Xarelto - instructions for use, dose, side effects, contraindications

Active substanceRivaroxabanRivaroxaban

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Xarelto®

pills inwards

Bayer Pharma AG Germany

Xarelto®

pills inwards

Bayer Pharma AG Germany

Xarelto®

pills inwards

Bayer AG Germany

Dosage form: & nbspfilm coated tablets

Composition:

One film-coated tablet contains:

Active substance: rivaroxaban micronized 15 mg or 20 mg,

Excipients: microcrystalline cellulose - 37,50 mg or 35,00 mg, croscarmellose sodium - 3,00 mg, hypromellose 5 cp - 3,00 mg, lactose monohydrate - 25,40 mg or 22.90 mg, magnesium stearate - 0.60 mg, sodium lauryl sulfate - 0.50 mg; shell: iron oxide red - 0.150 mg or 0.350 mg, hypromellose 15cP - 1.50 mg, macrogol 3350 - 0.50 mg, titanium dioxide - 0.350 mg or 0.150 mg, respectively.

Description:

Tablets 15 mg: round biconvex tablets of pink-brown color, covered with a film membrane; the method of extrusion is engraved: on one side - a triangle with the designation of dosage "15", on the other - a firm Bayer's cross. Type of tablet on the break: a homogeneous mass of white, surrounded by a shell of pink-brown color.

Tablets of 20 mg: round biconvex tablets of red-brown color, covered with a film membrane; the method of extrusion is engraved: on one side - a triangle with a designation of dosage "20", on the other - a firm Bayer's cross.Type of tablet on the break: a homogeneous mass of white, surrounded by a shell of red-brown color.

Pharmacotherapeutic group:Direct factor Xa inhibitors

ATX: & nbsp

B.01.A.F Direct inhibitors of factor Xa

B.01.A.F.01 Rivaroxaban

Pharmacodynamics:Mechanism of action

Rivaroxaban is a highly selective direct inhibitor of factor Xa, which has high bioavailability when ingested.

Activation of factor X with the formation of factor Xa through the internal and external ways of coagulation plays a central role in the coagulation cascade.

Pharmacodynamic effects

A dose-dependent inhibition of factor Xa was observed in humans. Rivaroxaban has a dose-dependent effect on prothrombin time and correlates well with plasma concentrations (r = 0.98) if Neoplastin®. When using other reagents, the results will differ. Prothrombin time should be measured in seconds, as the INR (international normalized ratio) is calibrated and certified only for coumarin derivatives and can not be used for other anticoagulants.

Patients with atrial fibrillation of non-valvular origin receiving rivaroxaban for the prevention of stroke and systemic thromboembolism, 5 / 95th percentile for prothrombin time (Neoplastin®) 1-4 hours after taking the pill (ie at the maximum effect) vary from 14 to 40 seconds in patients taking 20 mg once a day and 10 to 50 seconds in patients with renal insufficiency (creatinine clearance 49 -30 ml / min), taking 15 mg once a day.

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

Also rivaroxaban dose-dependent increase in activated partial thromboplastin time (APTT) and the result of HepTest®; However, these parameters are not recommended for evaluating the pharmacodynamic effects of rivaroxaban. Also, if there is a clinical rationale for this, the concentration of rivaroxaban can be measured using a calibrated quantitative anti-factor Xa test.

During the period of Xarelto's treatment® monitoring blood coagulation parameters is not required.

In healthy men and women older than 50 years, the elongation of the QT interval of the electrocardiogram under the influence of rivaroxaban was not observed.

Pharmacokinetics:

Absorption and bioavailability

Absolute bioavailability of rivaroxaban after taking a 10 mg dose is high (80-100%).

Rivaroxaban is rapidly absorbed; maximum concentration (Сmax) is achieved 2-4 hours after taking the pill.

When taking rivaroxaban at a dose of 10 mg with food, there was no change in AUC (area under the concentration-time curve) and Cmax (maximum concentration). The pharmacokinetics of rivaroxaban are characterized by moderate individual variability; Individual variability (variation coefficient) is from 30 to 40%.

In connection with a reduced degree of absorption, with the intake of 20 mg on an empty stomach, a bioavailability of 66% was observed. When taking Xarelto® 20 mg during meals, the mean AUC increased by 39% compared with fasting, showing almost complete absorption and high bioavailability.

Absorption of rivaroxaban depends on the site of release in the gastrointestinal tract (GIT).Reduction in 29% and 56% in AUC and Cmax, respectively, compared with the use of the whole tablet, it was observed when the granulate of rivaroxaban was released in the distal small intestine or the ascending colon. Avoid the introduction of rivaroxaban in the gastrointestinal tract distal to the stomach, as this can lead to a decrease in absorption and, accordingly, the exposure of the drug.

The study assessed bioavailability (AUC and Cmax) 20 mg of rivaroxaban taken internally in the form of a crushed tablet mixed with apple puree or suspended in water, as well as injected through a gastric tube and then receiving liquid food, compared to taking the whole tablet. The results demonstrated a predictable dose-dependent pharmacokinetic profile of rivaroxaban, with bioavailability at the above-mentioned admission consistent with that of lower doses of rivaroxaban.

Distribution

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

Metabolism and excretion

When ingested approximately 2/3 of the prescribed dose, rivaroxaban is metabolized and subsequently excreted in equal parts with urine and through the intestine. The remaining 1/3 dose is excreted by direct renal excretion in an unchanged form, mainly due to active renal secretion.

Rivaroxaban is metabolized by means of CYP3A4 and CYP2J2 isoenzymes, as well as by mechanisms independent of the cytochrome system. The main sites of biotransformation are the oxidation of the morpholino group and the hydrolysis of amide bonds.

According to the data received in vitro, rivaroxaban is a substrate for P-gp (P-glycoprotein) protein and Bcrp (breast cancer resistance protein) proteins.

Unchanged rivaroxaban is the only active compound in human plasma, major or active circulating metabolites in plasma are not detected. Rivaroxaban, a systemic clearance of about 10 l / h, can be attributed to drugs with low clearance. With the removal of rivaroxaban from the plasma, the final half-life period is from 5 to 9 hours in young patients and from 11 to 13 hours in elderly patients.

Sex / Elderly age (over 65 years)

In elderly patients, rivaroxaban concentrations in the blood plasma are higher than in young patients; the average AUC value is approximately 1.5 times higher than the corresponding values in young patients, mainly due to an apparent decrease in total and renal clearance.

In men and women, no clinically significant differences in pharmacokinetics were found.

Body mass

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

Childhood

Data on this age category are absent.

Interethnic differences

Clinically significant differences in pharmacokinetics and pharmacodynamics in patients of European, African American, Latin American, Japanese or Chinese ethnicity were not observed.

Impaired liver function

The effect of liver failure on the pharmacokinetics of rivaroxaban was studied in patients allocated according to the Child-Pew classification (according to standard procedures in clinical trials). Classification Child-Pugh allows you to assess the prognosis of chronic liver diseases, mainly cirrhosis.In patients who are scheduled to carry out anticoagulant therapy, the most important consequence of a liver function disorder is a decrease in the synthesis of clotting factors in the liver. Since this indicator corresponds only to one of the five clinical / biochemical criteria that constitute the Child-Pew classification, the risk of bleeding is not quite clearly correlated with this classification. The treatment of such patients with anticoagulants should be addressed regardless of the Child-Pugh class.

Xarelto® is contraindicated in patients with liver diseases that occur with coagulopathy, which causes a clinically significant risk of bleeding.

In patients with cirrhosis and mild liver failure (Child-Pugh class A), the pharmacokinetics of rivaroxaban differed only slightly from the corresponding parameters in the control group of healthy subjects (a mean increase in rivaroxaban AUC was 1.2 times). There were no significant differences in pharmacodynamic properties between the groups.

In patients with cirrhosis of the liver and liver failure of moderate severity (Child-Pugh class B), the mean AUCrivaroxaban was significantly increased (by 2.3 times) compared with healthy volunteers due to a significantly reduced clearance of the drug substance, indicating a serious liver disease. The 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 the prothrombin time, an external coagulation pathway including clotting factors VII, X, V, II and I, which are synthesized in the liver, is evaluated. 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 hepatic insufficiency of Class C according to the Child-Pugh classification are absent.

Impaired renal function

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

In 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, there was a 1.4-, 1.5- and 1.6-fold increase in concentrations rivaroxaban in blood plasma (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 overall inhibition of factor Xa activity increased by 1.5, 1.9 and 2 times compared with healthy volunteers; prothrombin time due to the action of factor Xa also increased in 1.3, 2.2 and 2.4 times, respectively.

Data on the application of Xarelto® in patients with creatinine clearance of 29-15 ml / min are limited, and therefore care should be taken when using the drug in this category of patients. Data on the application of Xarelto® in patients with creatinine clearance <15 ml / min are absent, and therefore it is not recommended to use the drug in this category of patients.

Indications:

- Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation;

- treatment of deep vein thrombosis and pulmonary embolism and prevention of recurrence of DVT and PE.

Contraindications:

- Hypersensitivity to rivaroxaban or any excipients contained in the tablet;

- clinically significant active bleeding (eg, intracranial hemorrhage, gastrointestinal bleeding);

- damage or condition associated with an increased risk of major bleeding, such as an existing or recent gastrointestinal ulcer, the presence of malignant tumors with a high risk of bleeding, recent trauma to the brain or spinal cord, surgery on the brain, spinal cord or eyes, intracranial hemorrhage, diagnosed or suspected varicose veins of the esophagus, arteriovenous malformations, vascular aneurysms or pathology of the vessels of the brain or spinal cord;

- concomitant therapy with any other anticoagulants, for example, unfractionated heparin, low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran, etc.), except for cases of transition from or to rivaroxaban (see section "Method of administration and dose") or when unfractionated heparin is used at the doses necessary to ensure the functioning of the central venous or arterial catheter;

- liver diseases that occur with coagulopathy, which causes clinically significant risk of bleeding;

- pregnancy and the period of breastfeeding;

- children and adolescents under 18 years of age (efficacy and safety in patients of this age group not established);

- renal insufficiency (creatinine clearance <15 ml / min) (clinical data on the use of rivaroxaban in this category of patients are absent);

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

Carefully:

With caution should use the drug:

· In the treatment of patients with an increased risk of bleeding (including congenital or acquired tendency to bleeding, uncontrolled severe arterial hypertension, peptic ulcer and duodenal ulcer in the acute stage, a recent gastric and duodenal ulcer, vascular retinopathy, bronchiectasis or pulmonary hemorrhage in anamnesis);

· In the treatment of patients with renal insufficiency (creatinine clearance of 49-30 ml / min) receiving simultaneously drugs that increase the concentration of rivaroxaban in blood plasma (see the section "Interaction with other drugs and other forms of interaction");

· Care should be taken when treating patients with renal insufficiency (creatinine clearance of 29-15 ml / min), since the concentration of rivaroxaban in blood plasma in such patients can significantly increase (on average 1.6 times), and as a result they are at increased risk of bleeding ;

· Patients receiving medications that affect hemostasis (eg, NSAIDs, antiaggregants or other antithrombotic agents);

· Xarelto® is not recommended for use in patients receiving systemic treatment with antifungal azole agents (eg, ketoconazole) or HIV protease inhibitors (eg, ritonavir). These drugs are potent inhibitors of the isoenzyme CYP3A4 and P-glycoprotein. As a consequence, these drugs can increase the concentration of rivaroxaban in blood plasma to a clinically significant level(an average of 2.6 times), which increases the risk of bleeding. Azole antifungal drug fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on the exposure of rivaroxaban and can be used simultaneously with it (see the section "Interaction with other drugs and other forms of interaction").

· Patients with renal insufficiency (creatinine clearance of 29-15 ml / min) or an increased risk of bleeding and patients receiving concomitant systemic treatment with antifungal azole agents or HIV protease inhibitors should be closely monitored for the timely detection of complications in the form of bleeding.

Pregnancy and lactation:

Pregnancy

Safety and effectiveness of Xarelto application® in pregnant women are not established. Data from experimental animals showed pronounced toxicity of rivaroxaban for the maternal organism due to the pharmacological action of the drug (eg complications in the form of hemorrhages) and resulting in reproductive toxicity.

Due to the possible risk of bleeding and the ability to penetrate the placenta Xarelto® contraindicated in pregnancy (see the section "Contraindications").

Women with preserved reproductive capacity should use effective methods of contraception during the treatment of Xarelto®.

Breast-feeding

Data on the application of Xarelto® for the treatment of women in the period of breastfeeding are absent. Data from experimental animals show that rivaroxaban excreted in breast milk. Xarelto® Can only be used after breastfeeding has been abolished (see the section "Contraindications").

Fertility

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

Dosing and Administration:

Inside. Xarelto® 15 mg and 20 mg should be taken with food.

If the patient is unable to swallow the whole tablet, the Xarelto tablet® can be ground and mixed with water or liquid food, for example, apple puree, just before the reception. After taking a crushed tablet Xarelto® 15 mg or 20 mg should be taken immediately to eat.

Xarelto Crushed Tablet® can be administered through a gastric tube. The position of the probe in the digestive tract must be agreed with the doctor in advance before taking Xarelto®. The ground tablet should be injected through a gastric tube in a small amount of water, after which a small amount of water must be introduced in order to wash off the drug residues from the probe walls. After taking a crushed tablet Xarelto® 15 mg or 20 mg should be immediately administered enteral feeding.

Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation

The recommended dose is 20 mg once a day.

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

The recommended maximum daily dose is 20 mg.

Duration of treatment: Xarelto therapy® should be considered as long-term treatment, conducted until the benefit of the treatment exceeds the risk of possible complications (cm.sections "With caution" and "Special instructions").

Actions when skipping the dose

If the next dose is missed, the patient should immediately take Xarelto® and the next day to continue the regular intake of the drug in accordance with the recommended regimen.

Do not double the dose taken to compensate for missed earlier.

Treatment of DVT and PE and prevention of relapses of DVT and PE

The recommended initial dose for the treatment of acute DVT or PE is 15 mg 2 times a day for the first 3 weeks, followed by a 20 mg dose once a 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.

Duration of treatment is determined individually after careful weighing of the benefits of treatment against the risk of bleeding (see the "Caution" section). The minimum duration of treatment (at least 3 months) should be based on an assessment of reversible risk factors (ie, previous surgical intervention, trauma, immobilization period).The decision to extend the course of treatment for a longer time is based on an assessment of the permanent risk factors, or in the case of the development of idiopathic DVT or PE.

Actions when skipping the dose

It is important to adhere to the established dosing regimen.

If the next dose is missed with a dosage regimen of 15 mg twice a day, the patient should immediately take Xarelto® to achieve a daily dose of 30 mg. Thus, two 15 mg tablets can be taken in one session. The next day the patient should continue to take the medication regularly according to the recommended regimen.

If the next dose is missed with a dosage regimen of 20 mg once a day, the patient should immediately take Xarelto® and the next day to continue the regular intake of the drug in accordance with the recommended regimen.

Individual patient groups

Dose adjustments are not required depending on the age of the patient (over 65 years of age), sex, body weight or ethnicity.

Patients with impaired hepatic function

Xarelto® contraindicated in patients with liver disease accompanied by coagulopathy, which causes a clinically significant risk of bleeding (see the section "Contraindications").

Patients with other liver diseases do not need dosage changes (see the section "Pharmacological properties / Pharmacokinetics").

The limited clinical data available for patients with moderate hepatic impairment (Child-Pugh class B) indicate a significant increase in the pharmacological activity of the drug. Patients with severe hepatic insufficiency (class C according to the Child-Pugh classification) do not have clinical data.

Patients with impaired renal function

When appointing Xarelto® patients with renal insufficiency (creatinine clearance 80-50 ml / min) dose adjustment is not required.

In the prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation with renal insufficiency (creatinine clearance of 49-30 ml / min), the recommended dose is 15 mg once a day.

In the treatment of DVT and PE and the prevention of recurrence of DVT and PE in patients with renal insufficiency (creatinine clearance of 49-30 ml / min), dose adjustment is not required.

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

Application of Xarelto® It is not recommended in patients with creatinine clearance <15 ml / min (see the sections "Contraindications", "Pharmacological properties / Pharmacokinetics").

Transition from antagonists of vitamin K (AVK) to Xarelto®

In the prevention of stroke and systemic thromboembolism should stop AVK treatment and start treatment Xarelto® with a MNO value of 3.0.

With DVT and PE, discontinue AVC treatment and start treatment Xarelto® with an INR of 2.5.

When patients with AVK go to Xarelto®, after taking Xarelto® the INR values will be erroneously overestimated. INR is not suitable for determining the anticoagulant activity of Xarelto® and therefore should not be used for this purpose (see "Interaction with other medicinal products and other forms of interaction").

Transition from Xarelto® on antagonists of vitamin K (AVK)

There is a possibility of an insufficient anticoagulant effect in the transition from Xarelto® on the AVC. 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® can help raise INR. Patients who have switched from Xarelto® on the AVC, it is necessary to simultaneously receive the AVC, while the INR does not reach ≥ 2.0. During the first two days of the transition period, the standard dose of AVK should be applied with the subsequent dose of AVK, determined depending on the magnitude of INR. Thus, during the simultaneous application of Xarelto® and AVK MNO should be determined not earlier than 24 hours after the previous administration, but before the next dose of Xarelto®. After the termination of application of Xarelto® the INR value can be reliably determined 24 hours after the last dose (see "Interaction with other medicinal products and other forms of interaction").

Transition from parenteral anticoagulants to Xarelto®

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

Transition from Xarelto® on parenteral anticoagulants

It should be canceled Xarelto® and to introduce the first dose of parenteral anticoagulant at the time when it was necessary to take the next dose of Xarelto®.

Cardioversion in the prevention of stroke and systemic thromboembolism

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

Side effects:

Security Xarelto® were evaluated in four phase III trials involving 6097 patients undergoing large orthopedic surgery on the lower extremities (total knee or hip joint endoprosthetics) and 3997 patients hospitalized for medical reasons who received Xarelto treatment® 10 mg for up to 39 days, as well as for three phase III trials of venous thromboembolism, involving 4,556 patients who received either 15 mg Xarelto® twice a day for 3 weeks, followed by a dose of 20 mg once a day, or 20 mg once daily to 21 months.

In addition, of the two Phase III trials involving 7750 patients, safety data were obtained in patients with non-valvular atrial fibrillation who received at least one dose of Xarelto® for a period of up to 41 months, and 10225 patients with ACS who received at least one dose of 2.5 mg (twice daily) or 5 mg (twice daily) Xarelto® in addition to therapy with acetylsalicylic acid or acetylsalicylic acid with clopidogrel or ticlopidine, the duration of treatment is up to 31 months.

Given the mechanism of action, the application of Xarelto® can be accompanied by an increased risk of latent or obvious bleeding from any organs and tissues that can lead to post-hemorrhagic anemia. The risk of bleeding may increase in patients with uncontrolled hypertension and / or when combined with drugs that affect hemostasis (see the "Caution" section). Symptoms, symptoms and severity (including possible fatal outcome) vary depending on localization, intensity or duration of bleeding and / or anemia (cm.section "Overdose"). Hemorrhagic complications can be manifested by weakness, pallor, dizziness, headache, dyspnea, and an increase in the extremity in volume or shock, which can not be explained by other causes. In some cases, the symptoms of myocardial ischemia, such as chest pain and angina, have developed as a result of anemia.

When applying Xarelto® also known complications secondary to severe bleeding, such as compartmentalism and renal insufficiency due to hypoperfusion, were also recorded. Therefore, bleeding should be considered when assessing the condition of any patient receiving anticoagulants.

Generalized data on the frequency of undesirable reactions recorded for Xarelto®, are given below. In groups divided by frequency, undesirable effects are presented in order of decreasing severity, as follows:

Frequently: from ≥1% to <10% (from ≥1 / 100 to <1/10),

Infrequently: from ≥0.1% to <1% (from ≥1 / 1000 to <1/100),

Rarely: from ≥0.01% to <0.1% (from ≥1 / 10000 to <1/1000),

Very rarely: <0.01% (<1/10000).

All undesirable reactions that occurred during the treatment period in patients who participated in phase III clinical trials

Violations of the blood and lymphatic system

Often: anemia (including relevant laboratory parameters)

Infrequently: thrombocythemia (including increased platelet count) *

Heart Disease

Infrequently: tachycardia

Disturbances on the part of the organ of sight

Often: hemorrhage in the eye (including hemorrhage in the conjunctiva)

Disorders from the digestive system

Often: bleeding gums, gastrointestinal bleeding (including rectal bleeding), pain in the area of the gastrointestinal tract, 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 well-being (including malaise)

Rarely: local edema *

Disorders from the side of the liver

Infrequently: abnormal liver function

Rarely: jaundice

Immune system disorders

Infrequently: allergic reaction, allergic dermatitis

Injuries, poisonings and procedural complications

Often: hemorrhages after the performed procedures (including postoperative anemia and bleeding from the wound), excessive hematoma with a bruise

Infrequently: excreting from a wound *

Rarely: cardiovascular pseudoaneurysm ***

Research results

Often: increased activity of "liver" transaminases

Infrequently: increased bilirubin concentration, increased activity of alkaline phosphatase *, increased LDH activity *, increased lipase activity *, increased activity of amylase *, increased activity of GGT *

Rarely: an increase in the concentration of conjugated bilirubin (with or without concomitant increase in ALT activity)

Disturbances from the musculoskeletal system and connective tissue

Often: pain in the extremities *

Infrequently: hemarthrosis

Rarely: muscle hemorrhage

Disturbances from the nervous system

Often: dizziness, headache

Infrequently: intracerebral and intracranial hemorrhages, short-term fainting

Disorders of the kidneys and urinary tract

Often: bleeding from the urogenital tract (including hematuria and menorrhagia **), renal failure (including increased creatinine levels, increased urea levels) *

Disturbances from the respiratory tract

Often: epistaxis, hemoptysis

Disturbances from the skin and subcutaneous tissues

Often: itching (including infrequent cases of generalized itching), rash, ecchymosis, cutaneous and subcutaneous hemorrhages

Infrequently: hives

Vascular disorders

Often: marked decrease in blood pressure, hematoma

* registered after large orthopedic operations

** were recorded in the treatment of VTE as very frequent in women <55 years

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

During post-registration monitoring, cases of the undesirable reactions listed below were reported, the development of which had a temporary connection with the reception of Xarelto®. It is not possible to assess the frequency of occurrence of such undesirable reactions within the framework of post-registration monitoring.

Impaired immune system: angioedema, allergic edema. In the framework of RCT Phase III, such undesirable events were regarded as infrequent (from> 1/1000 to <1/100).

Disturbances from the liver: cholestasis, hepatitis (including hepatocellular damage).In the framework of RCT Phase III, such undesirable events were regarded as rare (from> 1/10000 to <1/1000).

Disorders from the blood and lymphatic system: thrombocytopenia. In the framework of RCT Phase III, such undesirable events were regarded as infrequent (from> 1/1000 to <1/100).

Disturbances from the musculoskeletal system and connective tissue: frequency unknown - a syndrome of increased subfascial pressure (compartment-syndrome) due to hemorrhage into the muscles.

Violations from the kidneys and urinary tract: frequency unknown - Renal failure / acute renal failure due to bleeding, leading to kidney hypoperfusion.

Overdose:

There were rare cases of overdose with rivaroxaban up to 600 mg without the development of bleeding or other adverse reactions. Due to limited absorption, a low-level plateau of the drug concentration is expected to develop without further increase in its average plasma concentration when doses exceeding the therapeutic dose are equal to 50 mg or higher.

The specific antivot of rivaroxaban is unknown.In case of an overdose, to reduce the absorption of rivaroxaban, Activated carbon. Given the intense binding to plasma proteins, it is expected that rivaroxaban will not be displayed during dialysis.

Treatment of bleeding

If the patient receiving rivaroxaban, there was a complication in the form of bleeding, the next dose should be postponed or, if necessary, canceled treatment with this drug. The half-life of rivaroxaban is approximately 5-13 hours. Treatment should be individual, depending on the severity and localization of bleeding. If necessary, you can use the appropriate symptomatic treatment, such as mechanical compression (for example, with severe nasal bleeding), surgical hemostasis with an assessment of its effectiveness, infusion therapy and hemodynamic support, the use of blood products (erythrocyte mass or fresh frozen plasma, depending on the origin anemia or coagulopathy) or platelets.

If the above measures do not lead to the elimination of bleeding,Specific procoagulant drugs of reverse action, such as clotting factors II, VII, IX and X in combination [Prothrombin Complex], anti-inhibitory coagulant complex or eptakog alpha [activated]. However, the current experience with the use of these drugs in patients receiving Xarelto®, is very limited.

Expected that Protamine sulfate and vitamin K have no effect on the anticoagulant activity of rivaroxaban.

There is limited experience with tranexamic acid and there is no experience with aminocaproic acid and aprotinin in patients receiving Xarelto®. Scientific justification of the expediency or experience of using a systemic haemostatic drug desmopressin in patients receiving Xarelto®, absent.

Interaction:

Pharmacokinetic interactions

Removal of rivaroxaban is mainly mediated by liver metabolism mediated by the cytochrome P450 system (CYP3A4, CYP2J2), and also by renal excretion of unchanged drug substance using P-gp / Bcrp (P-glycoprotein / breast cancer resistance) .

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

The simultaneous use of Xarelto® and potent inhibitors of the isoenzyme CYP3A4 and P-glycoprotein can lead to a decrease in renal and hepatic clearance of rivaroxaban and, thus, significantly increase its systemic effect.

The combined use of Xarelto® and the azole antifungal agent ketoconazole (400 mg once daily), which is a potent inhibitor of CYP3A4 and P-glycoprotein, resulted in a 2.6-fold increase in the average equilibrium AUC of rivaroxaban and a 1.7-fold increase in the average Cmax of rivaroxaban, which was accompanied by a significant increase in the pharmacodynamic effect of the drug.

The simultaneous administration of Xarelto® and HIV protease inhibitor ritonavir (600 mg twice daily), a potent inhibitor of CYP3A4 and P-glycoprotein, resulted in a 2.5-fold increase in the mean equilibrium AUC of rivaroxaban and a 1.6-fold increase in the average Cmax of rivaroxaban, which was accompanied by a significant increase in the pharmacodynamic effect of the drug. In this regard, Xarelto® is not recommended for use in patients receiving systemic treatment with antifungal azole agents or HIV protease inhibitors (see the "Caution" section).

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

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

In patients with renal insufficiency (creatinine clearance ≤80-50 ml / min) erythromycin (500 mg 3 times a day) caused 1.8-fold increase in AUC values of rivaroxaban 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 of 49-30 ml / min) erythromycin caused an increase in the values of AUC of rivaroxaban 2.0 times and Cmax 1.6 times compared with patients with normal renal function who did not receive concomitant therapy (see the "Caution" section).

Fluconazole (400 mg once daily), a moderate inhibitor of the isoenzyme CYP3A4, caused an increase in the mean AUC of rivaroxaban by a factor of 1.4 and an increase in the mean Cmax of 1.3times. This increase is of the order of normal variability of AUC and Cmax and is considered clinically insignificant.

Avoid simultaneous application of rivaroxaban with dronedarone due to limited clinical data on joint use.

The combined 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. The combined use of rivaroxaban with other strong inducers of CYP3A4 (eg, phenytoin, carbamazepine, phenobarbital, or preparations of St. John's wort) can also lead to a decrease in rivaroxaban concentrations in plasma. Reducing concentrations of rivaroxaban in blood plasma is clinically insignificant. Strong inductors CYP3A4 should be used with caution.

Pharmacodynamic interactions

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

Due to the increased risk of bleeding should be careful when combined with any other anticoagulants (see the sections "Contraindications", "With caution" and "Special instructions").

Not detected pharmacokinetic interaction between Ksarelto® (15 mg) and clopidogrel (300 mg loading dose followed by maintenance doses purpose 75 mg), but in the subgroup of patients showed a significant increase in bleeding time is not correlated with the degree of platelet aggregation and the content of P-selectin or GPIIb / IIIa receptor (see the "Caution" section).

After application Ksarelto® joint (15 mg) and naproxen 500 mg clinically significant increase in bleeding time was observed. Nevertheless, in individuals, a more pronounced pharmacodynamic response is possible.

Care must be taken when used in conjunction with Ksarelto® NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors, since these agents usually increase the risk of bleeding.

Transition of patients with warfarin (INR 2.0 to 3.0) on Xarelto® (20 mg) or with Xarelto® (20 mg) per warfarin (INR 2.0 to 3.0) increased prothrombin time / MNO (Neo-Plastin) to a greater extent than would be expected with a simple summation of effects (individual INR values can reach 12), while the effect on APTT, suppression of factor Xa activity and endogenous thrombin potential was additive.

If necessary, studies of the pharmacodynamic effects of Xarelto® during the transition period, as necessary tests, which are not affected warfarin, the activity of anti-Xa, PiCT and HepTest® can be used. Starting from the 4th day after discontinuation of the use of warfarin, all test results (including PV, APTT, inhibition of factor Xa activity and on EPT (endogenous thrombin potential)) reflect only the influence of Xarelto® (see section "Method of administration and dose").

If it is necessary to study the pharmacodynamic effects of warfarin during the transition period, a measurement of the INR value at Intermediate may be used. rivaroxaban (24 hours after the previous administration of rivaroxaban), since rivaroxaban has a minimal effect on this indicator in this period.

There were no pharmacokinetic interactions between warfarin and Xarelto®.

The drug interaction of Xarelto® with a vitamin K antagonist (AVK) with phenindione has not been studied. It is recommended that transfer of patients from Xarelto therapy to AVK therapy with phenindione and vice versa is avoided whenever possible.

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

If there is a need to transfer a patient from Xarelto therapy to AVK therapy with phenindione or acenocoumarol, special care should be taken, daily monitoring of the pharmacodynamic action of the drugs (INR, prothrombin time) should be performed immediately before the next dose of Xarelto®.

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

Incompatibility

Unknown.

No interactions detected

No pharmacokinetic interactions between rivaroxaban and midazolam (substrate CYP3A4), digoxin (P-glycoprotein substrate), or atorvastatin (substrate CYP3A4 and P-glycoprotein) have been identified.

Co-administration with the proton pump inhibitor omeprazole, H2 receptor antagonist ranitidine, aluminum antacids hydroxide / magnesium hydroxide, naproxen, clopidogrel or enoxaparin does not affect the bioavailability and pharmacokinetics of rivaroxaban.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with the combined use of Xarelto® and 500 mg of acetylsalicylic acid.

Effect on laboratory parameters

The drug Xarelto® has an effect on blood coagulability (PV, APTTV, HepTest®) in connection with its mechanism of action.

Special instructions:

Application of Xarelto® It is not recommended in patients receiving concomitant systemic treatment with azole antifungals (eg, ketoconazole) or HIV protease inhibitors (eg, ritonavir). These drugs are potent inhibitors of CYP3A4 and P-glycoprotein. Thus, these drugs can increase the concentration of rivaroxaban in the blood plasma to clinically significant values (2.6 times on average), which can lead to an increased risk of bleeding.

However, an azole antifungal drug fluconazole, a moderate inhibitor of CYP3A4, has a less pronounced effect on the exposure of rivaroxaban and can be used simultaneously with it (see the section "Interaction with other medicinal products and other forms of interaction").

The drug Xarelto® should be used with caution in patients with moderate renal dysfunction (CC 49-30 ml / min) receiving concomitant drugs that can lead to an increase in the concentration of rivaroxaban in plasma (see the section "Interaction with other medicinal products and other forms of interaction").

In patients with severe renal dysfunction (CK <30 ml / min), the concentration of rivaroxaban in plasma can be significantly increased (1.6 times on average), which may lead to an increased risk of bleeding. Therefore, due to the presence of this underlying disease, such patients have an increased risk of developing both bleeding and thrombosis. Due to the limited amount of clinical data, the Xarelto preparation® should be used with caution in patients with QA 29-15 ml / min.

Clinical data on the use of rivaroxaban in patients with severe renal impairment (QC <15 mL / min) are not available. Therefore, the use of Xarelto® It is not recommended in such patients (cm.section "Dosing and Administration", "Pharmacokinetics", "Pharmacodynamics").

Patients with severe renal dysfunction or an increased risk of bleeding, as well as patients receiving concomitant systemic treatment with azole antifungal agents or HIV protease inhibitors, should be carefully monitored for signs of bleeding after initiation of treatment.

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

· patients with congenital or acquired tendency to bleeding;

· patients with uncontrolled severe arterial hypertension;

· patients with peptic ulcer and duodenal ulcer in the stage of exacerbation;

· patients who have recently undergone gastric ulcer and duodenal ulcer;

· patients with vascular retinopathy;

· patients who have recently undergone intracranial or intracerebral haemorrhage;

· patients with pathology of the vessels of the brain or spinal cord;

· patients who have recently undergone surgery on the brain, spinal cord or eyes;

· patients with bronchiectasis or pulmonary haemorrhage in the anamnesis.

Caution should be exercised if the patient simultaneously receives medications that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, or other antithrombotic drugs.

Patients with a risk of developing gastric ulcer and 12 duodenal ulcer can receive appropriate preventive treatment.

With an inexplicable decrease in hemoglobin or blood pressure, you need to look for a source of bleeding.

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

The drug 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 is not established.

If it is necessary to conduct an invasive procedure or a surgical procedure, taking Xarelto® should be discontinued, at least 24 hours before the intervention and on the basis of a doctor's opinion.

If the procedure can not be postponed, an increased risk of bleeding should be assessed in comparison with the need for urgent intervention.

Xarelto® should be resumed after an invasive procedure or surgery, subject to the availability of appropriate clinical indicators and adequate hemostasis (see the section "Pharmacological properties / Metabolism and excretion").

When the epidural / spinal anesthesia or spinal puncture in patients receiving platelet aggregation inhibitors in the prevention of thromboembolic complications, the risk of developing an epidural or spinal hematoma, which can result in permanent paralysis.

The risk of these events is further increased by the use of a permanent epidural catheter or concomitant therapy with drugs that affect hemostasis.Traumatic performance of an epidural or spinal puncture or repeated puncture can also increase the risk.

Patients should be monitored to identify signs and symptoms of neurological disorders (eg, numbness or weakness of the legs, bowel or bladder dysfunction). If neurological disorders are detected, urgent diagnosis and treatment is necessary.

The physician should compare the potential benefit and the relative risk before performing spinal surgery to patients receiving anticoagulants or who are scheduled to administer anticoagulants for the prevention of thrombosis. The experience of clinical application of rivaroxaban in dosages of 15 mg and 20 mg in the described situations is absent.

In order to reduce the potential risk of bleeding associated with the concomitant use of rivaroxaban and epidural / spinal anesthesia or spinal puncture, the pharmacokinetic profile of rivaroxaban should be considered. It is better to install or remove the epidural catheter or lumbar puncture when the anticoagulant effect of rivaroxaban is judged to be weak.

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

Based on the general pharmacokinetic characteristics, the epidural catheter is recovered after at least a two-fold half-life, i.e. not earlier than 18 hours after the appointment of the last dose of Xarelto® for young patients and not earlier than 26 hours for elderly patients. The drug Xarelto® should be prescribed no earlier than 6 hours after the extraction of the epidural catheter.

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

Safety data from preclinical studies

With the exception of the effects associated with the intensification of pharmacological action (bleeding), no specific human hazard was detected in the analysis of preclinical data obtained in pharmacological safety studies.

Effect on the ability to drive transp. cf. and fur:When applying Xarelto® cases of fainting and dizziness were noted (see section "Side effect"). Patients who experience these adverse reactions should not drive vehicles and work with moving machinery.

Form release / dosage:Tablets coated with a film coat of 15 mg and 20 mg.

Packaging:

In production at Bayer AG, Germany:

For tablets 15 mg: 14 or 10 tablets per blister from Al / PP or Al / PVC-PVDC. For 1, 2, 3 or 7 blisters for 14 tablets or 10 blisters for 10 tablets together with instructions for use in a cardboard box.

For tablets of 20 mg: 14 or 10 tablets per blister from Al / PP or Al / PVC-PVDC. For 1, 2 or 7 blisters for 14 tablets or 10 blisters for 10 tablets together with instructions for use in a cardboard box.

In the production of Bayer Helskar Manufakchuring Srl, Italy:

For tablets 15 mg: 14 or 10 tablets per blister from Al / PP or Al / PVC-PVDC. For 1, 2 or 7 blisters for 14 tablets or 10 blisters for 10 tablets together with instructions for use in a cardboard box.

Storage conditions:

At a temperature not higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001457

Date of registration:25.01.2012 / 17.10.2017

Expiration Date:Unlimited

The owner of the registration certificate:Bayer Pharma AGBayer Pharma AG Germany

Manufacturer: & nbsp

BAYER PHARMA, AG Germany

Representation: & nbspBAYER, AOBAYER, AO

Information update date: & nbsp05.02.2018

Illustrated instructions

Instructions

Xarelto® (Xarelto®)