Xarelto, 20 mg 98 pcs

Name: Xarelto, 20 mg 98 pcs
SKU: 505492
Availability: InStock

€236.08

EAN: 0400850003189 SKU: 505492 Categories: Anticoagulants, Blood Diseases, Medicine

Description

Pharmacotherapeutic group: direct factor Xa inhibitors.

ATX code: B01AF01.

Pharmacological properties

Pharmacodynamics

The mechanism of action

p> Rivaroxaban is a highly selective direct factor Xa inhibitor with high bioavailability when taken orally.

The activation of factor X to form factor Xa through the internal and external clotting pathways plays a central role in the coagulation cascade. Factor Xa is a component of the forming prothrombinase complex, the action of which leads to the conversion of prothrombin into thrombin. As a result, these reactions lead to the formation of fibrin thrombus and platelet activation by thrombin. One molecule of factor Xa catalyzes the formation of over 1000 molecules of thrombin, which has been called the “thrombin burst. The reaction rate of prothrombinase-bound factor Xa increases 300,000 times that of free factor Xa, providing a dramatic jump in thrombin levels. Selective factor Xa inhibitors can stop the thrombin burst. Thus, rivaroxaban affects the results of some specific or general laboratory tests used to evaluate clotting systems.

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 the assay. Results will differ if other reagents are used. Prothrombin time should be measured in seconds because 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 prevention of stroke and systemic thromboembolism, the 5/95 percentile for prothrombin time (Neoplastin) 1-4 hours after taking the tablet (ie.i.e., at maximum effect) range from 14 to 40 seconds in patients taking 20 mg once daily and from 10 to 50 seconds in patients with moderate renal impairment taking 15 mg once daily.

In patients receiving rivaroxaban for the treatment and prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (TELA), 5/95 percentiles for prothrombin time (Neoplastin) 2 to 4 hours after taking the tablet (ie.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 (APT) and the HepTest^® result; however, these parameters are not recommended for evaluating the pharmacodynamic effects of rivaroxaban. Also, if clinically warranted, rivaroxaban concentrations may be measured using a calibrated quantitative anti-factor Xa test.

Monitoring of clotting parameters is not required during treatment with Xarelto^®.

In healthy men and women over 50 years of age, no prolongation of the electrocardiogram QT interval was observed under the influence of rivaroxaban.

Pharmacokinetics

Intake and bioavailability

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

The absolute bioavailability of rivaroxaban after a dose of 10 mg is high (80-100%) regardless of food intake. No change in AUC (area under the curve “concentration – time”) and Cmax (maximum concentration) was observed when rivaroxaban 10 mg was taken with food.

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

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

The absorption of rivaroxaban depends on the site of release in the gastrointestinal tract (GIT). A 29% and 56% reduction in AUC and Cmax, respectively, compared to whole tablet administration was observed when rivaroxaban pellet was administered to the proximal small intestine. Exposure to the drug is also reduced when administered into the distal small intestine or the ascending colon. Administration of rivaroxaban in the gastrointestinal tract distal to the stomach should be avoided as it may reduce absorption and therefore 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 apple puree or suspended in water) and the bioavailability of the drug when administered via gastric tube followed by liquid food. Given the predictable dose-dependent pharmacokinetic profile of rivaroxaban, the results of this bioavailability study are also applicable to lower doses.

Distribution

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

Metabolism and excretion

On oral administration, approximately 2/3 of the administered dose of rivaroxaban is metabolized and subsequently excreted in equal amounts in the urine and through the intestine. The remaining 1/3 of the dose is excreted via direct renal excretion unchanged primarily through active renal secretion.

Rivaroxaban is metabolized by CYP3A4, 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 the amide bonds. According to in vitro data, rivaroxaban is a substrate for P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein) transporter proteins. Unchanged rivaroxaban is the only active compound in human plasma; no major or active circulating metabolites have been detected in plasma. Rivaroxaban, which has a systemic clearance of approximately 10 L/h, may be classified as a low clearance drug. In the plasma excretion of rivaroxaban, the final elimination half-life is 5 to 9 hours in young patients and 11 to 13 hours in elderly patients.

Gender/Elderly (>65 years)

The plasma concentrations of rivaroxaban are higher in elderly patients than in younger patients; the average AUC is approximately 1.5 times greater than in younger patients, primarily due to the apparent decrease in total and renal clearance (see section “Dosage and administration”).

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

Body weight

High or low body weight (less than 50 kg and greater than 120 kg) only slightly affects the plasma concentration of rivaroxaban (less than 25% difference) (see section “Administration and Dosages”).

Child and adolescent age (from birth to 18 years)

There are no data for this age group (see section on Dosage and administration).

Interethnic differences

There were no clinically significant differences in pharmacokinetics and pharmacodynamics in patients of Caucasian, African American, Hispanic, Japanese, or Chinese ethnicity (see section on Dosage and administration).

Patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of rivaroxaban has been studied in patients allocated according to the Child-Pugh classification (according to standard procedures in clinical trials). The Child-Pugh classification provides an assessment of the prognosis of chronic liver disease, mainly cirrhosis. In patients scheduled for anticoagulant therapy, the most important consequence of impaired liver function is reduced synthesis of blood clotting factors in the liver. Because this figure corresponds to only one of the five clinical/biochemical criteria that make up the Child-Pugh classification, the risk of bleeding does not correlate clearly with this classification. Treatment of such patients with anticoagulants should be decided regardless of the Child-Pugh classification.

Rivaroxaban is contraindicated in patients with liver disease presenting with coagulopathy that is clinically significant bleeding risk.

In patients with cirrhosis and mild hepatic impairment (Child-Pugh class A) the pharmacokinetics of rivaroxaban did not significantly differ from those of control group of healthy subjects (on the average there was 1.2-fold increase of AUC of rivaroxaban). There were no significant differences in pharmacodynamic properties between the groups.

In patients with cirrhosis and moderate hepatic impairment (Child-Pugh class B) the mean AUC of rivaroxaban was significantly increased (2.3-fold) compared to healthy volunteers due to significantly decreased clearance of the drug substance, indicating serious liver disease. Suppression of factor Xa activity was more pronounced (2.6-fold) than in healthy volunteers. Prothrombin time was also 2.1 times that of healthy volunteers. Prothrombin time measurement assesses the external coagulation pathway, which includes clotting factors VII, X, V, II and I, which are synthesized in the liver. Patients with moderate hepatic insufficiency are more sensitive to rivaroxaban, which is a consequence of a closer relationship between pharmacodynamic effects and pharmacokinetic parameters, especially between concentration and prothrombin time.

There are no data for patients with Child-Pugh class C hepatic impairment (see sections “Dosage and administration” and “Contraindications”).

Patients with impaired renal function

In patients with impaired renal function, there was an increase in the area under the concentration-time curve of rivaroxaban inversely proportional to the degree of decrease in renal function, as assessed by creatinine clearance.

. Patients with mild renal impairment (creatinine clearance 50-80 mL/min), moderate renal impairment (CLKR 30-49 mL/min), and severe renal impairment (CLKR 15-29 mL/min) showed 1.4-, 1.5-, and 1.6-fold increases in rivaroxaban plasma concentrations (AUC) compared to healthy volunteers, respectively(see Dosage and Administration, Caution, and Special Precautions).

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

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

Due to the underlying disease, patients with severe renal dysfunction 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 once daily for treatment of acute deep vein thrombosis (DVT), the geometric mean value of maximum concentration 2-4 hours after drug administration was 215 mcg/L (22-535 mcg/L); the geometric mean value of the minimum concentration 24 hours after the drug intake was 32 mcg/L (6-239 mcg/L). Prediction interval = 90%

Ratio of pharmacokinetic parameters and pharmacodynamic effects The ratio of pharmacokinetic parameters and pharmacodynamic effects (PK/PD) between the plasma concentration of rivaroxaban and the pharmacodynamic endpoints was assessed with the administration of rivaroxaban at doses of 5 to 30 mg twice daily <

(Factor Xa inhibition, prothrombin time, activated partial thromboplastin time (APTV) and HepTest^® results).

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

The linear slope model demonstrates the relationship between rivaroxaban concentration and prothrombin time value. The slope angle varied significantly depending on the reagents used to determine the prothrombin time. Using the Neoplastin kit, the baseline prothrombin time was about 13 s with a slope of about 3-4 s (100 µg/L). The results of the FK/FD ratio analysis in the phase II and III studies were similar to those of healthy patients.

Indications
Indications

Active ingredient
Active ingredient

Composition
Composition

How to take, the dosage
How to take, the dosage
Ingestion.
The drug XareltoÂ® 15 mg and 20 mg should be taken with food.
If the patient is unable to swallow the tablet whole, the XareltoÂ® tablet may be crushed and mixed with water or a liquid food such as apple puree immediately before intake. After taking a crushed tablet of XareltoÂ® 15 mg or 20 mg, a meal should be taken immediately.
The crushed tablet of XareltoÂ® may be administered through a gastric tube. The position of the tube in the gastrointestinal tract must be further agreed with the physician before taking XareltoÂ®. The crushed tablet should be inserted through the gastric tube in a small amount of water, after which a small amount of water should be injected to wash out the drug residues from the walls of the tube. After intake of crushed Xarelto Â® 15 mg or 20 mg tablet, enteral nutrition should be immediately administered (see section “Pharmacological properties”).
Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation
The recommended dose is 20 mg once daily.
For patients with impaired renal function (CLKR 30-49ml/min ), the recommended dose is 15 mg once daily.
The recommended maximum daily dose is 20 mg.
Long-term treatment: Therapy with XareltoÂ® should be considered long-term treatment for as long as the benefits of treatment outweigh the risk of possible complications (see Caution and Special Precautions).
Actions for Missed Dose
If another dose is missed, the patient must take a tablet of Xarelto immediatelyÂ® and continue the next day’s regular dosing according to the recommended regimen.
The dose taken should not be doubled to make up for a previously missed dose.
Treatment of DVT and TELA and prevention of recurrence of DVT and TELA
. The recommended starting dose in the treatment of acute DVT or TELA is 15 mg twice daily for the first 3 weeks, with a subsequent transition to a dose of 20 mg once daily for further treatment and prevention of recurrence of DVT and TELA.
After at least 6 months of treatment of deep vein thrombosis or pulmonary embolism, the recommended dose of XareltoÂ® is 10 mg* once daily or 20 mg once daily, depending on the individual risk ratio for recurrence of DVT or TELA to bleeding risk.
Table 1.
Period
Acceptance pattern
Total daily dose
Treatment and
prevention
1 to 21 days
15 mg twice daily
30 mg
After 22 days
20 mg once every
day
20 mg
TBV recurrence or
TELA
Preventing recurrence of DVT and TELA
After at least
6 months of treatment for DVT or TELA
10 mg* once daily or
20 mg once
daily
10 mg or 20 mg

Interaction
Interaction
Pharmacokinetic interactions
Excretion of rivaroxaban is primarily by metabolism in the liver mediated by the cytochrome P450 system (CYP3A4, CYP2J2) and also by renal excretion of unchanged drug using the P-gp/Bcrp (P-glycoprotein/milk cancer resistance protein) transporter systems.
Inhibiting CYP
Rivaroxaban does not inhibit CYP 3A4 or any other major CYP isoforms.
Induction of CYP
Rivaroxaban does not induce CYP 3A4 or any other major CYP isoforms.
The effects on rivaroxaban
The concomitant use of rivaroxaban and potent CYP3A4 and P-glycoprotein isoenzyme inhibitors may lead to decreased renal and hepatic clearance of rivaroxaban and thereby significantly increase its systemic effects.
. Co-administration of rivaroxaban and the azole antifungal agent ketoconazole (400 mg once daily), a potent CYP3A4 and P-glycoprotein inhibitor, resulted in a 2.6-fold increase in mean equilibrium AUC of rivaroxaban and a 1.7-fold increase in mean Cmax of rivaroxaban, with a significant increase in pharmacodynamic effects of the drug.
. Co-administration of rivaroxaban and the HIV protease inhibitor ritonavir (600 mg twice daily), a potent CYP3A4 and P-glycoprotein inhibitor, resulted in a 2.5-fold increase in mean equilibrium AUC of rivaroxaban and a 1.6-fold increase in mean Cmax of rivaroxaban, with significant enhancement of the drug pharmacodynamic action. Therefore, rivaroxaban is not recommended for use in patients receiving systemic treatment with azole antifungals or HIV protease inhibitors.
Clarithromycin (500 mg 2 times daily), a potent CYP3A4 isoenzyme inhibitor and moderate P-glycoprotein inhibitor, caused a 1.5-fold increase in AUC and 1.4-fold increase in Cmax values of rivaroxaban. This increase is of the order of the normal variability of AUC and Cmax and is considered clinically insignificant.
Eritromycin (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 of the order of the normal variability of AUC and Cmax and is considered to be clinically insignificant.
In patients with mild renal dysfunction (CLKR 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 with patients with normal renal function who were not receiving concomitant therapy. In patients with moderate renal impairment (CLKR 30-49 ml/min), erythromycin caused a 2.0-fold increase in the AUC of rivaroxaban and 1.6-fold increase in Cmax compared to patients with normal renal function who were not receiving concomitant therapy (see “Caution. Caution section).
Fluconazole (400 mg once daily), a moderate CYP3A4 isoenzyme inhibitor, caused a 1.4-fold increase in mean AUC of rivaroxaban and a 1.3-fold increase in mean Cmax. This increase is of the order of the normal variability of AUC and Cmax and is considered clinically insignificant.
The concomitant use of rivaroxaban with dronedarone should be avoided due to limited clinical data on co-administration.
The co-administration of XareltoÂ® and rifampicin, a potent inducer of CYP3A4 and P-glycoprotein, resulted in a reduction in the mean AUC of rivaroxaban by approximately 50% and a concomitant reduction in its pharmacodynamic effects. Co-administration of rivaroxaban with other potent CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or preparations of Saint John’s wort) may also lead to decreased plasma concentrations of rivaroxaban. Reduced plasma concentrations of rivaroxaban have been found to be clinically insignificant. Powerful CYP3A4 inducers should be used with caution.
Pharmacodynamic interactions
After concomitant use of enoxaparin sodium (single dose of 40 mg) and XareltoÂ® (single dose of 10 mg), a summation effect was observed with respect to anti-factor Xa activity, without additional summation effects with respect to clotting tests (prothrombin time, ACTV). Enoxaparin sodium did not alter the pharmacokinetics of rivaroxaban.
Due to the increased risk of bleeding, caution should be exercised when coadministered with any other anticoagulants.
No pharmacokinetic interaction has been found between XareltoÂ® (15 mg) and clopidogrel (a loading dose of 300 mg followed by a maintenance dose of 75 mg), but a significant increase in bleeding time was found in a subgroup of patients that did not correlate with the degree of platelet aggregation and P-selectin or GPIIb/IIIa-receptor content.
After co-administration of XareltoÂ® (15 mg) and naproxen at a dose of 500 mg, no clinically significant increase in bleeding time was observed. However, a more pronounced pharmacodynamic response is possible in individuals.
W Caution should be exercised when XareltoÂ® is coadministered with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors, as use of these drugs generally increases the risk of bleeding.
The conversion of patients from warfarin (INR 2.0 to 3.0) to XareltoÂ® (20 mg) or from XareltoÂ® (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/ INR (Neoplastin) to a greater extent than would be expected by simply summing the effects (individual INR values as high as 12), whereas the effects on AChTV, suppression of factor Xa activity, and endogenous thrombin potential were additive.
If the pharmacodynamic effects of XareltoÂ® need to be investigated during the transition period, anti-Xa activity, PiCT and HepTest determination may be used as necessary tests that are not affected by warfarin. From day 4 after discontinuation of warfarin, all test results (including PV, ACTV, inhibition of factor Xa activity, and on EPT (endogenous thrombin potential)) reflect only the effects of Xarelto.
If it is necessary to investigate the pharmacodynamic effects of warfarin during the transition period, the measurement of the INR value at the Spromerozaban (24 hours after the previous administration of rivaroxaban) may be used, since rivaroxaban has minimal effect on this parameter during this period.
No pharmacokinetic interactions have been reported between warfarin and XareltoÂ®.
The drug interaction of XareltoÂ® with the vitamin K antagonist (VKA) phenyndione has not been studied. It is recommended to avoid transferring patients from XareltoÂ® therapy to AVK therapy with phenyndione and vice versa whenever possible.
There is limited experience transferring patients from AVC therapy with acenocoumarol to XareltoÂ®.
If it becomes necessary to transfer a patient from XareltoÂ® to AVC therapy with phenyndione or acenocoumarol, extreme caution should be exercised and daily monitoring of pharmacodynamic effects of the drugs (INR, prothrombin time) should be performed immediately before the next dose of XareltoÂ® while XareltoÂ® and AVC are taken together.
If a patient needs to be switched from AVC therapy with phenyndione or acenocoumarol to therapy with XareltoÂ®, special care must be taken and pharmacodynamic monitoring of the drugs is not required.
As with other anticoagulants, caution should be exercised when XareltoÂ® is coadministered with selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs), as use of these drugs increases the risk of bleeding. Results of clinical trials have demonstrated a numerical increase in major and minor clinically significant bleeding in all treatment groups when these drugs are used together.
Foods and dairy products
The drug XareltoÂ® 15 mg and 20 mg should be taken with meals (see section “Pharmacological properties”).
No interactions have been identified
No pharmacokinetic interactions have been identified between rivaroxaban and midazolam (CYP3A4 substrate), digoxin (P-glycoprotein substrate) or atorvastatin (CYP3A4 and P-glycoprotein substrate).
The co-administration with the proton pump inhibitor omeprazole, the H2 receptor antagonist ranitidine, aluminum hydroxide/magnesium hydroxide antacids, naproxen, clopidogrel or enoxaparin does not affect bioavailability and pharmacokinetics of rivaroxaban.
No clinically significant pharmacokinetic or pharmacodynamic interactions have been observed when XareltoÂ® and 500 mg acetylsalicylic acid are used together.
Impact on laboratory parameters
The drug XareltoÂ® affects blood clotting parameters (PV, ACTV, HepTestÂ®) due to its mechanism of action (see “Pharmacological properties of XareltoÂ®. Pharmacological properties/Pharmacodynamic effects) .

Special Instructions
Special Instructions
The use of concomitant drugs
The use of rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole antifungals (e.g., ketoconazole) or HIV protease inhibitors (e.g., ritonavir). These drugs are potent inhibitors of CYP3A4 and P-glycoprotein. Thus, these drugs may increase plasma concentrations of rivaroxaban to clinically significant levels (2.6-fold on average), which may lead to an increased risk of bleeding (see sections Caution, Interaction with other medicinal products).
The azole antifungal drug fluconazole, a moderate CYP3A4 inhibitor, however, has a less pronounced effect on rivaroxaban exposure and can be used simultaneously with it (see section “Interaction with other medicinal products”).
Rivaroxaban should be used with caution in patients with moderate renal function impairment (QLcr 30-49 mL/min) receiving concomitant medications that may increase plasma concentrations of rivaroxaban (see sections. Sections
Cautions with Caution, Interaction with other medicinal products).
In patients with severe renal dysfunction (KlKr < 30 ml/min), plasma concentrations of rivaroxaban may be significantly elevated (1.6-fold on average), which may lead to an increased risk of bleeding. Therefore, due to the presence of the specified 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 a CLR of 15-29 mL/min.
There are no clinical data on the use of rivaroxaban in patients with severe renal impairment (CLKr < 15 ml/min). Therefore, the use of XareltoÂ® is not recommended in these patients (see sections “Contraindications”, “Dosage and administration”, “Pharmacological properties”).
Patients with severe renal dysfunction (CLKR 15-29 ml/min), increased risk of bleeding, and patients receiving concomitant systemic treatment with azole antifungal agents or HIV protease inhibitors should be monitored closely for signs of bleeding after treatment initiation.
The risk of bleeding
As with other anticoagulants, patients taking XareltoÂ® should be monitored closely for signs of bleeding.
In case of severe bleeding, XareltoÂ® should be stopped.
In clinical studies, bleeding from mucous membranes (namely, bleeding from the nose, 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 AVC treatment. Thus, in addition to appropriate clinical monitoring, a laboratory hemoglobin/hematocrit study may be relevant to detect hidden bleeding and to quantify the clinical significance of overt bleeding that would be deemed tolerable.
The drug XareltoÂ®, like other antithrombotic agents, should be used with caution in patients who have an increased risk of bleeding, including:
Patients at high risk of triple positive antiphospholipid syndrome The use of XareltoÂ® is not recommended in patients with a history of thrombosis who have a history of resistant triple positive antiphospholipid syndrome (presence of lupus anticoagulant, antibodies to cardiolipin and antibodies to beta-2-glycoprotein I), since rivaroxaban therapy is associated with an increased rate of recurrent thrombotic events compared to therapy with vitamin K antagonists (VKA).
Patients with non-valvular atrial fibrillation undergoing PCI with stenting
There are data from an international clinical trial whose primary objective was to evaluate safety in patients with non-valvular atrial fibrillation undergoing PCI with stenting. Data on efficacy in this therapy are limited (see section “Dosage and administration”).

Synopsis
Synopsis

Contraindications
Contraindications

Side effects
Side effects
The safety of XareltoÂ® was evaluated in thirteen phase III studies involving 53,103 patients taking XareltoÂ®.
The number of patients enrolled in the study who received at least 1 dose of rivaroxaban, the total daily dose, and the maximum duration of treatment in the phase III clinical trials with XareltoÂ® are shown in Table 2 below:
Table 2.
Therapeutic area
Number
/p>
patients*
The maximum duration of treatmentMaximum treatment duration
Prevention of venous thromboembolism (VTE) in patients who have undergone elective hip or knee replacement surgery
6,097
10 mg
39 days
Prevention of venous thromboembolism in medically hospitalized patients
3,997
10 mg
39 days
Treatment of DVT, TELA and prevention of recurrence of DVT, TELA
6,790
Day 1 – 21: 30 mg
From day 22: 20 mg
After at least 6 months of therapy: 10 mg or 20 mg
21 months
Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation of unclogged origin
width= 196,
Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation of unclogged origin./p>
7,750
20 mg
41 months
Prevention of atherotic complications in patients after acute coronary syndrome (ACS)
10,225
5 mg or 10 mg, respectively, in combination with acetylsalicylic acid or acetylsalicylic acid with clopidogrel or ticlopidine
/p>
31 months
Prevention of stroke, myocardial infarction, and death due to cardiovascular causes, as well as for the prevention of acute limb ischemia and overall mortality in patients with coronary heart disease (CHD) or ASD
Windows therapies
18244
5 mg in combination with acetylsalicylic acid 100 mg or 10 mg in monotherapy
47 months
* Patients who have received at least one dose of rivaroxaban.
Frequency of bleeding and anemia in patients treated with XareltoÂ® phase III clinical trials:
Table 3.
Indication for use
Number of patients
Any bleeding
/td>
Anemia
Prevention of venous thromboembolism (VTE) in patients who have undergone elective replacement surgery
6.8%
5.9%
hip or knee
Prevention of venous thromboembolism in medically hospitalized patients
Prevention of venous thromboembolism in medically hospitalized patients
12.6%
2.1%
Treatment of DVT, TELA and pro- phylaxis of recurrence of DVT, TELA
23%
1.6%
Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation
28 events
per 100 patient-years
2.5 events
per 100 patient-years
Prevention of atherothrombotic complications in patients after acute coronary syndrome (ACS)
22 events
per 100 patient-years
1.4 events
per 100 patient-years
Prevention of stroke, myocardial infarction and death from cardiovascular causes, as well as prevention of acute limb ischemia and overall mortality in patients with CHD or AFS/p>
6.7 events
per 100 patient-years
0.15 events
per 100 patient-years*
Bleeding in the eye (including hemorrhage in
conjunctival hemorrhage)
Disorders from
the heart side
/p>
Tachycardia
vascular disorders
Significant decrease in arterial
pressure, hematoma
Disorders of the respiratory system, thoracic organs, and
mediastinum
Nasal bleeding, hemoptysis
/p>
Gastrointestinal tract disorders
Gingival bleeding, gastrointestinal bleeding (including rectal bleeding), abdominal pain, dyspepsia, nausea, constipationA,
diarrhea, vomitingA
Dry mouth
Disorders of the liver and biliary tract
Disorders of liver function
Jaundice
Pain in the extremitiesA
Hemarthrosis
Muscle hemorrhage
Renal and urinary tract disorders
Bleeding from the urogenital tract (including hematuria and menorrhagia
sup>B), renal dysfunction (including increased creatinine concentration, increased urea concentration)A
General disorders and disorders at the site of administration
Fever
sup>A, peripheral edema, decreased overall muscle strength and tone (including weakness,
asthenia)
Deterioration in general well-being (including malaise)
Local edema
sup>A
Laboratory and instrumental findings
Elevated activity
“hepatic” transaminases
Increased bilirubin concentration, increased alkaline phosphataseA activity, increased LDHA activity, increased lipaseA activity, increased amylaseA activity, increased
GGTA activity
Increased concentration of conjugated bilirubin (with or without concomitant increase in ALT activity)
Injuries, intoxications and complications of manipulation
Bleeding after procedures performed (including postoperative anemia and bleeding from
wound), hematoma
Wound secretionA
Vascular pseudoaneurysmC
A were observed predominantly after major orthopedic lower extremity surgery
B observed in the treatment of VTE as very frequent in women aged < 55 years
C observed as infrequent in the prevention of complications in ACS (after percutaneous interventions).
* A prespecified selective approach to the collection of data on adverse events was applied. Because the incidence of adverse drug reactions did not increase and because no new adverse drug reactions were identified, data from the COMPASS study were not included for the frequency calculation in this table.
The following adverse reactions were reported during post-registration monitoring and had a temporary association with XareltoÂ® administration. It is not possible to estimate the incidence of these adverse reactions in post-treatment monitoring.
immune system disorders: angioneurotic edema, allergic edema. In a phase III RCT, such adverse events were considered infrequent (>1/1000 to <1/100).
Hepatic and biliary tract disorders: cholestasis, hepatitis (including hepatocellular damage). In a phase III RCT, such adverse events were considered rare (>1/10000 to <1/1000).
Disorders of the circulatory and lymphatic system: thrombocytopenia. In a phase III RCT, such adverse events were considered infrequent (
>1/1000 to <1/100).

Overdose
Overdose
Rare cases of overdose have been reported when taking rivaroxaban up to 600 mg without the development of bleeding or other adverse reactions. Due to limited absorption, a low-level plateau of drug concentration is expected with no further increase in its average plasma concentration when using doses higher than therapeutic, equal to 50 mg or higher.
The specific antidote for rivaroxaban is unknown. In case of overdose, activated charcoal may be used to reduce absorption of rivaroxaban. Given the intense binding to plasma proteins, rivaroxaban is not expected to be excreted by dialysis.
Treatment of bleeding
If a patient receiving rivaroxaban has a bleeding complication, the next administration of the drug should be delayed or, if necessary, treatment with this drug should be discontinued. The half-life of rivaroxaban is approximately 5 to 13 hours. Treatment should be individualized depending on the severity and localization of bleeding. If necessary, appropriate symptomatic treatment such as mechanical compression (e.g., in severe nasal bleeding), surgical hemostasis with assessment of its effectiveness, infusion therapy and hemodynamic support, use of blood products (red blood cell mass or fresh frozen plasma, depending on whether anemia or coagulopathy occurred) or platelets may be used.
If the above measures do not eliminate bleeding, specific procoagulant drugs such as prothrombin complex concentrate, activated prothrombin complex factor concentrate or recombinant factor VIIa may be prescribed. However, there is currently limited experience with these drugs in patients receiving XareltoÂ®.
Protamine sulfate and vitamin K are not expected to affect the anticoagulation activity of rivaroxaban.
There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in patients receiving XareltoÂ®. There is no scientific evidence or experience with the systemic hemostatic drug desmopressin in patients receiving XareltoÂ®.

Pregnancy use
Pregnancy use
Pregnancy
The safety and efficacy of rivaroxaban in pregnant women have not been established. The data obtained on experimental animals showed a pronounced maternal toxicity of rivaroxaban associated with the pharmacological action of the drug (e.g., complications in the form of hemorrhages) and leading to reproductive toxicity. No primary teratogenic potential has been identified.
Because of the possible risk of bleeding and the ability to penetrate the placenta, rivaroxaban is contraindicated in pregnancy (see section Contraindications.
Women who are fertile should use effective contraception during treatment with XareltoÂ®.
Breastfeeding
There are no data on the use of rivaroxaban to treat women during breastfeeding. Data obtained in experimental animals show that rivaroxaban is excreted with breast milk. XareltoÂ® may only be used after withdrawal of breastfeeding (see section “Contraindications”.
Fertility
Studies have shown that rivaroxaban has no effect on male or female fertility in rats. There have been no studies of the effect of rivaroxaban on fertility in humans.

Additional information
Weight 0.037 kg
Shelf life
3 years. Do not use after the expiration date
Conditions of storage
At a temperature not higher than 30 ° C. Keep out of reach of children.
Manufacturer
Bayer AG, Germany
Medication form
pills
Brand
Bayer AG