Xarelto pills 15 mg, 98 pcs.

Composition

One film-coated tablet contains:Active ingredient:rivaroxaban micronized 15.00 mg; excipients:microcrystalline cellulose-37.50 mg, croscarmellose sodium-3.00 mg, hypromellose 5 cP (hydroxypropylmethylcellulose 2910) – 3.00 mg, lactose monohydrate-25.40 mg, magnesium stearate-0.60 mg, sodium lauryl sulfate-0.50 mg; shell:iron oxide red dye-0.15 mg, hypromellose 15 cP(hydroxypropylmethylcellulose 2910) – 1.50 mg, macrogol 3350 (polyethylene glycol (3350)) – 0.50 mg, titanium dioxide-0.35 mg

. Pharmacological action

PHARMACOTHERAPY GROUP: direct inhibitors of factor Xa.

ATX code: IN 01AF01.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics

Mechanism of action

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

Activation of factor X to form factor Xa 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, there is a dose-dependent inhibition of factor Xa activity. Rivaroxaban has a dose-dependent effect on prothrombin time and correlates well with plasma concentrations (r=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 with non-valvular atrial fibrillation taking rivaroxaban for the prevention of stroke and systemic thromboembolism, the 5/95 percentiles for prothrombin time (Neoplastin) 1-4 hours after taking the pill (i. e. at maximum effect) range from 14 to 40 seconds in patients taking 20 mg once a day, and from 10 to 50 seconds in patients with moderate renal impairment taking 15 mg once a day.

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

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. Also, if there is a clinical justification for this, the concentration of rivaroxaban can be measured using a calibrated quantitative anti-factor Xa test.

Blood clotting parameters should not be monitored during treatment with Xarelto®.

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.

Pharmacokinetics

Absorption and bioavailability

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

The absolute bioavailability of rivaroxaban after taking a dose of 10 mg is high (80-100%) regardless of food intake. When taking rivaroxaban at a dose of 10 mg with food, there were no changes in AUC (area under the concentration – time curve) and Cmax (maximum concentration).

Due to the reduced degree of absorption, a 66% bioavailability was observed when taking 20 mg on an empty stomach. When taking Xarelto® 20 mg with a meal, there was an increase in the average AUC by 39% compared to fasting, showing almost complete absorption and high bioavailability. Xarelto ® 20 mg,15 mg should be taken with a meal.

The pharmacokinetics of rivaroxaban are characterized by moderate individual variability; individual variability (coefficient of variation) is 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. Administration 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

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

Metabolism and elimination

When taken orally, approximately 2/3 of the prescribed dose of rivaroxaban is metabolized and subsequently excreted in equal parts in the urine and through the intestines. The remaining 1/3 of the 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 human 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.

Paul/Older age (over 65 years)

In elderly patients, the concentration of rivaroxaban in blood plasma is higher than in young patients; the average AUC value is approximately 1.5 times higher than the corresponding values in young patients, mainly due to the apparent decrease in total and renal clearance (see the section “Dosage and administration”).

There were no clinically significant differences in pharmacokinetics between men and women (see section “Dosage and administration”).

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 administration”).

Childhood and adolescence (from birth to 18 years)

Data for this age category are not available (see the section “Dosage and administration”).

Ethnic differences

No clinically significant differences in pharmacokinetics and pharmacodynamics were observed in patients of Caucasian, African-American, Hispanic, Japanese or Chinese ethnicity (see the section “Dosage and administration”).

Patients with 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). The Child-Pugh classification makes it possible to assess the prognosis of chronic liver diseases, mainly cirrhosis. In patients who are scheduled for anticoagulant therapy, the most important consequence of impaired liver function is a decrease in the synthesis of blood 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 subjects (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 (see sections “Dosage and administration”, “Contraindications”).

Patients with impaired renal function

In patients with impaired renal function, an increase in the area under the rivaroxaban concentration – time curve was observed, inversely proportional to the degree of decrease in renal function, which was estimated by creatinine clearance.

In patients with mild renal dysfunction (creatinine clearance 50-80 ml/min), moderate renal dysfunction (Clcr 30-49 ml/min) and severe renal dysfunction (Clcr 15-29 ml/min) were observed, respectively,1,4-,1,5 – and 1,6-fold increase in the concentrations of rivaroxaban in plasma (AUC) compared to healthy volunteers (see section “Method of administration and dose”, “carefully”, the “Special instructions”).

The corresponding increase in pharmacodynamic effects was more pronounced. In patients with CLcr of 50-80 ml / min, CLcr of 30-49 ml / min, and CLcr of 15-29 ml / min, the total suppression of factor Xa activity increased 1.5,1.9, and 2-fold compared to healthy volunteers; prothrombin time due to factor Xa also increased 1.3,2.2, and 2.4-fold, respectively.

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. Data on the use of Xarelto® in patients with CLcr

Due to the underlying disease, patients with severe renal impairment are at high risk of bleeding and thrombosis.

Patients with acute deep vein thrombosis (DVT)

In patients receiving rivaroxaban at a dose of 20 mg for the treatment of acute deep vein thrombosis (DVT) once a day, the geometric mean value of the maximum concentration 2-4 hours after taking the drug was 215 mcg/l (22-535 mcg/l); the geometric mean value of the minimum concentration 24 hours after taking the drug was 32 mcg/l (6-239 mcg/l). Prediction interval = 90%

Correlation of pharmacokinetic parameters and pharmacodynamic effectsWhen receiving rivaroxaban at a dose of 5 to 30 mg twice per day was estimated by the ratio of pharmacokinetic parameters and pharmacodynamic effects (PK/PD) between the con – centration of rivaroxaban in plasma and pharmacodynamic end points

(inhibition of factor XA, prothrombin time, activated partial tromble – Stanovoe time (APTT) and the result HepTest®).

The relationship between rivaroxaban concentration and factor Xa activity is best demonstrated using the Emax model.

The linear segment model demonstrates the relationship between rivaroxaban concentration and prothrombin time. The angle of inclination varied significantly depending on the reagents used to determine prothrombin time. When using the Neoplastin kit, the baseline prothrombin time was about 13 seconds with a slope of about 3-4 seconds (100 mcg / L). The results of the analysis of the FC/PD ratio in phase II and III studies corresponded to similar indicators in healthy patients.

Indications

• prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation;
• treatment of deep vein thrombosis and pulmonary embolism and prevention of recurrent DVT and PE.

Use during pregnancy and lactation

Pregnancy

The 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 Xarelto®.

Breast-feeding

There are no data on the use of rivaroxaban for the treatment of breast-feeding women. 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”). .

Fertility

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

Contraindications

• hypersensitivity to rivaroxaban or any of the auxiliary substances contained in the pill;
• clinically significant active bleeding (e. g., intracranial hemorrhage, gastrointestinal bleeding);
• damage or condition associated with an increased risk of bleeding is large, for example, existing or recent gastrointestinal ulcer, the presence of malignant tumors with a high risk of bleeding, recent brain or spinal cord, surgery on the brain, spinal cord or eyes, intracranial hemorrhage, diagnosed or perceived esophageal varicose veins, arteriovenous malformation, aneurysm or vascular pathology of the brain or spinal cord;
• concomitant treatment with any other anticoagulants e. g. unfractionated heparin, low molecular weight heparins (enoxaparin, dalteparin, etc. ), heparin derivatives (fondaparinux loaded, etc. ), oral anticoagulants (warfarin, apixaban, dabigatran, etc. ), except in the case of transition or rivaroxaban (see section “Method of administration and dose”) or when using unfractionated heparin in doses necessary to ensure the functioning of the central venous or arterial catheter;
• liver diseases that occur with coagulopathy, which causes a clinically significant risk of bleeding (see the section “Pharmacological properties”);
• pregnancy and lactation (see section “Use during pregnancy and lactation”);
• childhood and adolescence to 18 years (efficacy and safety in patients in this age group have not been established);
• severe degree of renal dysfunction (Clcr <15 ml/min) (clinical data on the use of rivaroxaban in this category of patients do not exist);
• congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption (due to the presence of lactose).

WITH CAUTION

The drug should be used with caution:

• When treating patients with an increased risk of bleeding (including those with an innate or acquired tendency to bleed, uncontrolled severe arterial hypertension, acute gastric and duodenal ulcers, recent gastric and duodenal ulcers, vascular retinopathy, bronchiectasis, or a history of pulmonary bleeding);
• In the treatment of patients with moderate renal impairment (CLcr 30-49 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”);
• Patients receiving concomitant medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antiaggregants, 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 agents (e. g. ketoconazole) or HIV protease inhibitors (e. g. ritonavir). (see the sections “Interaction with other medicinal products”, “Special instructions”).
• Patients with severe renal impairment (CLcr 15-29 ml / min), 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®.

The number of patients who participated in the study and took at least 1 dose of rivarok-saban, the total daily dose and the maximum duration of treatment in phase III clinical trials using Xarelto® are shown in table 2 below:

Table 2.

* Patients who have received at least one dose of rivaroxaban.

Incidence of bleeding and anemia in patients treated with Xarelto® in phase III clinical trials:

Table 3.

* A pre-established sampling approach was used to collect data on adverse eventsGiven the mechanism of action, the use of Xarelto® may be associated with an increased risk of latent or obvious bleeding from any organs and tissues, which can lead to post-hemorrhagic anemia. The risk of bleeding may increase in patients with uncontrolled arterial hypertension and / or when co-administered with drugs that affect hemostasis (see section “With caution”). . Signs, symptoms, and severity (including possible death) vary depending on the location, intensity, or duration of bleeding and / or anemia (see section “Overdose”). . Hemorrhagic complications can manifest as weakness, pallor, dizziness, headache, or unexplained swelling, shortness of breath, or shock that cannot be attributed to other causes. In some cases, symptoms of myocardial ischemia, such as chest pain and angina pectoris, have developed due to anemia.

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, the possibility of bleeding should be considered when evaluating any patient receiving anticoagulants.

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: (≥1/1,000 to <1/100), rare: (≥1/10,000 to <1/1,000),

Table 4: 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

and EINSTEIN (DVT/PE/Extension CHOICE) and COMPASS*)

A were observed mainly after major orthopedic operations on the lower extremities

B were observed in the treatment of VTE as very frequent in women aged <55 years

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

* 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.

During post-marketing monitoring, 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 a phase III RCT, such adverse events were considered infrequent (from >>1/1000 to.

Liver and biliary tract disorders: cholestasis, hepatitis (including hepatocellular damage). In a phase III RCT, such adverse events were considered rare (from >>1/10000 to.

Disorders of the circulatory and lymphatic system: thrombocytopenia. In a phase III RCT, such adverse events were considered infrequent (from >>1/1000 to.

Interaction

Pharmacokinetic interactions

The elimination of rivaroxaban is mainly carried out by liver metabolism mediated by the cytochrome P450 system (CYP3A4, CYP2J2), as well as by renal excretion of unchanged drug substance using the P – gp/Bcrp (P-glycoprotein/breast cancer resistance protein) transporter systems.

CYP inhibition

Rivaroxaban does not inhibit CYP 3A4 or any other major isoforms of CYP.

CYP Induction

Rivaroxaban does not induce CYP 3A4 or any other major isoforms of CYP.

Effect on Rivaroxaban

Concomitant use of rivaroxaban and potent inhibitors of the CYP3A4 isoenzyme and P-glycoprotein may lead to a decrease in the renal and hepatic clearance of rivaroxaban and, thus, significantly increase its systemic exposure.

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

Co-administration of rivaroxaban and the HIV protease inhibitor ritonavir (600 mg twice daily), which is a potent inhibitor of CYP3A4 and P-glycoprotein, resulted in a 2.5-fold increase in the mean steady-state AUC of rivaroxaban and a 1.6-fold increase in the mean Cmax of rivaroxaban, which was accompanied by a significant increase in the pharmacodynamic effect of the drug. Therefore, rivaroxaban is not recommended for use in patients receiving systemic treatment with azole group antifungal drugs or HIV protease inhibitors (see sections “With caution”, “Special instructions”). .

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

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

In patients with mild renal impairment (CLcr 50-80 ml/min), erythromycin (500 mg 3 times daily) caused an increase in rivaroxaban AUC values by 1.8 times and Cmax by 1.6 times 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), a moderate inhibitor of the CYP3A4 isoenzyme, caused an increase in the average AUC of rivaroxaban by 1.4 times and an increase in the average Cmax by 1.3 times. This increase is on the order of normal variability in AUC and Cmax and is considered clinically insignificant.

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

Co-administration of Xarelto® and rifampicin, a potent inducer of CYP3A4 and P-glycoprotein, resulted in a decrease in the mean AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects. Concomitant administration of rivaroxaban with other potent CYP3A4 inducers (e. g., phenytoin, carbamazepine, phenobarbital, or St. John’s wort) may also result in a decrease in rivaroxaban plasma concentrations. A decrease in rivaroxaban plasma concentrations was found to be clinically insignificant. Powerful inducers of CYP3A4 should be used with caution.

Pharmacodynamic interactions

After simultaneous administration of enoxaparin sodium (a single dose of 40 mg) and Xarelto® (a single dose of 10 mg), a summation effect was observed with respect to the activity of anti-factor Xa, which was not accompanied by additional summation effects with respect to blood clotting tests (prothrombin time, APTT). Enoxaparin sodium did not alter the pharmacokinetics of rivaroxaban (see section “With caution”). .

Due to the increased risk of bleeding, caution should be exercised when co – administered topically with any other anticoagulants.

Not found pharmacokinetic interaction between the drug Xarelto® (15 mg) and clopidogrel (loading dose of 300 mg followed by the appointment of support – ing the dose of 75 mg), but in a subgroup of patients found a significant increase in bleeding time, not korrelirovala with the degree of platelet aggregation and maintenance of P-se – lectin or GPIIb/IIIa receptor (see section “caution”).

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

Caution should be exercised when Xarelto® is co-administered with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors, 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) to a greater extent than would be expected with a simple summation of effects (individual INR 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 Xarelto® during the transition period, anti-Xa, PiCT and HepTest®activity tests can be used as necessary tests that are not affected by warfarin. Starting from the 4th day after discontinuation of warfarin, all test results (including PV, APTT, inhibition of factor Xa activity and EPT (endogenous potential of thrombin))are available. reflect only the effect of Xarelto.

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

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

The drug interaction of Xarelto® with the vitamin K antagonist (VKA) phenindione has not been studied. It is recommended to avoid, as far as possible, switching patients from Xarelto® therapy to AVC phenindione therapy and vice versa.

There is limited experience in transferring patients from AVC therapy with acenocoumarol to Xarelto®.

If there is a need to transfer a patient from Xarelto® therapy to AVC therapy with phenindione or acenocoumarol, special care should be taken. During the period of co-administration of Xarelto® and AVC, daily monitoring of the pharmacodynamic effect of drugs (INR, prothrombin time) should be carried out immediately before taking the next dose of Xarelto®.

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

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 products

Xarelto ® 15 mg and 20 mg should be taken with a meal (see section 4.4). section ” Pharmacological properties”).

No interactions were detected

No pharmacokinetic interactions were observed between rivaroxaban and midazolam (a CYP3A4 substrate), digoxin (a P-glycoprotein substrate), or atorvastatin (a CYP3A4 and P-glycoprotein substrate).

Co-administration with the proton pump inhibitor omeprazole, the H2 – receptor antagonist ranitidine, the aluminum hydroxide / magnesium hydroxide antacids, 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 500 mg of acetylsalicylic acid.

Influence on laboratory parameters

Xarelto ® has an effect on blood clotting parameters (PV, APTT, HepTest®) due to its mechanism of action (see the section “Pharmacological properties/Pharmacodynamic effects”)

How to take, course of administration and dosage

Inside.

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

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

A crushed tablet of Xarelto® can be administered through a gastric tube. The position of the probe in the gastrointestinal tract should be additionally agreed with the doctor before taking Xarelto®. The crushed tablet should be administered through a gastric tube in a small amount of water, after which it is necessary to introduce a small amount of water in order to wash off the remnants of the drug from the walls of the probe. After taking a crushed Xarelto® tablet 15 mg or 20 mg, enteral nutrition should be taken immediately (see the section “Pharmacological properties”).

Prevention of stroke and systemic thromboembolism in patients with nonvalvular atrial fibrillation

The recommended dose is 20 mg once a day.

For patients with impaired renal function (CLcr 30-49 ml / min), the recommended dose is 15 mg once a day.

The recommended maximum daily dose is 20 mg.

Duration of treatment: Xarelto ® therapy should be considered as a long-term treatment, carried out as long as the benefit of treatment exceeds the risk of possible complications (see the sections “With caution” and “Special instructions”).

Actions when skipping a dose

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

Do not double the dose taken to compensate for the previously missed one.

Treatment of DVT and PE and prevention of recurrent DVT and PE

The recommended starting dose for the treatment of acute DVT or PE is 15 mg twice daily for the first 3 weeks, followed by switching to a dose of 20 mg once daily for further treatment and prevention of relapses of DVT and PE.

After at least 6 months of treatment for deep vein thrombosis or pulmonary embolism, the recommended dose of Xarelto® is 10 mg*once daily or 20 mg once daily, depending on the individual risk ratio of DVT or PE relapse and the risk of bleeding.

Table 1.

* if necessary, take the drug at a dose of 10 mg, Xarelto®, available in the appropriate dosage, should be used.

The maximum daily dose is 30 mg (15 mg twice daily) for the first 3 weeks of treatment and a maximum of 20 mg with further use of the drug.

The duration of treatment is determined individually after carefully weighing the benefits of treatment against the risk of bleeding (see section “With caution”). The minimum duration of treatment (at least 3 months) should be based on an assessment of reversible risk factors (i. e. previous surgery, trauma, period of immobilization). The decision to extend the course of treatment for a longer period of time is based on an assessment of persistent risk factors, or in the case of idiopathic DVT or PE. Actions when skipping a dose

It is important to adhere to the established dosage regimen.

If the next dose is missed with the 15 mg twice-daily dosage regimen, the patient should immediately take a Xarelto tablet to reach the daily dose of 30 mg. Thus, two 15 mg tablets can be taken at one time. The next day, the patient should continue to take the drug regularly in accordance with the recommended regimen.

If the next dose is missed during the once-daily dosage regimen, the patient should immediately take a tablet of Xarelto® and continue taking the drug regularly the next day in accordance with the recommended regimen.

Individual patient groups

No dose adjustment is required depending on the patient’s age (over 65 years), gender, body weight, or ethnicity.

Patients with impaired liver function

Rivaroxaban is contraindicated in patients with liver diseases associated with coagulopathy, which causes a clinically significant risk of bleeding (see the section “Contraindications”). .

Patients with other liver diseases do not need to change the dosage (see the section

“Pharmacological properties / Pharmacokinetics”). .

The available limited clinical data obtained in patients with moderate hepatic insufficiency (Child-Pugh class B) indicate a significant increase in the pharmacological activity of the drug. There are no clinical data available in patients with severe hepatic insufficiency (Child-Pugh class C).

Patients with impaired renal function

Limited clinical data show a significant increase in rivaroxaban concentrations in patients with severe renal impairment (CLR 15-29 ml / min). Xarelto® should be used with caution in this category of patients.

The use of rivaroxaban is not recommended in patients with CLcr < 15 ml / min (see sections

“Pharmacological properties”, “Contraindications”, “Special instructions”). .

When prescribing Xarelto® to patients with moderate (CLcr 30-49 ml / min) or severe (CLcr 15-29 ml/min) renal impairment, follow the recommendations below:

• In the prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation with moderate renal impairment (CLcr 30-49 ml / min), the recommended dose is 15 mg once a day (see section “Pharmacological properties”).
• For the treatment of DVT and PE and the prevention of recurrent DVT and PE, the recommended dose of Xarelto® is 15 mg twice daily for the first three weeks. Subsequently, when the recommended dose of Xarelto® is 20 mg once a day, you should consider reducing the dose to 15 mg once a day if the risk of bleeding is higher than the risk of recurrent DVT and PE. Recommendations for the use of Xarelto® at a dose of 15 mg are based on pharmacokinetic modeling and have not been studied in clinical studies (see sections “Special instructions”, “Pharmacological properties”).

When using Xarelto® in a dosage of 10 mg, no dose adjustment is required. When prescribing Xarelto® to patients with mild renal impairment (CLcr 50-80 ml/min), no dose adjustment is required (see section “Pharmacological properties”). .

Switching from vitamin K antagonist (VKA) treatment to Xarelto®

In the prevention of stroke and systemic thromboembolism, AVC treatment should be discontinued and Xarelto® treatment should be initiated at an INR of 3.0.

In DVT and PE, AVC treatment should be discontinued and Xarelto® treatment should be initiated at an INR of 2.5.

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

Switching from Xarelto® to vitamin K antagonist (VKA) therapy

There is a possibility of insufficient anticoagulant effect when switching from Xarelto® 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 Xarelto® may contribute to an increase in INR. Patients who have switched from Xarelto® to AVA should take AVA concomitantly until the INR reaches ≥ 2.0. During the first two days of the transition period, a standard dose of AVA should be applied, followed by a dose of AVA determined depending on the INR value. Therefore, during concomitant use of Xarelto® and AVC, INR should be determined no earlier than 24 hours after the previous dose, but before taking the next dose of Xarelto®. After discontinuation of Xarelto®, the INR value can be reliably determined 24 hours after the last dose (see “Interaction with other drugs”).

Switching from parenteral anticoagulants to Xarelto®

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

Switching from Xarelto® to parenteral anticoagulants

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

Cardioversion in the prevention of stroke and systemic thromboembolism

Treatment with Xarelto® may be initiated or continued in patients who may require cardioversion. For cardioversion under the control of transesophageal

echocardiography (CPECHO-CG) in patients who have not previously received anticoagulant therapy, treatment with Xarelto® should begin at least 4 hours before cardioversion to ensure adequate anticoagulation.

Prevention of stroke in patients with atrial fibrillation who underwent percutaneous coronary intervention (PCI) with stenting

Patients with atrial fibrillation of non-valvular origin after PCI with stenting are recommended to take Xarelto® in a reduced dose of 15 mg 1 time per day (or 10 mg 1 time per day for patients with moderate renal impairment (CLcr 30-49 ml / min)) in combination with a P2Y12 receptor inhibitor. It is recommended to continue this treatment regimen for a maximum of 12 months after PCI with stenting. After 12 months of therapy, the P2Y12 receptor inhibitor should be discontinued and Xarelto® monotherapy should be continued using standard dosages for patients with non-valvular atrial fibrillation (see sections “Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation”, “Patients with impaired renal function”).

Overdose

Rare cases of overdose have been reported when taking rivaroxaban up to 600 mg without developing bleeding or other adverse reactions. Due to limited absorption, a low-level plateau of the drug concentration is expected to develop without further increasing its average concentration in blood plasma when using doses higher than therapeutic, equal to 50 mg or higher.

The specific antidote of rivaroxaban is unknown. In case of overdose, activated charcoal can be used to reduce the absorption of rivaroxaban. Given the intense binding to plasma proteins, rivaroxaban is not expected to be eliminated during dialysis.

Treatment of bleeding

If a patient receiving rivaroxaban has experienced a bleeding complication, the next dose of the drug should be postponed or, if necessary, treatment with this drug should be discontinued. 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 with an assessment of its effectiveness, 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 the measures listed above do not lead to the elimination of bleeding, specific procoagulant drugs may be prescribed, such as prothrombin complex concentrate, activated prothrombin complex factor concentrate, or recombinant VIIa factor. However, at present, the experience of using these drugs in patients receiving Xarelto® is very limited.

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

There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in patients receiving Xarelto®. There is no scientific justification for the expediency or experience of using the systemic hemostatic drug desmopressin in patients receiving Xarelto®.

Description

round biconvex tablets of pink-brown color, covered with a film shell; method of squeezinganesenagravirovka:on one side – a triangle with the dosage designation “15”, on the other-a branded Bayer cross.

Special instructions

Use of concomitant medications

Rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole antifungal agents (e. g. ketoconazole) or HIV protease inhibitors (e. g. 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 (see fig. sections “With caution”, “Interaction with other medicinal products”).

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 fig. section “Interaction with other medicinal products”).

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 sections

“With caution”, “Interaction with other medicinal products”).

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, the use of Xarelto® is not recommended in such patients (see sections “Contraindications”, “Method of administration and dosage”, “Pharmacological properties”).

Patients with severe renal impairment (CLcr 15-29 ml / min) and 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.

Risk of bleeding

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

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

In clinical studies, mucosal bleeding (i. e., nosebleeds, gums, gastrointestinal tract, genitourinary system, including abnormal vaginal or increased menstrual bleeding) and anemia were observed more frequently with long-term treatment with rivaroxaban compared to treatment with AVK. Thus, in addition to proper clinical follow – up, laboratory hemoglobin/hematocrit testing may be relevant for detecting latent bleeding and quantifying the clinical significance of overt bleeding deemed acceptable.

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

• patients with congenital or acquired bleeding tendency;
• patients with uncontrolled severe arterial hypertension;
• patients with gastric ulcer and 12 duodenal ulcer in the acute stage;
• patients who recently had gastric ulcer and 12 duodenal ulcer;
• patients with vascular retinopathy;
• patients who recently had an intracranial or intracerebral hemorrhage;
• patients with pathology of the vessels of the brain or spinal cord;
• patients who recently had surgery on the head, spinal cord or eyes;
• patients with bronchoectases or pulmonary hemorrhage in history.

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 “Interaction with other drugs”).

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

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

Rivaroxaban therapy does not require routine monitoring of its exposure. However, measuring rivaroxaban concentrations using a calibrated test to quantify anti-Xa activity may be useful in exceptional cases where information about rivaroxaban exposure can be used to make clinically relevant decisions, such as in the case of overdose or emergency surgery.

Patients with artificial heart valves

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

Patients at high risk of triple positive antiphospholipid syndromeThe use of Xarelto® is not recommended in patients with a history of thrombosis who have been diagnosed with persistent triple-positive antiphospholipid syndrome (lupus anticoagulant, cardiolipin antibodies, and beta-2-glycoprotein I antibodies), since rivaroxaban therapy is accompanied by an increased frequency of recurrent thrombotic events compared to therapy with vitamin K antagonists (AVK).

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

There are data from an international clinical trial, the primary objective of which was to evaluate safety in patients with non – valvular atrial fibrillation who underwent PCI with stenting. Data on efficacy in this population are limited (see section “Dosage and administration”). There are no data on such patients with a history of stroke/ transient ischemic attack.

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

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

Surgical operations and interventions

If an invasive procedure or surgical intervention is required, Xarelto® should be discontinued at least 24 hours prior to the intervention and based on the doctor’s opinion.

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

Xarelto® should be resumed after an invasive procedure or surgical intervention, provided that appropriate clinical indications are available and adequate hemostasisis achieved. section “Pharmacological properties”).

Spinal anesthesia

Patients receiving platelet aggregation inhibitors to prevent thromboembolic events are at risk of developing an epidural or spinal hematoma, which can lead to long – term paralysis, when performing epidural/spinal anesthesia or spinal puncture. 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 operations or repeated punctures may also increase the risk.

Patients should be monitored for signs and 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 for the prevention of thrombosis. There is no experience of clinical use of rivaroxaban in dosages of 15 mg and 20 mg 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.

However, the exact time to achieve a sufficiently low anticoagulant effect in each patient is unknown.

Based on general pharmacokinetic characteristics, the epidural catheter is withdrawn after a minimum of two-fold half-life, i. e. not earlier than 18 hours after the last dose of Xarelto® for young patients and not earlier than 26 hours for elderly patients. Xarelto® should be administered no earlier than 6 hours after removal of the epidural catheter.

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

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, with its spread, intensification and/or blistering) or in the presence of other symptoms of hypersensitivity associated with mucosal damage, therapy with Xarelto®should be discontinued.

Women of reproductive age

Xarelto® can only be used in women of childbearing age 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.

Safety data obtained from preclinical studies

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

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND MECHANISMS

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

Form of production

Film-coated tablets of 15 mg and 20 mg.

For 15 mg tablets: 14 or 10 tablets in blisters made of Al/PP or Al / PVC-PVDH.1,2,3 or 7 blisters of 14 tablets or 10 blisters of 10 tablets together with the instructions for use in a cardboard pack with the control of the first opening.

For 20 mg tablets: 14 or 10 tablets in blisters made of Al/PP or Al / PVC-PVDH.1,2 or 7 blisters of 14 tablets or 10 blisters of 10 tablets together with the instructions for use in a cardboard pack with the control of the first opening.

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

Active ingredient

Rivaroxaban

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Weight

Weight: 36 gr.