.

If there is a need to transfer a patient from AVK therapy with phenindione or acenocoumarol to XareltoŽ therapy, 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 (substrate CYP3A4), digoxin (P-gp substrate), or atorvastatin (substrate CYP3A4 and Pgp) have been identified.

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

There were no clinically significant pharmacokinetic or pharmacodynamic interactions in the combined use of XareltoŽ and acetylsalicylic acid at a dose of 500 mg.

Influence on laboratory parameters. The drug XareltoŽ has an effect on blood clotting parameters (PT, APTT, HepTestŽ) in connection with its mechanism of action.

Dosing and Administration

Inside, with food.

If the patient is not able to swallow the whole tablet, the XareltoŽ tablet can be ground and mixed with water or liquid food, such as apple puree, just before taking. After taking a crushed XareltoŽ 15 or 20 mg tablet, you should immediately take food.

The crushed XareltoŽ tablet can be administered through a gastric tube. The position of the probe in the digestive tract should be agreed with the doctor in advance before taking XareltoŽ. The ground tablet should be injected through a stomach probe in a small amount of water, after which it is necessary to introduce a small amount of water in order to wash off the drug residues from the probe walls. After taking a crushed XareltoŽ 15 or 20 mg tablet, the enteral feeding should be taken immediately.

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

The recommended dose is 20 mg 1 time per day.

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

The recommended maximum daily dose is 20 mg.

Duration of treatment: XareltoŽ therapy should be considered a long-term treatment until the benefits of treatment exceed the risk of possible complications (see "Contraindications", subsection C Cautions and "Special instructions").

Actions when missing a dose. If the next dose is missed, the patient should immediately take XareltoŽ and continue the regular intake of the drug the next day in accordance with the recommended regimen. Do not double the dose taken to compensate for missed earlier.

Treatment of DVT and PE and prevention of relapses of DVT and PE

The recommended initial dose for the treatment of acute DVT or PE is 15 mg 2 times a day for the first 3 weeks, followed by a 20 mg dose once a day for further treatment and prevention of relapses of DVT and PE.

The maximum daily dose is 30 mg for the first 3 weeks of treatment and 20 mg for further treatment. Duration of treatment is determined individually after careful weighing of the benefits of treatment against the risk of bleeding (see "Contraindications", subsection C CAUTION). The minimum duration of treatment (at least 3 months) should be based on an estimate of reversible risk factors (ie, previous surgical intervention, trauma, immobilization period). The decision to prolong the course of treatment for a longer time is taken in assessing the permanent risk factors or in the case of the development of idiopathic DVT or PE.

Actions when missing a dose. It is important to adhere to the established dosing regimen. If the next dose is missed with a dosage regimen of 15 mg 2 times a day, the patient should immediately take XareltoŽ to achieve a daily dose of 30 mg. Thus, 2 tab. 15 mg can be taken in one step. The next day the patient should continue to take the drug regularly according to the recommended regimen. If the next dose is missed with a dosage regimen of 20 mg once a day, the patient should immediately take XareltoŽ and continue the regular intake of the drug the next day, according to the recommended regimen.

Individual patient groups

Correction of dose, depending on the age of the patient (over 65 years of age), sex, body weight or ethnicity is not required.

Patients with impaired liver function. XareltoŽ is contraindicated in patients with liver disease accompanied by coagulopathy, which causes a clinically significant risk of bleeding (see "Contraindications"). Patients with other liver diseases do not need to change the dosage (see "Pharmacokinetics").

The limited clinical data available for patients with moderate hepatic impairment (Child-Pugh class B) indicate a significant increase in the pharmacological activity of the drug. For patients with severe hepatic insufficiency (class C according to the Child-Pugh classification), clinical data are not available.

Patients with impaired renal function. In the appointment of XareltoŽ to patients with renal insufficiency (Cl creatinine <80-50 ml / min), dose adjustment is not required.

In the prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation with renal insufficiency (Cl creatinine 49-30 ml / min), the recommended dose is 15 mg 1 time per day.

When treating DVT and PE and preventing relapses of DVT and PE in patients with renal insufficiency (Cl creatinine 49-30 ml / min), dose adjustment is not required.

Available limited clinical data demonstrate a significant increase in rivaroxaban concentrations in patients with renal insufficiency (Cl creatinine 29-15 ml / min). To treat this category of patients XareltoŽ 15 mg should be used with caution. Use of XareltoŽ is not recommended in patients with Cl creatinine <15 ml / min (see "Contraindications", "Pharmacokinetics").

Transition from antagonists of vitamin K (AVK) to XareltoŽ. In the prevention of stroke and systemic thromboembolism, AVC should be discontinued and XareltoŽ treated with MHO ≤3.

With DVT and PE, AVC should be discontinued and XareltoŽ treated with MHO ≤2.5.

When patients with AVK pass to XareltoŽ, after XareltoŽ is taken, the MHO values will be erroneously overestimated. MHO is not suitable for determining the anticoagulant activity of XareltoŽ and therefore should not be used for this purpose (see "Interaction").

Transition from XareltoŽ to AVK. There is a possibility of an insufficient anticoagulant effect in the transition from XareltoŽ to AVK. In this regard, it is necessary to ensure a continuous sufficient anticoagulant effect during such a transition with the help of alternative anticoagulants. It should be noted that XareltoŽ can help increase MHO. Patients who have switched from XareltoŽ to AVK should simultaneously receive AVC until MHO reaches ≥2. During the first two days of the transition period, a standard dose of AVK should be applied, followed by a dose of AVK, determined depending on the MHO value. Thus, during simultaneous application of XareltoŽ and AVK MHO should be determined no earlier than 24 hours after the previous administration, but before the next dose of XareltoŽ is taken. After discontinuing XareltoŽ, the MHO value can be reliably determined 24 hours after the last dose (see "Interaction").

Transition from parenteral anticoagulants to XareltoŽ. For patients receiving parenteral anticoagulants, XareltoŽ should be started 0-2 hours before the next scheduled parenteral administration of the drug (eg, low molecular weight heparin) or at the time of the continuous parenteral administration of the drug (eg intravenous administration of unfractionated heparin).

Transition from XareltoŽ to parenteral anticoagulants. XareltoŽ should be withdrawn and the first dose of parenteral anticoagulant administered at the time the next dose of XareltoŽ was to be taken.

Cardioversion in the prevention of stroke and systemic thromboembolism. Treatment with XareltoŽ can be initiated or continued in patients who may require cardioversion. In cardioversion under the control of transesophageal echocardiography in patients who had not previously received anticoagulant therapy, to ensure adequate anticoagulation, XareltoŽ treatment should begin at least 4 hours before cardioversion.

Overdose

There were rare cases of overdose with rivaroxaban up to 600 mg without the development of bleeding or other adverse reactions. Due to the limited absorption, a low-level plateau of the drug concentration is expected to develop without further increase in its average plasma concentration when doses exceeding therapeutic levels are equal to 50 mg or higher.

The specific antivot of rivaroxaban is unknown. In case of an overdose, activated charcoal can be used to reduce the absorption of rivaroxaban. Given the intense binding to blood plasma proteins, it is expected that rivaroxaban will not be excreted during dialysis.

Treatment of bleeding

If the patient receiving rivaroxaban experienced a complication of bleeding, the next dose should be postponed or, if necessary, canceled with this medication. T1 / 2 rivaroxaban is approximately 5-13 hours. Treatment should be individual, depending on the severity and localization of bleeding. If necessary, appropriate symptomatic treatment, such as mechanical compression (for example, with severe nasal bleeding), surgical hemostasis with an evaluation of its effectiveness, infusion therapy and hemodynamic support, the use of blood products (erythrocyte mass or fresh frozen plasma, depending on whether anemia arose Or coagulopathy) or platelets.

If the above measures do not lead to the elimination of bleeding, specific procoagulant preparations of reversible action, such as clotting factors II, VII, IX and X in combination (prothrombin complex), anti-inhibitory coagulant complex or eptactog alpha (activated) can be assigned. However, currently the experience of using these drugs in patients receiving XareltoŽ is very limited.

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

There is limited experience in the use of tranexamic acid and there is none for aminocaproic acid and aprotinin in patients receiving XareltoŽ.

There is no scientific justification for the expediency or the experience of using the system hemostatic drug desmopressin in patients receiving XareltoŽ.

Special instructions

The use of XareltoŽ is not recommended in patients receiving concomitant systemic treatment with azole antifungal agents (eg, ketoconazole) or HIV protease inhibitors (eg ritonavir). These drugs are potent inhibitors of CYP3A4 and P-glycoprotein. Thus, these drugs can increase the concentration of rivaroxaban in blood plasma to clinically significant values (2.6 times on average), which can lead to an increased risk of bleeding. However, the azole antifungal preparation fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on the exposure of rivaroxaban and can be used with it simultaneously (see "Interaction"). XareltoŽ should be used with caution in patients with moderate renal impairment (Cl creatinine 49-30 ml / min) receiving concomitant medications that may increase rivaroxaban plasma concentrations (see "Interaction").

In patients with severe renal impairment (Cl creatinine <30 ml / min), the concentration of rivaroxaban in plasma can be significantly increased (1.6 times on average), which can lead to an increased risk of bleeding. Therefore, due to the presence of this underlying disease, such patients have an increased risk of developing both bleeding and thrombosis. Due to the limited amount of clinical data, XareltoŽ should be used with caution in patients with Cl creatinine of 29-15 ml / min. Clinical data on the use of rivaroxaban in patients with severe renal impairment (Cl creatinine <15 ml / min) are not available. Therefore, the use of XareltoŽ is not recommended in such patients (see "Dosage and Administration", "Pharmacokinetics", "Pharmacodynamics").

Patients with severe renal dysfunction or an increased risk of bleeding, as well as patients receiving concomitant systemic treatment with azole antifungal agents or HIV protease inhibitors, should be closely monitored for signs of bleeding after initiation of treatment.

XareltoŽ, like other antithrombotic agents, should be used with caution in patients who have an increased risk of bleeding, including:

- with a congenital or acquired tendency to bleed;

- with uncontrolled severe arterial hypertension; Patients with gastric ulcer and duodenal ulcer in the acute stage;

- with vascular retinopathy;

- recently undergone intracranial or intracerebral haemorrhage;

- with the pathology of the vessels of the brain or spinal cord;

- recently undergone surgery on the brain, spinal cord or eyes;

- with bronchiectasis or pulmonary hemorrhage in the anamnesis.

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

Patients with a risk of developing gastric ulcer and duodenal ulcer may receive appropriate preventive treatment. If there is an inexplicable decrease in hemoglobin or blood pressure, you need to look for a source of bleeding. The safety and effectiveness of XareltoŽ in patients with artificial heart valves have not been studied, therefore, there is no evidence that the use of XareltoŽ 20 mg (15 mg in patients with Cl creatinine 49-30 ml / min) provides a sufficient anticoagulant effect in this Category of patients. XareltoŽ is not recommended as an alternative to unfractionated heparin in patients with hemodynamically unstable PE, as well as in patients who may need thrombolysis or thrombectomy, since the safety and effectiveness of XareltoŽ have not been established in such clinical situations.

If an invasive procedure or surgery is required, XareltoŽ should be discontinued at least 24 hours before the intervention and on the basis of a doctor's report.

If the procedure cannot be postponed, an increased risk of bleeding should be assessed in comparison with the need for urgent intervention.

Admission of XareltoŽ should be resumed after an invasive procedure or surgery, provided that appropriate clinical indicators and adequate hemostasis are available.

When epidural / spinal anesthesia or spinal puncture is performed in patients receiving platelet aggregation inhibitors for the prevention of thromboembolic complications, there is a risk of developing epidural or spinal hematoma, which can lead to prolonged paralysis.

The risk of these events is further increased by the use of a permanent epidural catheter or concomitant therapy with drugs that affect hemostasis.

Traumatic performance of an epidural or spinal puncture or repeated puncture may also increase the risk.

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

The physician should compare the potential benefit and the relative risk before performing spinal surgery to patients receiving anticoagulants, or who are scheduled to administer anticoagulants for the prevention of thrombosis.

To reduce the potential risk of hemorrhage associated with the concomitant use of rivaroxaban and epidural / spinal anesthesia or spinal puncture, the pharmacokinetic profile of rivaroxaban should be considered. It is better to install or remove the epidural catheter or lumbar puncture when the anticoagulant effect of rivaroxaban is judged to be weak.

Based on the general pharmacokinetic characteristics, the epidural catheter is removed after at least a two-fold half-life, i.e. Not earlier than 18 hours after the appointment of the last dose of XareltoŽ for young patients and not earlier than 26 hours for elderly patients. The drug XareltoŽ should be prescribed no earlier than 6 hours after the extraction of the epidural catheter.

In case of a traumatic puncture, the appointment of XareltoŽ should be postponed for 24 hours.

Safety data obtained from preclinical studies. With the exception of the effects associated with the intensification of pharmacological action (bleeding), no specific hazard to humans has been identified in the analysis of preclinical data obtained in pharmacological safety studies.

Influence on the ability to drive vehicles / work with moving mechanisms. When using XareltoŽ, there were cases of fainting and dizziness (see "Side effects"). Patients who experience these adverse reactions should not drive vehicles and work with moving machinery.

Release form

film-coated tablets, 15 mg or 20 mg.

Tablets, 15 mg. In the blister of aluminum / polypropylene or aluminum / PVC-PVDC 14 or 10 table. 1, 2 or 3 bl. On 14 tab. Or 10 bl. On 10 tab. Are placed in a cardboard box.

Tablets, 20 mg. In the blister of aluminum / polypropylene or aluminum / PVC-PVDC 14 or 10 table. 1 or 2 bl. On 14 tab. Or 10 bl. On 10 tab. Are placed in a cardboard box.

Manufacturer

Bayer Pharma AG. D-51368, Leverkusen, Germany.

A legal entity in whose name the registration certificate was issued: Bayer Pharma AG. Müller Strasse, 178, 13353 Berlin, Germany.

For additional information and with claims, please contact: 107113, Moscow

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Xarelto

At a temperature not higher than 30 ° C.

Keep out of the reach of children.

The shelf life of the drug Xarelto

3 years.

Do not use beyond the expiration date printed on the package.