Xarelto pills 2.5mg, 56pcs

Composition

1 film-coated tablet contains: Active ingredient: rivaroxaban micronized 2.50 mg, excipients: microcrystalline cellulose-40.00 mg, croscarmellose sodium-3.00 mg, hypromellose 5 cP -3.00 mg, lactose monohydrate-35.70 mg, magnesium stearate-0.60 mg, sodium lauryl sulfate-0.20 mg; shell: iron oxide yellow dye – 0.015 mg, hypromellose 15 cP-1,500 mg, macrogol 3350-0.500 mg, titanium dioxide-0.485 mg

Pharmacological action

Pharmacotherapy group: direct inhibitors of factor Xa. ATX code: 01 AR 01Pharmacological PROPERTIESPHARMACODYNAMICMECHANISM of action Ivaroxaban is a highly selective direct factor Xa inhibitor with high oral bioavailability. Activation of factor X to form factor Xa via the internal and external 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 clot and platelet activation by thrombin. One molecule of factor Xa catalyzes the formation of more than 1,000 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 the level of thrombin. Selective factor Xa inhibitors can stop the “thrombin burst”. Thus, rivaroxaban has an impact on the results of some specific or general laboratory tests used to evaluate clotting systems. Pharmacodynamic effects In humans, dose-dependent inhibition of factor Xa activity is observed. Rivaroxaban has a dose-dependent effect on the change in prothrombin time, which is closely correlated with the concentration of rivaroxaban in blood plasma (correlation coefficient 0.98), if the Neoplastin kit is used for analysis. If you use other reagents, the results will be different. Prothrombin time should be measured in seconds, since the INR (International Normalized Ratio) is calibrated and certified only 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) 2-4 hours after taking the pill (i. e. at the maximum effect) vary from 13 to 25 seconds. Rivaroxaban also dose-dependently increases activated partial thromboplastin time (APTT) and HepTest score; however, these parameters are not recommended for evaluating the pharmacodynamic effects of rivaroxaban. Blood clotting parameters should not be monitored during treatment with Xarelto®. However, if there is a clinical justification for this, the concentration of rivaroxaban can be measured using a calibrated quantitative anti-factor Xa test. In healthy men and women over 50 years of age, no prolongation of the QT interval of the electrocardiogram under the influence of rivaroxaban was observed. Pharmacokineticsabsorption and bioavailability Ivaroxaban is rapidly absorbed; the maximum concentration (Cmax) is reached 2-4 hours after taking the tablet. After oral use, rivaroxaban is almost completely absorbed and its bioavailability with 2.5 mg tablets is high (80-100%), regardless of food intake. Food intake does not affect the AUC (area under the concentration – time curve) and Ctax at a dose of 10 mg. Xarelto ® tablets in a dosage of 2.5 mg can be taken both with food and on an empty stomach (see the section “Dosage and use”). The pharmacokinetics of rivaroxaban are characterized by moderate interindividual variability, with a Cv% variability coefficient ranging from 30% to 40%. The absorption of rivaroxaban depends on the site of release in the gastrointestinal tract (GI). A decrease of 29% and 56% in AUC and Cmax, respectively, compared with taking a whole tablet, was observed with the introduction of rivaroxaban granulate into the proximal small intestine. Exposure to the drug also decreases when it is introduced into the distal small intestine or ascending colon. use 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 to the drug. The bioavailability (AUC and Cmax) of rivaroxaban 20 mg when taken as a whole tablet is comparable to the bioavailability of the drug taken orally as a crushed tablet (mixed with applesauce or suspended in water), as well as with the bioavailability of the drug when administered through a gastric tube followed by liquid nutrition. Given the predictable dose-dependent pharmacokinetic profile of rivaroxaban, the results of this bioavailability study are also applicable to lower doses. 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 taken 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 received dose is excreted unchanged by direct renal excretion, mainly due to active renal secretion. Rivaroxaban is metabolized by CYP3A4 and CYP2J2 isoenzymes, as well as by mechanisms independent of the cytochrome system. The main sites of biotransformation are oxidation of the morpholine group and 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 the blood plasma, with no major or active circulating metabolites detected in the plasma. Rivaroxaban, which has a systemic clearance of approximately 10 l / h, can be classified as a low-clearance drug. When rivaroxaban is eliminated from plasma, the final half-life is 5 to 9 hours in young patients and 11 to 13 hours in elderly patients. Gender/Older age (over 65 years)In elderly patients, rivaroxaban concentrations in blood plasma are higher than in young patients; the average AUC value is approximately 1.5 times higher than the corresponding values in young patients, mainly due to the apparent decrease in total and renal clearance (see the section “Dosage and use”). There were no clinically significant differences in pharmacokinetics between men and women (see section “Dosage and use”). Body weight 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%) (see the section “Dosage and use”). Childhood and adolescence (from birth to 18 years)Data for this age category are not available (see the section “Dosage and use”). Clinically significant differences in pharmacokinetics and Pharmacodynamics were not observed in patients of Caucasian, African-American, Hispanic, Japanese or Chinese ethnicity (see the section “Dosage and use”). Impaired liver function The effect of hepatic insufficiency on the pharmacokinetics of rivaroxaban was studied in patients assigned according to the Child-Pugh classification (according to standard procedures in clinical trials). The Child-Pugh classification makes it possible to assess the prognosis for patients with chronic liver diseases, 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 clotting factors in the liver. Since this indicator corresponds to only one of the five clinical/biochemical criteria that make up the Child-Pugh classification, the risk of bleeding does not clearly correlate with this classification. The question of treating such patients with anticoagulants should be decided independently of the Child-Pugh class. Rivaroxaban is contraindicated in patients with liver diseases associated with coagulopathy, which causes 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 the corresponding parameters in the control group of healthy volunteers (on average, there was a 1.2-fold increase in the AUC of rivaroxaban). There were no significant differences in pharmacodynamic properties between the groups. In patients with cirrhosis of the liver and moderate hepatic insufficiency (Child-Pugh class B), the average AUC of rivaroxaban was significantly increased (2.3 times) compared to healthy volunteers due to significantly reduced clearance of the drug, which indicates serious liver disease. 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 prothrombin time, the external coagulation pathway is evaluated, 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. Data on patients with Child-Pugh Class C hepatic insufficiency are not available.Renal impairment Patients with impaired renal function experienced an increase in the area under the rivaroxaban concentration – time curve, inversely proportional to the degree of decrease in renal function, which was assessed by creatinine clearance. In patients with mild renal impairment (creatinine clearance CLcr 50-80 ml/min), moderate renal impairment (creatinine clearance CLcr 30-49 ml/min) or severe renal impairment (creatinine clearance CLcr 15-29 ml/min), respectively, there was a 1.4 -,1.5 – and 1.6-fold increase in rivaroxaban plasma concentrations (AUC), compared with healthy volunteers (see sections “Dosage and use”, “Special instructions”, “With caution”). The corresponding increase in pharmacodynamic effects was more pronounced. In patients with mild, moderate, and severe renal impairment, the overall suppression of factor Xa activity increased 1.5,1.9, and 2-fold compared to healthy volunteers; the prothrombin time due to factor Xa was also extended 1.3,2.2, and 2.4-fold, respectively. Data on the use of Xarelto® in patients with CLcr Data on the use of Xarelto® in patients with CLcr of 15-29 ml/min are limited, and therefore caution should be exercised when using the drug in this category of patients. (see the sections “Dosage and use”, “Special instructions”, “With caution”). Due to the underlying disease, patients with severe renal impairment are at an increased risk of bleeding and thrombosis.

Indications

Prevention of death due to cardiovascular causes, myocardial infarction and stent thrombosis in patients after acute coronary syndrome (ACS), which occurred with an increase in cardiospecific biomarkers, in combination therapy with acetylsalicylic acid or with acetylsalicylic acid and thienopyridines-clopidogrel or ticlopidine. Prevention of stroke, myocardial infarction and death due to cardiovascular causes, as well as prevention of acute limb ischemia and general mortality in patients with coronary heart disease (CHD) or peripheral artery disease (PAD) in combination therapy with acetylsalicylic acid.

Use during pregnancy and lactation

Pregnancy safety and efficacy of rivaroxaban in pregnant women have not been established. Data obtained on experimental animals showed a pronounced toxicity of rivaroxaban to the maternal body, associated with the pharmacological action of the drug (for example, complications in the form of hemorrhages) and leading to reproductive toxicity. No primary teratogenic potential was found. Due to the possible risk of bleeding and the ability to cross the placenta, rivaroxaban is contraindicated during pregnancy (see section “Contraindications”). Women with preserved reproductive capacity should use effective methods of contraception during treatment with rivaroxaban. Breast-feeding Data on the use of Xarelto® for the treatment of women during breastfeeding are not available. Data obtained on experimental animals show that rivaroxaban is excreted in breast milk. Xarelto® can only be used after discontinuation of breast-feeding (see section “Contraindications”).

Contraindications

• Hypersensitivity to rivaroxaban or any excipient that is part of the drug.
• Clinically significant active bleeding (for example, intracranial hemorrhage, gastrointestinal bleeding).
• Liver diseases that occur with coagulopathy leading to a clinically significant risk of bleeding, including cirrhosis of the liver and impaired liver function of class B and C according to the Child-Pugh classification (see the section “Pharmacological properties”).
• Pregnancy and lactation (see the section “Use during pregnancy and lactation”).
• Children and adolescents under 18 years of age (efficacy and safety for patients of this age group have not been established).
• Severe renal impairment (CLcr
• 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 (enoxaparin, dalteparin, etc. ), heparin derivatives (fondaparinux, etc. ), oral anticoagulants (warfarin, apixaban, dabigatran, etc. ), except in cases of switching from or to rivaroxaban (see the section “Dosage and use”) or when using unfractionated heparin b in the doses required to ensure the functioning of the central venous or arterial catheter.
• Hereditary lactose or galactose intolerance (for example, congenital lactase deficiency or glucose-galactose malabsorption), because the drug contains lactose.

With caution

The drug should be used with caution:

• In the treatment of patients with an increased risk of bleeding (including those with a congenital or acquired tendency to bleed, uncontrolled severe arterial hypertension, acute gastric and duodenal ulcer in the acute stage, recent acute gastric and duodenal ulcer, vascular retinopathy, recent intracranial or intracerebral hemorrhage, in the presence of known vascular abnormalities of the spinal cord or brain, after recent surgery on the brain, spinal cord or eyes, if there is a history of bronchiectasis or pulmonary hemorrhage).
• In the treatment of patients with moderate renal impairment (CLcr 3049 ml / min), receiving concomitant medications that increase the concentration of rivaroxaban in blood plasma (see the section “Interaction with other drugs”).
• In the treatment of patients with severe renal impairment (CLcr 15 -29 ml / min) (see section “Special instructions”).
• In patients receiving concomitant medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents, other antithrombotics, or selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SSRIs).

Rivaroxaban is not recommended for use in patients receiving systemic treatment with azole antifungal drugs (for example, ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (for example, ritonavir). (see the sections “Interaction with other medicinal products”, “Special instructions”). Patients with severe renal impairment (CLcr 15-29 ml / min) or an increased risk of bleeding and patients receiving concomitant systemic treatment with azole antifungal drugs or HIV protease inhibitors should be closely monitored after starting treatment for timely detection of bleeding complications.

Side effects

The safety of Xarelto® was evaluated in thirteen phase III trials involving 53,103 patients treated with Xarelto®. Table 1: Number of patients who participated in the study and received at least 1 dose of rivaroxaban, total daily dose and maximum duration of treatment in phase III clinical trials using Xarelto®

* Patients who received at least one dose of rivaroxaban.

Table 2: Incidence of bleeding and anemia in patients treated with Xarelto®, based on the results of phase III studies

* A pre-established sampling approach was used to collect data on adverse events

Given the mechanism of action, the use of Xarelto® may be associated with an increased risk of hidden or obvious bleeding from any tissues and organs that can lead to the development of post-hemorrhagic anemia. The risk of bleeding may increase in patients with severe uncontrolled arterial hypertension and / or when co-administered with drugs that affect hemostasis (see section “With caution”). Signs, symptoms, and severity (including possible death) will vary depending on the source and extent or severity of bleeding and / or anemia (see section “Overdose”). Hemorrhagic complications can manifest as weakness, pallor, dizziness, headache, or unexplained swelling, shortness of breath, or shock that cannot be attributed to other causes. In some cases, as a consequence of anemia, symptoms of myocardial ischemia are observed, such as chest pain or angina pectoris. Known complications secondary to severe bleeding, such as high subfascial pressure syndrome (compartment syndrome) and renal failure due to hypoperfusion, have also been reported with Xarelto®. Therefore, when evaluating the condition of any patient receiving anticoagulants, the possibility of bleeding should be taken into account. The frequency of NLR (adverse drug reactions) when using Xarelto® is shown in the table below. Within each frequency group, adverse events are presented in decreasing order of severity. The frequency of occurrence is defined as: very often (>1/10), often (>>1/100 to >><1/10), infrequently (>1/1,000 to <1/10), infrequently (><1/100), rarely (>1/10,000 to <1/100), rarely (>

Table 3: All treatment-related adverse drug reactions reported in patients in Phase III clinical trials (cumulative data from RECORD 1-4, ROCKET AF, J-ROCKET, MAGELLAN, ATLAS, EINSTEIN (DVT/PE/Extension/CHOICE) and COMPASS*)

A were observed mainly after major orthopedic operations on the lower extremities B were observed during the treatment of VTE as very frequent in older women * A pre-defined, selective approach to collecting data on adverse events was applied.Since the frequency of adverse drug reactions did not increase, and since no new adverse drug reactions were identified, data from the COMPASS study were not included for frequency calculation in this table. The most frequent NLR in patients treated with the drug was bleeding. The most frequent bleeding events (>4%) were nosebleeds (5.9%) and gastrointestinal bleeding (4.2%). During post-marketing monitoring, cases of the following adverse reactions were reported, the development of which was temporarily associated with taking Xarelto®. It is not possible to estimate the frequency of occurrence of such adverse reactions in the framework of post-marketing monitoring. Immune system disorders: angioedema, allergic edema. In phase III registration clinical trials (RCTs), such adverse reactions were considered infrequent (from >1/1000 to > Liver and biliary tract disorders: cholestasis, hepatitis (including hepatocellular damage). In a phase III RCT, such adverse reactions were considered rare (from >1/10000 to > Disorders of the blood and lymphatic system: thrombocytopenia. In a phase III RCT, such adverse reactions were considered infrequent (from >1/1000 to >

Interaction

Pharmacokinetic Interactionsrivaroxaban is mainly eliminated by cytochrome P450 (CYP 3A4, CYP 2J2) – mediated metabolism in the liver and renal excretion of an unchanged drug involving the P-glycoprotein (P-dr) / Hrv transport protein system (breast cancer resistance protein). Caution should be exercised when rivaroxaban is co-administered with dronedarone due to limited clinical data on co-use. Surrivaroxaban does not inhibit CYP 3A4 or any other major isoforms of CYP. Surrivaroxaban does not induce CYP 3A4 or any other major isoforms of CYP. Effects on Rivaroxaban Simultaneous use of rivaroxaban with potent CYP3A4 and P-gp inhibitors may result in reduced hepatic and renal clearance, thus significantly increasing systemic exposure. Concomitant use of rivaroxaban with the azole antifungal drug ketoconazole (400 mg once daily), a potent inhibitor of CYP 3A4 and P-gp, resulted in a 2.6-fold increase in the mean steady-state AUC and a 1.7-fold increase in the mean Cmax of rivaroxaban, with a significant increase in the pharmacodynamic effects of this drug. Concomitant use of rivaroxaban with the HIV protease inhibitor ritonavir (600 mg twice daily), a potent inhibitor of CYP 3A4 and P-gp, resulted in a 2.5-fold increase in mean AUC and a 1.6-fold increase in mean Cmax of rivaroxaban, with a significant increase in the pharmacodynamic effects of this drug. Therefore, rivaroxaban is not recommended for use in patients receiving concomitant systemic treatment with azole antifungal drugs or HIV protease inhibitors (see sections “With caution”, “Special instructions”). Other active substances that inhibit at least one of the rivaroxaban elimination pathways mediated by either CYP 3A4 or P-gp are likely to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice daily), which is considered a potent inhibitor of CYP 3A4 and a moderate inhibitor of P-gp, resulted in a 1.5-fold increase in the mean AUC of rivaroxaban and a 1.4-fold increase in its mean Cmax. This increase, which is close to the normal variability of AUC and Cmax, was considered clinically insignificant. Erythromycin (500 mg three times daily), which moderately inhibits CYP 3A4 and P-gp, resulted in a 1.3-fold increase in the mean AUC and Cmax of rivaroxaban. This increase was within the normal range of AUC and Cmax variability and was considered clinically insignificant. In patients with mild renal impairment (CLcr 50-80 ml/min), erythromycin (500 mg 3 times daily) caused a 1.8-fold increase in rivaroxaban AUC and 1.6-fold increase in Cmax compared to patients with normal renal function who did not receive concomitant therapy. In patients with moderate renal impairment (CLcr 30-49 ml/min), erythromycin increased the AUC of rivaroxaban by 2.0 times and Cmax by 1.6 times compared to patients with normal renal function who did not receive concomitant therapy (see section “With caution”). Fluconazole (400 mg once daily), which is considered a moderate CYP 3A4 inhibitor, resulted in a 1.4-fold increase in the mean rivaroxaban AUC and a 1.3-fold increase in the mean Cmax. This increase was within the normal range of AUC and Cmax variability and was considered clinically insignificant (see section “Special instructions”). Concomitant use of rivaroxaban with the potent inducer of CYP 3A4 and P-gp rifampicin resulted in a decrease in the AUC of rivaroxaban by an average of approximately 50%, with a parallel decrease in its pharmacodynamic effects. Concomitant use of rivaroxaban with other potent inducers of CYP 3A4 (e. g., phenytoin, carbamazepine, phenobarbital, or St. John’s wort) may also lead to a decrease in rivaroxaban plasma concentrations. Potent CYP3A4 inducers should be used with caution in patients with CHD, PAD, or post-ACS receiving Xarelto ® 2.5 mg twice daily. Pharmacodynamic interactions After concomitant use of enoxaparin (40 mg single dose) with Xarelto® (10 mg single dose), a cumulative effect was observed associated with an inhibitory effect on the activity of factor Xa without any additional effect on clotting parameters (PV (prothrombin time), APTT (activated partial thromboplastin time). Enoxaparin does not affect the pharmacokinetics of rivaroxaban (see section “Special instructions”). Clopidogrel (a saturating dose of 300 mg followed by a maintenance dose of 75 mg) did not demonstrate a pharmacokinetic interaction (with Xarelto® at a dose of 15 mg), but there was a significant increase in bleeding time in a subset of patients that did not correlate with the degree of platelet aggregation, the number of P-selectin receptors or GPIIb/Sha (see section “Special Instructions”). No clinically significant increase in bleeding time was observed after concomitant use of Xarelto® (15 mg) and naproxen 500 mg. However, patients with a more pronounced pharmacodynamic response may occur (see section “Special instructions”). Due to the increased risk of bleeding, caution should be exercised when co-administered with any other anticoagulants (see sections “Contraindications”, “With caution” and “Special Instructions”). Caution should be exercised when Xarelto® is co-administered with NSAIDs (including acetylsalicylic acid) and antiplatelet agents, as 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) more than with simple summation of effects (individual INR values can reach 12), while the effect on APTT, suppression of factor Xa activity, and the effect on endogenous thrombin potential (EPT) was additive. If it is necessary to study the pharmacodynamic effects of Xarelto® during the transition period, anti-factor Xa activity determination, 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 laboratory parameters (including PV, APTT, inhibition of factor Xa activity and on EPT) reflect only the effect of Xarelto® (see the section “Dosage and use”). If it is necessary to investigate the pharmacodynamic effects of warfarin during the transition period, you can use the INR value at Ctrough of rivaroxaban (24 hours after taking the first dose of rivaroxaban), since at this point in time rivaroxaban has almost no effect on this indicator. No pharmacokinetic interactions have been reported between warfarin and Xarelto®. As with other anticoagulants, caution should be exercised when Xarelto® is co-administered with selective serotonin reuptake inhibitors (SSRIs). and selective serotonin and norepinephrine reuptake inhibitors (SSRIs), since the use of these drugs increases the risk of bleeding. The results of clinical studies demonstrated a numerical increase in large and small clinically significant bleeding in all treatment groups with the combined use of these drugs. Food and dairy productspreparation Xarelto® can be taken regardless of food intake (see the section “Pharmacological properties”). Pharmacokinetic interactions between rivaroxaban and midazolam (a CYP3A4 substrate), digoxin (a P-glycoprotein substrate), or atorvastatin (a CYP3A4 and P-gp substrate) are absent. Concomitant use of the proton pump inhibitor omeprazole, the H2-histamine receptor antagonist ranitidine, the aluminum hydroxide/magnesium hydroxide antacid, naproxen, clopidogrel, or enoxaparin did not affect the bioavailability or pharmacokinetics of rivaroxaban. No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when Xarelto® was co-administered with acetylsalicylic acid at a dose of 500 mg.Effect of Xarelto®on laboratory parameters It has an effect on blood clotting parameters (PV, APTT, Hep test) due to its mechanism of action.

How to take, course of use and dosage

Inside. Xarelto ® 2.5 mg should be taken one tablet twice daily. Xarelto ® 2.5 mg should be taken regardless of food intake. Prevention of death due to cardiovascular causes, myocardial infarction and stent thrombosis in patients after ACS

After ACS, the recommended treatment regimen for the prevention of vascular events is 1 tablet of Xarelto ® 2.5 mg twice daily. Patients should also 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. Treatment should be regularly evaluated in order to balance the risk of ischemic events with the risk of bleeding. The duration of treatment is 12 months. Treatment can be extended up to 24 months for individual patients, as data on treatment of this duration are limited.

Treatment with Xarelto ® 2.5 mg should be initiated as early as possible after the patient has stabilized during ongoing ACS (including revascularization procedures). Treatment with Xarelto® should begin at least 24 hours after hospitalization. Xarelto ® 2.5 mg should be started when parenteral anticoagulant therapy is usually discontinued. Prevention of stroke, myocardial infarction and death due to cardiovascular causes, as well as prevention of acute limb ischemia and general mortality in patients with CHD or PAD

The recommended dosage regimen for the prevention of vascular events in patients with CHD or PAD is 1 tablet of Xarelto ® 2.5 mg twice daily in combination with a daily dose of acetylsalicylic acid 75-100 mg. Treatment with Xarelto ® 2.5 mg should be long-term, provided that the benefits obtained outweigh the existing risks.

In patients with an acute thrombotic event or the need for vascular intervention who require dual antiplatelet therapy, the need to continue taking Xarelto® 2.5 mg twice daily should be evaluated, depending on the type of thrombotic event or procedure, as well as the type of antiplatelet therapy. The safety and efficacy of Xarelto® 2.5 mg taken twice daily in combination with acetylsalicylic acid and clopidogrel or ticlopidine have only been studied in patients with recent ACS. The use of dual antiplatelet therapy in combination with Xarelto® 2.5 mg twice daily in patients with CHD or PAD has not been studied.

Patients who have been diagnosed with CHD or PAD may be treated with Xarelto® 2.5 mg twice daily in combination with acetylsalicylic acid 75100 mg once daily at any time. If the dose is missed, the patient should continue taking Xarelto ® 2.5 mg at the usual dose, that is, at the next scheduled appointment in accordance with the recommendations.

If the patient is unable to swallow the tablet whole, the Xarelto ® tablet can be crushed or mixed with water or a liquid food, such as applesauce, immediately before ingestion. A crushed tablet of Xarelto® can be administered through a gastric tube. The position of the probe in the gastrointestinal tract should be additionally coordinated 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 drug residues from the walls of the probe (see the section “Pharmacological properties”).

Additional information for special patient groups

Patients with impaired liver function

Xarelto® is contraindicated in patients with liver diseases associated with coagulopathy leading to a clinically significant risk of bleeding (see ” Contraindications “).

Patients with other liver diseases do not need to adjust the dose (see the section “Pharmacological properties”).

Limited clinical data obtained in patients with moderate hepatic impairment (Child-Pugh class B) indicate a significant increase in pharmacological activity. For patients with severe hepatic impairment (Child-Pugh Class C), clinical data are not available (see sections “Contraindications”, “Pharmacological properties”). Patients with impaired renal function

No dose adjustment is required if Xarelto® is used in patients with mild (CLR 50-80 ml/min) or moderate (CLR 30-49 ml/min) renal impairment (see section “Pharmacological properties”).

Limited clinical data obtained in patients with severe renal impairment (CLcr 15-29 ml/min) indicate that the concentration of rivaroxaban in the blood plasma in this patient population is significantly increased. Therefore, in such patients, Xarelto®should be used with caution (see the section “Special instructions”, “Pharmacological properties”).

The use of Xarelto® is not recommended in patients with CLcr Switching from vitamin K antagonists (VKA) to Xarelto®

When patients with AVC switch to Xarelto®, INR values will be erroneously inflated after taking Xarelto®. INR is not suitable for determining the anticoagulant activity of Xarelto® and therefore should not be used for this purpose (see section “Interactions with other medicinal products”).

Switching from Xarelto®therapy for treatment with vitamin K antagonists (VKA)

There is a possibility of insufficient anticoagulant effect when switching from therapy with Xarelto® for AVC therapy. 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 when switching from Xarelto® In response to AVK therapy, Xarelto® may increase INR.

In patients who are transitioning from Xarelto®therapy For AVK therapy, the latter should be taken continuously until the INR value is >2.0. During the first two days of the transition period, AVA should be used in standard doses, subsequently adapting the dose of AVA in accordance with the INR value. Since patients receive both Xarelto® and AVC simultaneously during this period, INR should be evaluated no earlier than 24 hours (after the first dose, but before the next Xarelto®dose). Thus, after discontinuation of the drug Xarelto® INR as a reliable assessment of the therapeutic effect of AVK can be used no earlier than 24 hours after the last use of Xarelto® (see the section “Interaction with other drugs”, “Method of use and doses”).

Transition 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 scheduled parenteral use of the drug (for example, low-molecular-weight heparin) or at the time of discontinuation of continuous parenteral use of the drug (for example, intravenous use of unfractionated heparin).

Switching from Xarelto®therapy on therapy with parenteral anticoagulants

Xarelto® should be discontinued and the first dose of parenteral anticoagulant should be administered at the time when the next dose of Xarelto®should have been taken.

Children and adolescents (from birth to 18 years)

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

Elderly patients

No age-dependent dose adjustment is required (see section “Pharmacological properties”).

Gender

No gender-specific dose adjustment is required (see section “Pharmacological properties”).

Body weight

No dose adjustment is required depending on body weight (see section “Pharmacological properties”).

Ethnicity

No dose adjustment based on ethnicity is required (see section “Pharmacological properties”).

Overdose

Rare cases of overdose of up to 600 mg without bleeding or other adverse events have been reported. Due to limited absorption, a concentration plateau is expected to form without further increasing the average plasma concentration of rivaroxaban when using supratherapeutic doses of 50 mg or higher. There is no specific antidote to counteract the pharmacodynamic effects of rivaroxaban. In case of overdose with 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. Treatment of bleeding

If a patient receiving rivaroxaban has a bleeding complication, the next dose of the drug should be postponed or, if necessary, treatment with this drug should be discontinued altogether. The elimination half-life of rivaroxaban is approximately 5 to 13 hours. Treatment should be individual, depending on the severity and location of the bleeding.If necessary, appropriate symptomatic treatment can be used, such as mechanical compression (for example, for severe nosebleeds), surgical hemostasis using procedures to control the continuation of bleeding, infusion therapy and hemodynamic support, the use of blood preparations (red blood cell mass or fresh frozen plasma, depending on whether anemia or coagulopathy has occurred) or platelets.

If it is not possible to control the bleeding using the above procedures, the use of specific reverse-acting procoagulant drugs, such as prothrombin complex concentrate, activated prothrombin complex concentrate, or recombinant factor Vila (rf VIIa), can be used. However, at present, the experience of using these drugs in patients receiving Xarelto® is very limited. It is assumed 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 scientific justification for the expediency or experience of using the systemic hemostatic drug desmopressin in patients receiving Xarelto®.

Special instructions

Use of concomitant medications

Rivaroxaban is not recommended for use in patients receiving concomitant systemic treatment with azole antifungal drugs (for example, ketoconazole) or HIV protease inhibitors (for example, ritonavir). These drugs are potent inhibitors of CYP 3A4 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 (see the section “Interaction with other drugs”). However, the azole antifungal drug fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on the exposure of rivaroxaban and can be used simultaneously with it (see the section “Interaction with other drugs”).

Impaired renal function

Rivaroxaban should be used with caution in patients with moderate renal impairment (CLcr 30-49 ml / min), receiving concomitant medications that may lead to an increase in the concentration of rivaroxaban in plasma (see the section “Interaction with other drugs”).

In patients with severe renal impairment (CLcr Therefore, due to the presence of this underlying disease, such patients have an increased risk of developing both bleeding and thrombosis. Due to limited clinical data, rivaroxaban should be used with caution in patients with CLcr of 15-29 ml/min.

Clinical data on the use of rivaroxaban in patients with severe renal impairment (CLcr Therefore, rivaroxaban is not recommended for use in such patients (see sections “Dosage and use”, “Pharmacological properties”). Patients with severe renal impairment (CLcr 15-29 ml / min) or an increased risk of bleeding, as well as patients receiving concomitant systemic treatment with azole antifungal drugs or HIV protease inhibitors, should be closely monitored for signs of bleeding after starting treatment. Monitoring can be carried out by conducting a regular physical examination of patients, carefully monitoring the state of drainage of the postoperative wound, as well as by periodically determining hemoglobin.

Patients with a history of stroke and / or TIA

Xarelto ® 2.5 mg twice daily is contraindicated in patients with ACS who have a history of stroke or TIA. Only a handful of ACS patients with a history of stroke or TIA have been studied, but the limited data obtained demonstrate that there is no clinical benefit from treatment with rivaroxaban in such patients.

Patients with hemorrhagic or lacunar stroke

Patients with CHD or PAD with a history of hemorrhagic or lacunar stroke were not studied. Such patients should not be treated with Xarelto ® 2.5 mg twice daily in combination with acetylsalicylic acid.

Patients with ischemic non-lacunar stroke

Patients with CHD or PAD who had experienced an ischemic non-lacunar stroke during the previous month were not studied. Such patients should not be treated with Xarelto ® 2.5 mg twice daily in combination with acetylsalicylic acid for the first month after stroke.

Risk of bleeding

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

• congenital or acquired clotting disorders
• uncontrolled severe arterial hypertension
• active gastrointestinal pathology with ulceration
• recent acute gastrointestinal ulcer
• vascular retinopathy
• recent intracranial or intracerebral hemorrhage
• intraspinal or intracerebral vascular abnormalities
• recent brain, spinal cord or ophthalmic surgery for
• bronchiectasis or a history of pulmonary bleeding episode

Caution should be exercised if the patient is receiving concomitant medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, other antithrombotic drugs, or selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SSRIs) (see section “Interactions with other drugs”). Patients receiving Xarelto® in combination with acetylsalicylic acid or Xarelto® in combination with acetylsalicylic acid and clopidogrel/ticlopidine as long-term concomitant treatment may receive NSAIDs only if the positive effects of treatment justify the existing risk of bleeding. In patients at risk of developing ulceration in the gastrointestinal tract, appropriate preventive treatment can be used (see the section “Interaction with other drugs”). Any unexplained decrease in hemoglobin or blood pressure should lead to a search for the source of bleeding. In patients after ACS, the efficacy and safety of Xarelto® 2.5 mg twice daily were studied in combination with the antiplatelet agent acetylsalicylic acid or with acetylsalicylic acid and clopidogrel/ticlopidine. The use in combination therapy with other antiplatelet agents (for example, prasugrel or ticagrelor) has not been studied, and therefore it is not recommended for use. Spinal anesthesia

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

The risk of these events is further increased with the use of a permanent epidural catheter or concomitant therapy with drugs that affect hemostasis. Traumatic epidural or spinal tap procedures or repeated punctures may also increase the risk. Patients should be monitored for signs or symptoms of neurological disorders (such as numbness or weakness in the legs, bowel or bladder dysfunction). If neurological disorders are detected, urgent diagnosis and treatment is necessary.

The physician should weigh the potential benefit and relative risk before performing spinal surgery in patients receiving anticoagulants or who are scheduled to receive anticoagulants to prevent thrombosis.

There is no experience of clinical use of rivaroxaban 2.5 mg twice daily with acetylsalicylic acid or with acetylsalicylic acid and clopidogrel or ticlopidine in these situations.

The pharmacokinetic profile of rivaroxaban should be considered in order to reduce the potential risk of bleeding associated with concomitant use of rivaroxaban and epidural / spinal anesthesia or spinal puncture. Insertion or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is assessed as weak (see section “Pharmacological properties / Pharmacokinetics”).

However, the exact time to achieve a sufficiently low anticoagulant effect in each patient is unknown. Attention should be paid to the concomitant use of platelet aggregation inhibitors and, if necessary, discontinue their use.

Surgical operations and interventions

If an invasive procedure or surgical intervention is required, Xarelto® 2.5 mg should be discontinued at least 12 hours prior to the intervention, if possible, and based on the doctor’s clinical assessment.

If a patient receiving platelet aggregation inhibitors who is undergoing elective surgery does not need an antiplatelet effect, 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 postponed, a comparative assessment of the increased risk of bleeding and the need for urgent intervention should be made.

Xarelto® should be resumed as soon as possible, after an invasive procedure or surgical intervention, provided that the clinical parameters are sufficient and adequate hemostasis is achieved (see the section “Pharmacological properties”).

Patients with artificial heart valves

The safety and efficacy of Xarelto® have not been studied in patients with artificial heart valves. Evidence that the drug Xarelto® provides sufficient anticoagulation in this patient population, are absent.

Skin reactions

Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in post-marketing observations. At the first appearance of a severe skin rash (for example, when it spreads, intensifies and/or blisters form) or if there are other symptoms of hypersensitivity associated with mucosal damage, Xarelto®therapy should be discontinued.

Women of childbearing age

Xarelto® can be used in women of childbearing age only if effective methods of contraception are used. Lengthening of the corrected QT interval

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

Influence on the ability to drive vehicles and mechanisms

Fainting and dizziness have been reported during the course of taking the drug, which may affect the ability to drive vehicles or other mechanisms (see the section “Side effects”). Patients who experience similar adverse reactions should not drive vehicles or other mechanisms.

Form of production

Film-coated tablets 2.5 mg.

14 or 10 tablets in blisters made of Al/PP or Al / PVC-PVDH. By 1,2,4,7,12,14 14 tablets or 10 blisters of 10 tablets together with the instructions for use in a cardboard box.

Storage conditions

At a temperature not exceeding 30°C. Keep out of reach of children.

Shelf

life is 3 years. Do not use after the expiration date indicated on the package

Active ingredient

Rivaroxaban

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

Adults as prescribed by a doctor

Indications

Thrombophlebitis, Prevention of thrombosis, Consequences of stroke, Prevention of heart attacks and strokes, Angina Pectoris