Xarelto, 2,5mg 98 pcs

Pharmacotherapeutic group: direct factor Xa inhibitors.

ATC code: B01AR01.

Pharmacological properties

Pharmacodynamics

Mechanism of action

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

Activation of factor X to form factor Xa through the internal and external coagulation 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 to 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 more than 1,000 molecules of thrombin, which has been called the “thrombin explosion.”

The reaction rate of factor Xa bound in prothrombinase increases 300,000 times that of free factor Xa, which provides a sharp spike 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 the change in prothrombin time, which correlates closely with the plasma concentration of rivaroxaban (correlation coefficient 0.98) if the Neoplastin kit is used for the analysis. Results will be different 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 undergoing major orthopedic surgery, 5/95 percentile values for prothrombin time (Neoplastin) 2-4 hours after taking the tablet (i.e., at maximum effect) range from 13 to 25 seconds.

Also, rivaroxaban dose-dependently increases the activated partial thromboplastin time (APT) and HepTest result; however, these parameters are not recommended for evaluating the pharmacodynamic effects of rivaroxaban. Monitoring of clotting parameters is not required during treatment with Xarelto®. However, if clinically justified, rivaroxaban concentrations may be measured using a calibrated quantitative anti-factor Xa test.

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

Pharmacokinetics

Absorption and bioavailability

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

After oral administration, rivaroxaban is almost completely absorbed and its bioavailability with 2.5 mg tablets is high (80-100%) regardless of food intake. Food intake has no effect on AUC (area under the curve “concentration – time”) and Stache at a dose of 10 mg. Xarelto® tablets in 2.5 mg dose can be taken both with food and on an empty stomach (see section “Dosage and administration”). The pharmacokinetics of rivaroxaban are characterized by moderate interindividual variability, with a Cv% coefficient of variability ranging from 30% to 40%.

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 with 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 because it may result in reduced absorption and, consequently, 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 given 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

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

Metabolism and excretion

When administered orally, approximately 2/3 of the dose of rivaroxaban is metabolized and excreted by the kidneys and through the intestine in equal proportions.

The remaining 1/3 of the dose received 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 amide bonds.

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

Gender/Elderly Age (older than 65 years)

Elderly patients have higher plasma concentrations of rivaroxaban than younger patients; the average AUC is approximately 1.5 times that of younger patients, primarily due to seemingly lower total and renal clearance (see section “Dosage and administration”). No clinically significant differences in pharmacokinetics were found in 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 plasma concentration of rivaroxaban (difference is less than 25%) (see section “Dosage and administration”).

Childhood and adolescence (birth to 18 years)

No data are available for this age group (see section “Administration and Doses”).

Interethnic differences

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

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 prognosis for patients with chronic liver disease, primarily cirrhosis. For patients scheduled for anticoagulant therapy, the most important consequence of impaired liver function is decreased synthesis of blood clotting factors in the liver.

Because this score meets 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 irrespective of the Child-Pugh classification. Rivaroxaban is contraindicated in patients with hepatic disease with coagulopathy that is clinically significant bleeding risk. Pharmacokinetics of rivaroxaban in patients with cirrhosis and mild hepatic impairment (Child-Pugh class A) did not significantly differ from those in control group of healthy volunteers (on average there was 1.2 times AUC increase of rivaroxaban). There were no significant differences of pharmacodynamic properties between the groups.

In patients with liver cirrhosis and hepatic insufficiency of the average degree of severity (B class according to Child-Pugh) the average AUC of rivaroxaban was significantly increased (2.3 times) comparing to healthy volunteers due to the significantly decreased clearance of the medicine substance that indicates a 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.

The prothrombin time measurement assesses the external coagulation pathway, which includes clotting factors VII, X, V, II and I that are synthesized in the liver. Patients with moderate hepatic insufficiency are more sensitive to rivaroxaban, which is a consequence of the closer relationship between pharmacodynamic effects and pharmacokinetic parameters, especially between concentration and prothrombin time.

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

Renal dysfunction

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

. Patients with mild renal impairment (creatinine CLKR clearance 50 -80 ml/min), moderate renal impairment (creatinine CLKR clearance 30 -49 ml/min) or severe renal impairment (creatinine CLKR clearance 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

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

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

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

Indications

Active ingredient

Composition

How to take, the dosage

After ACS the recommended regimen for 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. The ongoing treatment should be regularly evaluated in terms of the balance between the risk of coronary events and the risk of bleeding. The duration of treatment is 12 months. Treatment may be prolonged up to 24 months for individual patients, since data on treatment of such duration are limited.

The treatment with Xarelto® 2.5 mg should be initiated as soon as possible after the patient is stabilized during the current ACS (including revascularization procedures). Treatment with Xarelto® should be initiated 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 overall mortality in patients with CHD or VTE

Preventive regimen The recommended dosing regimen for prevention of vascular events in patients with CHD or IPA 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 risks.

In patients with an acute thrombotic event or vascular intervention requiring dual antiplatelet therapy, the need for continued Xarelto® 2.5 mg twice daily should be evaluated depending on the type of thrombotic event or procedure and the type of antiplatelet therapy. Safety and efficacy of Xarelto® 2.5 mg when taken twice daily in combination with acetylsalicylic acid and clopidogrel or ticlopidine have been studied only 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 OSA has not been studied.

In patients diagnosed with CHD or ZPA, treatment with Xarelto® 2.5 mg twice daily in combination with acetylsalicylic acid 75100 mg once daily may be initiated at any time. If a dose is missed, the patient should continue Xarelto® 2.5 mg at the usual dose, which is the next scheduled appointment as recommended.

If the patient is unable to swallow the tablet whole, the Xarelto® tablet may be crushed or mixed with water or a liquid food such as apple puree immediately before ingestion. The crushed tablet of Xarelto® may be inserted through a gastric tube. The position of the tube in the gastrointestinal tract should be additionally coordinated with the physician before taking Xarelto®. 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 introduced to wash off the drug residues from the walls of the tube (see section “Pharmacological properties”).

Additional information for special patient groups

Patients with impaired liver function

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

Patients with other liver diseases do not require dose adjustment (see section “Pharmacological properties”).

Limited clinical data obtained in patients with moderate hepatic impairment (Child-Pugh class B) indicate a significant increase in pharmacological activity. No clinical data are available for patients with severe hepatic impairment (Child-Pugh class C) (see sections “Contraindications”, “Pharmacological properties”).
Patients with impaired renal function

Dose adjustment is not required if Xarelto® is used in patients with impaired renal function of mild (CLKR 50-80 ml/min) or moderate (CLKR 30-49 ml/min) severity (see “Pharmacological properties” section).

Limited clinical data obtained in patients with severe renal impairment (CLKR 15-29 mL/min) indicate that plasma concentrations of rivaroxaban are significantly elevated in this patient population. Therefore, Xarelto® should be used with caution in these patients (see section “Special Indications”, “Pharmacological properties”).

The use of Xarelto® is not recommended in patients with CLR<15 ml/min (see section “Contraindications”).
Conversion from vitamin K antagonists (VKAs) to Xarelto®

If patients switch from VKAs to Xarelto® , the INR will be erroneously high after taking Xarelto®. The INR is not suitable for determining the anticoagulant activity of Xarelto® and therefore should not be used for this purpose (see section “Interaction with other drugs”).

Transition from Xarelto® therapy to therapy with vitamin K antagonists (VKAs)

There is a possibility of insufficient anticoagulant effect when switching from Xarelto® therapy to AVC therapy. In this regard, it is necessary to ensure continuous sufficient anticoagulant effect during such transition with the help of alternative anticoagulants. It should be noted that when switching from Xarelto® to AVC therapy, Xarelto® may contribute to increased INR.

In patients who switch from Xarelto® therapy to AVC therapy, the latter should be taken continuously until the INR value is >2.0. During the first two days of the transition period, standard doses of AVC should be used, subsequently adjusting the dose of AVC according to the INR value. Since patients receive both Xarelto® and AVC at the same time during this period, the INR should be assessed no earlier than 24 hours (after the first dose but before the next dose of Xarelto®). Thus, after discontinuation of Xarelto®, INR can be used as a reliable assessment of the therapeutic effect of AVC no earlier than 24 hours after the last dose of Xarelto® (see section “Interaction with other medicinal products”, “How to use and doses”).

Transition from therapy with parenteral anticoagulants to therapy with Xarelto®

. For patients receiving parenteral anticoagulants, Xarelto® therapy should be started 0 to 2 hours before the time of the next scheduled parenteral administration of the drug (e.g., low molecular weight heparin) or at the time of discontinuation of continuous parenteral administration of the drug (e.g., intravenous infractional heparin).

Transition from therapy with Xarelto® to therapy with parenteral anticoagulants

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

Children and adolescents (birth to 18 years)

The safety and effectiveness of use in children and adolescents under 18 years has not been established.

Elderly patients

There is no need to adjust the dose according to age (see section “Pharmacological properties”).

Gender

Dose adjustment depending on gender is not required (see section “Pharmacological properties”).

Body weight

Dose adjustment depending on body weight is not required (see section “Pharmacological properties”).

Ethnicity

Dose adjustment depending on ethnicity is not required (see section “Pharmacological properties”).

Interaction

Special Instructions

The use of concomitant drugs

Rivaroxaban is not recommended for use 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 CYP 3A4 and P-glycoprotein. Thus, these drugs may increase the plasma concentration of rivaroxaban to clinically significant values (2.6-fold on average), which may lead to an increased risk of bleeding (see section “Interaction with other medicinal products”). However, the azole antifungal drug fluconazole, a moderate CYP3A4 inhibitor, has a less pronounced effect on the exposure of rivaroxaban 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 impairment (QClKr 30-49 mL/min) receiving concomitant medications that may increase plasma concentrations of rivaroxaban (see “Interaction with other drugs. section “Interaction with other medicinal products”).

In patients with severe renal dysfunction (KlKr<30 ml/min), the plasma concentration 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 CLR of 15-29 ml/min.

There are no clinical data on the use of rivaroxaban in patients with severe renal impairment (KlKr<15 ml/min). Therefore, rivaroxaban is not recommended for use in these patients (see sections “Dosage and administration”, “Pharmacological properties”).
Patients with severe renal dysfunction (CLR 15-29 ml/min) or 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 initiation of treatment. Follow-up can be accomplished by regular physical examination of patients, close monitoring of postoperative wound drainage, and periodic hemoglobin determination.

Patients with a history of stroke and/or TIA

The administration of Xarelto® twice daily at a dose of 2.5 mg is contraindicated in patients with ACS who have a history of stroke or TIA. Only a few ACS patients with a history of stroke or TIA have been studied, but the limited data demonstrate no clinical benefit from rivaroxaban treatment in these patients.

Patients with a history of hemorrhagic or lacunar stroke

Patients with CHD or TIA with a history of hemorrhagic or lacunar stroke have not been studied. Treatment with Xarelto® 2.5 mg twice daily in combination with acetylsalicylic acid is contraindicated in these patients.

Patients with ischemic nonlacunar stroke

Patients with CHD or OSA who have had an ischemic nonlacunar stroke in the previous month have not been studied. Treatment with Xarelto® 2.5 mg twice daily in combination with acetylsalicylic acid is contraindicated in such patients during the first month after stroke.

Risk of bleeding

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

Contraindications

Side effects

Table 2: Frequency of bleeding and anemia in patients receiving Xarelto® from phase III studies

Overdose

Pregnancy use