Xarelto pills 20mg, 28pcs

Composition

1 tablet contains:

rivaroxaban micronized 20 mg

Pharmacological 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.

Pharmacodynamic effects

In humans, dose-dependent inhibition of factor Xa was observed. 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 MHO is calibrated and certified only for coumarin derivatives and cannot be used for other anticoagulants.

In patients with non-valve atrial fibrillation of origin, receiving rivaroxaban for prevention of stroke and systemic embolism,5/95-percentile for prothrombin time (Neoplastin®) after 1-4 hours after taking the tablet (i. e., the maximum effect) range from 14 to 40 h in patients receiving 20 mg 1 time/day, and from 10 to 50 h in patients with renal insufficiency (CC 49-30 ml/min) receiving 15 mg 1 time/day.

In patients receiving rivaroxaban for the treatment and prevention of recurrence of deep venous thrombosis (DVT) and pulmonary embolism (PE),5/95-percentile for prothrombin time (Neoplastin®) 2-4 hours after taking the tablet (i. e., the maximum effect) range from 17 to 32 h in patients receiving 15 mg 2 times/day, and 15 to 30 sec in patients receiving 20 mg 1 time/day.

rivaroxaban also dose-dependently increases APTT and HepTest® outcome; 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 test of anti-factor Xa.

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

In healthy men and women over 50 years of age, QT prolongation was not observed under the influence of rivaroxaban.

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.

Contraindications

— hypersensitivity to rivaroxaban or any of the auxiliary components of the drug;

— clinically significant active bleeding (e. g., intracranial bleeding, 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 suspected varicose veins of the esophagus, 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 (including enoxaparin, dalteparin), heparin derivatives (including fondaparinux), oral anticoagulants (including warfarin, apixaban, dabigatran), except in cases of transition from or to rivaroxaban or unfractionated heparin in doses necessary to ensure the functioning of the Central venous or arterial catheter;

— diseases of the liver, occurring with coagulopathy, which leads to a clinically significant risk of bleeding;

— renal failure in QA <15 ml/min (clinical data on the use of rivaroxaban in this category of patients do not exist);

the treatment of ACS with antiplatelet agents in patients with stroke or transient ischemic attack;

— pregnancy;

— lactation (breastfeeding);

— children and adolescence to 18 years (efficacy and safety for patients in this age group have not been established);

— congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption (due to the presence of lactose).

The drug should be used with caution:

— in the treatment of patients with an increased risk of bleeding (including congenital or acquired predisposition to bleeding, uncontrolled severe arterial hypertension, gastric ulcer and duodenal ulcer in acute phase, recent gastric ulcer and duodenal ulcer, vascular retinopathy, bronchiectasis or pulmonary bleeding in the anamnesis);

— in the treatment of patients with renal insufficiency (CC 49-30 ml/min) receiving both drugs that increase the concentration of rivaroxaban in plasma;

in the treatment of patients with renal insufficiency (CC 29-15 ml/min) be careful, because the concentration of rivaroxaban in plasma in these patients may be significantly increased (on average 1.6 times) and as a result, they are at increased risk of bleeding;

— patients receiving drugs that affect hemostasis (e. g., NSAIDs, antiplatelet agents or other antithrombotic agent);

— Xarelto® is not recommended for use in patients receiving systemic treatment with antifungal drugs of the group of azoles (e. g. ketoconazole) or HIV protease inhibitors (eg, ritonavir). These drugs are strong inhibitors of the CYP3A4 isoenzyme and P-glycoprotein. As a result, these drugs can increase the concentration of rivaroxaban in plasma to a clinically significant level (on average 2.6 times), which increases the risk of bleeding. Fluconazole (an antifungal drug group of azole), a moderate inhibitor of CYP3A4, has a less pronounced effect on the exposure of rivaroxaban and can be used with it at the same time;

— patients with renal insufficiency in QA 15-29 ml/min or increased risk of bleeding, and patients receiving concomitant systemic treatment with antifungal drugs group or azole inhibitors of HIV protease, after the start of treatment should be closely monitored for early detection of complications in the form of bleeding.

Side effects

The safety of Xarelto® was evaluated in four phase III trials involving 6,097 patients undergoing major orthopedic surgery on the lower extremities (total knee or hip replacement) and 3,997 patients hospitalized for medical reasons treated with Xarelto® at a dose of 10 mg for up to 39 days, as well as in three phase III studies of venous thromboembolism, including 4,556 patients treated with Xarelto® at a dose of either 15 mg 2 times/day daily for 3 weeks, This was followed by a dose of 20 mg 1 time/day, or 20 mg 1 time/day with a treatment duration of up to 21 months.

In addition, from two phase III studies involving 7,750 patients, data were obtained on the safety of the drug in patients with non-valvular atrial fibrillation who received at least one dose of Xarelto® for a period of up to 41 months, as well as 10,225 patients with ACS who received at least one dose of Xarelto® 2.5 mg (2 times/day) or 5 mg (2 times / day) in addition to acetylsalicylic acid or acetylsalicylic acid therapy with clopidogrel or ticlopidine, the duration of treatment is up to 31 months.

Given 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. Signs, symptoms, and severity (including possible death) vary depending on the location, intensity, or duration of bleeding and/or anemia. Hemorrhagic complications can be manifested by weakness, pallor, dizziness, headache, shortness of breath, as well as an increase in limb volume or shock, which cannot be explained by 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 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.

Summary data on the frequency of adverse reactions reported for Xarelto® are given below. In groups divided by frequency, undesirable effects are presented in order of decreasing severity as follows: common: ≥1% to <10% (≥1/100 to <1/10); uncommon: ≥0.1% to <1% (≥1/1000 to <1/100); rare: ≥0.01% to <0.1% (≥1/10,000 to <1/1000); very rare: <0.01% (

All adverse reactions that occurred during treatment in patients participating in phase III clinical trials

From the hematopoietic system: often-anemia (including relevant laboratory parameters); infrequently-thrombocythemia (including elevated platelet count)*.

From the cardiovascular system: often-a marked decrease in blood pressure, hematoma; infrequently-tachycardia.

From the side of the visual organ: often – hemorrhage in the eye (including conjunctival hemorrhage).

From the digestive system: often – bleeding gums, gastrointestinal bleeding (including rectal bleeding), gastrointestinal pain, dyspepsia, nausea, constipation*, diarrhea, vomiting*; infrequently-dry mouth.

Systemic disorders and reactions at the injection site: often – fever*, peripheral edema, decreased overall muscle strength and tone (including weakness, asthenia) infrequently – deterioration of general health (including malaise) rarely-local edema*.

From the liver: infrequently-impaired liver function; rarely-jaundice.

Research results: often-increased activity of hepatic transaminases; infrequently-increased bilirubin concentration, increased ALP activity*, increased LDH activity*, increased lipase activity*, increased amylase activity*, increased GGT activity*; rarely-increased concentration of conjugated bilirubin (with or without concomitant increase in ALT activity).

Nervous system disorders: often – dizziness, headache; infrequently-intracerebral and intracranial hemorrhage, short-term fainting.

From the genitourinary system: frequently – urogenital bleeding (including hematuria and menorrhagia**), renal failure (including increased creatinine concentration, increased urea concentration)*.

Respiratory system disorders: often-nosebleeds, hemoptysis.

Skin and subcutaneous tissue disorders: often-pruritus (including infrequent cases of generalized pruritus), rash, ecchymoses, skin and subcutaneous hemorrhages; infrequently-urticaria.

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

Musculoskeletal disorders: often-pain in the extremities*; infrequently-hemarthrosis; rarely-muscle hemorrhage.

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

Injuries, poisoning, and procedural complications: often – hemorrhage after the procedures performed (including postoperative anemia and bleeding from the wound), excessive hematoma in the bruise; infrequently-discharge from the wound*; rarely-vascular pseudoaneurysm***.

* registered after major orthopedic surgeries.

* * VTE treatment was reported as very frequent in women

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

During post-marketing monitoring, cases of the following adverse reactions were reported, the development of which was temporarily associated with the use of Xarelto®. It is not possible to estimate the frequency of occurrence of such adverse reactions in the framework of post-marketing monitoring.

From the immune system: angioedema, allergic edema. In a phase III RCT, such undesirable effects were considered infrequent (from >1/1000 to >

From the liver: cholestasis, hepatitis (including hepatocellular damage). In a phase III RCT, such undesirable effects were considered rare (from >1/10,000 to >

From the hematopoietic system: thrombocytopenia. In a phase III RCT, such undesirable effects were considered infrequent (from >1/1000 to >

Musculoskeletal disorders: frequency unknown – increased subfascial pressure syndrome (compartment syndrome) due to muscle hemorrhage.

From the urinary system: frequency unknown – renal failure/acute renal failure due to bleeding leading to renal hypoperfusion.

Interaction

Pharmacokinetic interaction

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.

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

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

The combined use of rivaroxaban and an antifungal agent from the azole group ketoconazole (400 mg 1 time / day), which is a strong 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-use of Xarelto® 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, Xarelto® is not recommended for use in patients receiving systemic treatment with azole antifungal drugs or HIV protease inhibitors.

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

Erythromycin (500 mg 3 times / day), 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 renal insufficiency (creatinine clearance < 80-50 ml/min), erythromycin (500 mg 3 times / day) It caused a 1.8-fold increase in rivaroxaban AUC and 1.6-fold increase in Cmax compared to patients with normal renal function who did not receive concomitant therapy. In patients with renal insufficiency (creatinine clearance 49-30 ml / min) erythromycin caused a 2.0-fold increase in rivaroxaban AUC and 1.6-fold increase in Cmax compared to patients with normal renal function who did not receive concomitant therapy.

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-use.

Co-use of Xarelto® and rifampicin, which is a strong inducer of CYP3A4 and P-glycoprotein, resulted in a decrease in the average AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects.

Concomitant use of rivaroxaban with other strong inducers of CYP3A4 (for example, phenytoin, carbamazepine, phenobarbital or St. John’s wort) may also lead to a decrease in the concentration of rivaroxaban in plasma. A decrease in the plasma concentration of rivaroxaban was found to be clinically insignificant.

Strong inducers of CYP3A4 should be used with caution.

Pharmacodynamic interaction

After concomitant use of enoxaparin sodium (a single dose of 40 mg) and Xarelto® (a single dose of 10 mg), a cumulative effect on anti-factor Xa activity was observed, without additional cumulative effects on blood clotting tests (prothrombin time, APTT). Enoxaparin did not alter the pharmacokinetics of rivaroxaban.

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

There was no pharmacokinetic interaction between Xarelto® at a dose of 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 the subgroup of patients, which did not correlate with the degree of platelet aggregation and the content of P-selectin or GPIIb/IIIa receptor.

No clinically significant increase in bleeding time was observed after co-use of Xarelto® (15 mg) and naproxen (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 (MHO from 2 to 3) to Xarelto® (20 mg) or from Xarelto® (20 mg) to warfarin (MHO from 2 to 3) increased prothrombin time/INR (Neoplastin) to a greater extent than would be expected with simple summation of effects (individual MHO values can reach 12), while the effect on APTT, suppression of factor Xa activity, and endogenous thrombin potential was additive.

If it is necessary to study the pharmacodynamic effects of 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 thrombin potential))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 MHO value can be used at Spromeput. rivaroxaban (24 hours after the previous use of rivaroxaban), since rivaroxaban has minimal effect on this indicator during this period.

No pharmacokinetic interaction has been reported between warfarin and Xarelto®.

The drug interaction of Xarelto® with AVC phenindione has not been studied. It is recommended to avoid transferring patients from Xarelto®therapy as much as possible for AVK therapy with phenindione and vice versa. There is limited experience in transferring patients from AVC therapy with acenocoumarol to Xarelto®.

If there is a need to transfer the patient from therapy with Xarelto® If the drug is used in combination with phenindione or acenocoumarol, then special care should be taken, and daily monitoring of the pharmacodynamic effect of drugs (MHO, 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.

Incompatibility

Unknown.

No interaction was detected

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

Co-use with the proton pump inhibitor omeprazole, the histamine H2 receptor blocker 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 interaction was observed when Xarelto® and acetylsalicylic acid were co-administered at a dose of 500 mg.

Influence on laboratory parameters

Xarelto®preparation It affects blood clotting parameters (prothrombin time, APTT, Hep-Test®) due to its mechanism of action.

How to take, course of use and dosage

The drug is taken orally with meals.

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

A crushed Xarelto ® tablet 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® 15 mg or 20 mg tablet, enteral nutrition should be taken immediately.

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

The recommended dose is 20 mg 1 time / day

for patients with impaired renal function (creatinine clearance 49-30 ml / min). the recommended dose is 15 mg 1 time/day. The recommended maximum daily dose is 20 mg. Xarelto ® therapy should be considered as a long-term treatment, carried out as long as the benefit of treatment outweighs the risk of possible complications.

Actions when skipping a dose

If the next dose is missed, the patient should immediately take 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 2 times / day for the first 3 weeks, followed by a transition to a dose of 20 mg 1 time/day for further treatment and prevention of relapses of DVT and PE.

The maximum daily dose is 30 mg for the first 3 weeks of treatment and 20 mg for further treatment.

The duration of treatment is determined individually after carefully weighing the ratio of the benefit of treatment and the risk of bleeding. 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 at a dosage regimen of 15 mg 2 times / day, the patient should immediately take Xarelto® to achieve a 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 at the dosage regimen of 20 mg 1 time / day, the patient should immediately take 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.

Xarelto® is contraindicated in patients with liver diseases associated with coagulopathy, which causes a clinically significant risk of bleeding. Patients with other liver diseases do not need to change the dose. 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. For patients with severe hepatic insufficiency (Child-Pugh Class C) no clinical data are available.

When prescribing Xarelto® to patients with renal insufficiency (creatinine clearance 80-50 ml / min) no dose adjustment is required.

Prevention of stroke and systemic thromboembolism in patients with nonvalvular atrial fibrillation and renal insufficiency (creatinine clearance 49-30 ml / min) the recommended dose is 15 mg 1 time/day.

In the treatment of DVT and PE and prevention of recurrent DVT and PE in patients with renal insufficiency (creatinine clearance 49-30 ml / min) no dose adjustment is required.

Available limited clinical data obtained in patients with renal insufficiency (creatinine clearance 29-15 ml/min) show a significant increase in rivaroxaban concentrations in these patients. For the treatment of this category of patients, Xarelto® should be used with caution.

Use of Xarelto® in patients with CC

Switching patients from vitamin K antagonists (VKA) to Xarelto®

In the prevention of stroke and systemic thromboembolism, AVC treatment should be discontinued and Xarelto® treatment should be initiated if the MHO value is < 3.

In DVT and PE, AVC treatment should be discontinued and Xarelto® treatment should be initiated if the MHO value is less than 2.5.

When patients with AVC switch to Xarelto®, MHO values will be erroneously elevated after Xarelto® use. The MHO score is not suitable for determining the anticoagulant activity of Xarelto® and therefore should not be used for this purpose.

Switching from Xarelto® to vitamin K antagonists (VKA)

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 MHO. Patients who have switched from Xarelto® to AVA should take AVA concomitantly until the MHO reaches ≥2. 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 MHO value. Thus, during the simultaneous use of Xarelto® and AVK, MHO should be determined no earlier than 24 hours after the previous use, but before taking the next dose of Xarelto®. After discontinuation of Xarelto®, the MHO value can be reliably determined 24 hours after the last dose.

Switching from parenteral anticoagulants to Xarelto®

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

Switching from Xarelto® to parenteral anticoagulants

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

Cardioversion in the prevention of stroke and systemic thromboembolism

Treatment with Xarelto® may be initiated or continued in patients who may require cardioversion. When cardioversion is performed under the control of transesophageal echocardiography (CPECHO-CG) in patients who have not previously received anticoagulant therapy, treatment with Xarelto® should be initiated at least 4 hours before cardioversion to ensure adequate anticoagulation.

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 used at doses higher than therapeutic (≥50 mg).

Treatment

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.

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. T 1/2 of rivaroxaban leaves approximately 5-13 hours. Treatment should be selected individually, according to 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 products (red blood cell mass or fresh frozen plasma, depending on the concomitant anemia or coagulopathy) or platelets.

If the measures listed above do not lead to the elimination of bleeding, specific reverse-acting procoagulant drugs, such as clotting factors II, VII, IX and X in combination, may be prescribed[Prothrombin complex], anti-inhibitory coagulant complex or eptacog alpha [activated]. 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 feasibility or experience of using the systemic hemostatic drug desmopressin in patients receiving Xarelto®.

Functional features

Suction

Rivaroxaban is rapidly absorbed; Cmax is reached 2-4 hours after taking the tablet. The absolute bioavailability of rivaroxaban after taking a dose of 10 mg is high (80-100%). When taking rivaroxaban at a dose of 10 mg with food, no changes in AUC and Cmax were observed. The pharmacokinetics of rivaroxaban are characterized by moderate individual variability; individual variability (coefficient of variation) ranges from 30% to 40%.

When taking the drug at a dose of 20 mg on an empty stomach, a bioavailability of 66% was observed, due to a reduced degree of absorption. When taking Xarelto® at a dose of 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.

The absorption of rivaroxaban depends on the site of release in the gastrointestinal tract. A decrease in AUC and Cmax of 29% and 56%, respectively, compared with taking a whole tablet, was observed when rivaroxaban granulate was released in the distal small intestine or ascending colon. use of rivaroxaban into the gastrointestinal tract distal to the stomach should be avoided, as this may lead to a decrease in absorption and, accordingly, exposure to the drug.

The study evaluated the bioavailability (AUC and Cmax) of rivaroxaban taken orally at a dose of 20 mg in the form of a crushed tablet mixed with applesauce or suspended in water, as well as administered through a gastric tube followed by liquid nutrition, compared with taking a whole tablet. The results showed a predictable dose-dependent pharmacokinetic profile of rivaroxaban, with bioavailability at the above-mentioned dose consistent with that of rivaroxaban at lower doses.

Distribution

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

Metabolism

When taken orally, approximately 2/3 of the prescribed dose of rivaroxaban is metabolized and subsequently excreted in equal parts in the urine and feces. 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 carrier proteins P-gp (P-glycoprotein) and Hrv (breast cancer resistance protein).

Unchanged rivaroxaban is the only active compound in the blood plasma, no significant or active circulating metabolites were detected in the plasma.

Deduction

Rivaroxaban, which has a systemic clearance of approximately 10 l / h, can be classified as a drug with a low level of clearance.

With the elimination of rivaroxaban from plasma, the final T1 / 2 is from 5 to 9 hours in young patients.

Pharmacokinetics in special clinical cases

In elderly patients, the plasma concentration of rivaroxaban 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. With the elimination of rivaroxaban from plasma, the final T1 / 2 in elderly patients is from 11 to 13 hours.

No clinically significant differences in pharmacokinetics were found in men and women.

Too little or too much body weight (less than 50 kg and more than 120 kg) only slightly affects the concentration of rivaroxaban in plasma (the difference is less than 25%).

Data on pharmacokinetics in children are not available.

Clinically significant differences in pharmacokinetics and pharmacodynamics were not observed in patients of Caucasian, Black and Asian race, as well as in representatives of Latin American, Japanese or Chinese ethnicity.

The effect of hepatic insufficiency on the pharmacokinetics of rivaroxaban was studied in patients classified 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.

Xarelto® 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 with mild hepatic insufficiency (Child-Pugh class A), the pharmacokinetics of rivaroxaban only slightly differed from the corresponding indicators in the control group of healthy subjects (on average, there was an increase in the AUC of rivaroxaban by 1.2 times). 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 a significantly reduced clearance of the drug, indicating 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.

In patients with renal insufficiency, an increase in rivaroxaban exposure was observed, inversely proportional to the degree of decrease in renal function, which was assessed by creatinine clearance.

Patients with renal insufficiency with creatinine clearance of 80-50 ml/min, creatinine clearance of 49-30 ml/min, and creatinine clearance of 29-15 ml/min showed 1.4 -,1.5 -, and 1.6-fold increases in rivaroxaban plasma concentrations (AUC), respectively, compared with healthy volunteers. The corresponding increase in pharmacodynamic effects was more pronounced.

In patients with creatinine clearance of 80-50 ml/min, creatinine clearance of 49-30 ml/min, and creatinine clearance of 29-15 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 creatinine clearance of 29-15 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 CC

Special instructions

The use of Xarelto® is not recommended in patients receiving concomitant systemic treatment with antifungal drugs of the azole group (for example, ketoconazole) or HIV protease inhibitors (for example, ritonavir). These drugs are strong inhibitors of CYP3A4 and P-glycoprotein. Thus, these drugs can increase the concentration of rivaroxaban in blood plasma to clinically significant values (2.6 times on average), which can lead to an increased risk of bleeding. However, the azole antifungal drug fluconazole, a moderate CYP3A4 inhibitor, has a less pronounced effect on rivaroxaban exposure and can be used simultaneously with it.

Xarelto® should be used with caution in patients with moderate renal impairment (creatinine clearance 49-30 ml / min), receiving concomitant medications that may lead to an increase in the concentration of rivaroxaban in plasma. In patients with renal insufficiency with creatinine clearance 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, Xarelto® should be used with caution in patients with creatinine clearance of 29-15 ml/min. Clinical data on the use of rivaroxaban in patients with severe renal impairment (CC Therefore, the use of Xarelto® is not recommended in such patients.

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

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

patients with congenital or acquired bleeding tendency;

-patients with uncontrolled severe arterial hypertension;

patients with peptic ulcer of stomach and duodenum in the acute phase;

patients who recently had gastric ulcer and 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 recently undergoing 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 NSAIDs, platelet aggregation inhibitors, or other antithrombotic medications.

Patients at risk of developing gastric and duodenal ulcers may be given appropriate preventive treatment.

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

The safety and efficacy of Xarelto® in patients with artificial heart valves have not been studied, therefore, there are no data confirming that the use of Xarelto® 20 mg (15 mg in patients with creatinine clearance of 49-15 ml/min) provides a sufficient anticoagulant effect in this category of patients.

Xarelto® 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.

If an invasive procedure or surgical intervention is necessary, Xarelto® should be discontinued at least 24 hours before 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 parameters and adequate hemostasis are present.

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

The risk of these events is further increased with the use of a permanent epidural catheter or concomitant therapy with drugs that affect hemostasis. Traumatic epidural or spinal tap procedures or repeated punctures may also increase the risk.

Patients should be monitored for signs 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 at doses of 15 mg and 20 mg in these situations.

To reduce the potential risk of bleeding associated with concomitant use of rivaroxaban and epidural/spinal anesthesia or spinal puncture, the pharmacokinetic profile of rivaroxaban should be considered. 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 the general pharmacokinetic characteristics, the epidural catheter is removed after at least twice T 1/2, 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 case of a traumatic puncture, Xarelto® should be postponed for 24 hours.

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 motor vehicles and manage mechanisms

When using Xarelto® there were cases of fainting and dizziness. Patients who experience these adverse reactions should not drive vehicles or work with moving mechanisms.

Form of production

coated tablets

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Active ingredient

Rivaroxaban

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

Adults as prescribed by a doctor

Indications

Prevention of acute myocardial infarction, Prevention of heart attacks and strokes, Prevention of thrombosis, Thrombophlebitis, Angina