Xarelto tablets 15 mg, 14 pcs. (Rivaroxaban)

Release form

Film-coated tablets.

Packing

14 pcs.

Pharmacological action

Xarelto is a direct-acting anticoagulant. Rivaroxaban is a highly selective direct factor Xa inhibitor with high oral bioavailability. The activation of factor X with the formation of factor XA through the internal and external coagulation pathways plays a central role in the coagulation cascade. In humans, dose-dependent inhibition of factor Xa was observed. Rivaroxaban has a dose-dependent effect on prothrombin time and is closely correlated with plasma concentrations (r = 0/98) if the Neoplastin kit is used for analysis. When using other reagents, the results will be different. Prothrombin time should be measured in seconds, since the MHO is calibrated and certified only for coumarin derivatives and cannot be used for other anticoagulants. In patients undergoing major orthopedic surgery, the 5/95 percentile for prothrombin time (Neoplastin) 2-4 hours after taking the pill (i.e., at the maximum effect) varies from 13 to 25 seconds. Rivaroxaban also dose-dependently increases APTT and the result of HepTest, however, these parameters are not recommended for evaluating the pharmacodynamic effects of rivaroxaban. Rivaroxaban also affects the activity of the anti-Xa factor, but there are no standards for calibration. During the treatment with rivaroxaban, monitoring of blood coagulation parameters is not required. In healthy men and women over 50 years of age, prolongation of the QT interval under the influence of rivaroxaban was not observed.

Indications

Prevention of venous thromboembolism (VTE) in patients undergoing major orthopedic surgery on the lower extremities.

Contraindications

clinically significant active bleeding (e.g., intracranial bleeding, gastrointestinal bleeding)

liver disease associated with coagulopathy, which causes a clinically significant risk of bleeding

pregnancy

lactation (breastfeeding)

children and adolescents under 18 years of age (efficacy and safety for patients of this age group have not been established)

hypersensitivity to rivaroxaban or any excipients contained in the tablet.

The use of rivaroxaban has not been studied in clinical trials in surgical interventions in patients for a fracture of the femur. Therefore, the use of rivaroxaban is not recommended for this category of patients.

Clinical data on the use of rivaroxaban in patients with severe renal failure (CC <15 ml / min) are not available. Therefore, the use of rivaroxaban is not recommended for this category of patients.

Hereditary intolerance to lactose or galactose (for example, caused by lack of lactase or malabsorption of glucose-galactose), since lactose is part of this drug.

Use in pregnancy and lactation

Pregnancy

There are no data on the use of rivaroxaban in pregnant women.

Data from experimental animals, showed pronounced toxicity of rivaroxaban to the mother's body, associated with the pharmacological action of the drug (for example, complications in the form of hemorrhages) and leading to reproductive toxicity.

Due to the possible risk of bleeding and the ability to cross the placenta, rivaroxaban is contraindicated in pregnancy.

Women with preserved reproductive ability should use effective methods of contraception during treatment with rivaroxaban.

Lactation

There are no data on the use of rivaroxaban for the treatment of women during lactation. Data from experimental animals show that rivaroxaban is excreted in breast milk. Rivaroxaban can be used only after the abolition of breastfeeding.

Special instructions

The use of rivaroxaban has not been studied in clinical trials for surgical interventions for hip fractures.

With an unexplained decrease in hemoglobin or blood pressure, it is necessary to look for a source of bleeding.

No lengthening of the QT interval was observed during treatment with rivaroxaban.

When performing spinal puncture and epidural / spinal anesthesia for patients, receiving platelet aggregation inhibitors in order 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 permanent catheters or the concomitant use of drugs that affect hemostasis. Injury during epidural or spinal puncture or repeated puncture can also increase the risk. Patients should be monitored to detect signs or symptoms of neurological disorders (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological disorders are detected, urgent diagnosis and treatment is necessary. The physician must compare the potential benefits and risks before performing spinal intervention in patients receiving anticoagulants or preparing to receive anticoagulants to prevent thrombosis. The epidural catheter is removed no earlier than 18 hours after the last dose of rivaroxaban. Rivaroxaban should not be prescribed earlier than 6 hours after extraction of the epidural catheter. In case of traumatic puncture, the administration of rivaroxaban should be postponed for 24 hours.

Safety data obtained from preclinical studies

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

Influence on the ability to drive vehicles and control mechanisms

Studies of the effects of rivaroxaban on the ability to drive vehicles and work with potentially dangerous moving mechanisms have not been conducted.

In the postoperative period, cases of fainting and dizziness have been infrequent. Patients who experience these adverse reactions should not drive vehicles or work with moving machinery.

Composition

1 tab. contains rivaroxaban micronized 15 mg.

Excipients: microcrystalline cellulose - 37.5 mg, croscarmellose sodium - 3 mg, 5cP hypromellose - 3 mg, lactose monohydrate - 25.4 mg, magnesium stearate - 600 ?g, sodium lauryl sulfate - 500 ?g.

Shell composition: iron dye red oxide - 150 ?g, hypromellose 15cP - 1.5 mg, macrogol 3350 - 500 ?g, titanium dioxide - 350 ?g.

Dosage and administration of

For the prevention of VTE in large orthopedic operations

It is recommended to prescribe 1 tablet (10 mg) 1 time / day.

Duration of treatment: 5 weeks after major surgery on the hip joint 2 weeks after major surgery on the knee joint.

Rivaroxaban can be taken with or without food.

The initial dose should be taken 6-10 hours after surgery, provided hemostasis is achieved.

If a dose is missed, the patient should take rivaroxaban immediately and continue treatment the next day with 1 tablet / day, as before.

Dose adjustment is not required depending on the patient's age (over 65 years), gender, body weight or ethnic group.

In liver disease

Rivaroxaban is contraindicated in patients with liver disease accompanied by coagulopathy, which causes a clinically significant risk of bleeding. Dose changes are not required for patients with other liver diseases. Limited clinical data available in patients with moderate hepatic impairment (Child-Pugh class B), indicate a significant increase in the pharmacological activity of the drug. For patients with severe hepatic impairment (Child-Pugh class C), clinical data are not available.

In case of kidney disease

When prescribing rivaroxaban to patients with renal failure of mild (QC 80-50 ml / min) or medium (QC

Side effects

The safety of rivaroxaban at a dose of 10 mg was evaluated in four phase III trials in 6097 patients who underwent major orthopedic surgery on the lower extremities (total prosthetics of the knee or hip joint), receiving treatment for up to 39 days.

Adverse reactions are classified by frequency of occurrence and organ systems and should be interpreted taking into account the surgical situation.

Given the mechanism of action, the use of rivaroxaban may be accompanied by an increased risk of latent or overt bleeding from any organs and tissues, which can lead to posthemorrhagic anemia. Signs, symptoms, and severity (including possible fatal outcome) vary depending on location, severity, or duration of bleeding and / or anemia. The risk of bleeding may increase in patients with uncontrolled arterial hypertension and / or when used together with drugs that affect hemostasis. Hemorrhagic complications may be manifested by weakness, pallor, dizziness, headache, shortness of breath, as well as an increase in the limb in volume or shock, inexplicable other reasons. In some cases, symptoms of myocardial ischemia, such as chest pain and angina, may develop due to anemia. Therefore, when assessing the condition of a patient receiving anticoagulants, the possibility of hemorrhage should be considered.

Summarized data on the frequency of adverse reactions recorded for Xarelto® are shown in the table below. In frequency groups, unwanted effects are presented in order of decreasing severity. Depending on the frequency of occurrence, frequent (? 1/100 and <1/10), infrequent (? 1/1000 and <1/100) and rare adverse reactions (? 1/10 000 and <1/1000) were distinguished. Adverse reactions which were identified only at the stage of post-marketing observational studies or for which it was impossible to estimate the frequency, are designated as the frequency is unknown.

Listed below are all adverse reactions that occurred during the treatment period in patients participating in phase III clinical trials.

From the hematopoietic system: infrequently - anemia (including appropriate laboratory parameters), thrombocythemia (including high platelet count).

From the cardiovascular system: infrequently - tachycardia, hypotension (including lowering blood pressure, hypotension during the procedure), hematoma (including rare cases of muscle hemorrhage), gastrointestinal bleeding (including bleeding from the gums, rectum, bloody vomiting), urogenital haemorrhage, nosebleeds. digestive system: often - nausea, increased GGT levels, transaminases (including ALT, ACT) infrequently - constipation, diarrhea, abdominal pain (including pain in the upper abdomen, discomfort in the stomach), dyspepsia (including discomfort in epigastrium), dry mouth, vomiting, increased activity of lipase, amylase, increased concentration of bilirubin, increased activity of LDH, alkaline phosphatase rarely — impaired liver function, increased concentration of conjugated bilirubin (with or without an increased ALT activity).

From the side of the central nervous system: infrequently - dizziness, headache rarely - short-term loss of consciousness (including syncope).

From the urinary system: infrequently - renal failure (including increased creatinine concentration, increased urea concentration).

From the skin: infrequently - itching (including rare cases of generalized itching), rash, rarely post-traumatic hematomas - urticaria (including rare cases of generalized urticaria), allergic dermatitis.

From the musculoskeletal system: infrequently - pain in the limbs.

On the part of the body as a whole: often - fever, peripheral edema infrequently - local edema, deterioration of general well-being (including weakness, asthenia) rarely - poor health (including discomfort).

Other: often - hemorrhages after procedures (including postoperative anemia and bleeding from the wound) infrequently - discharge from the wound.

Other clinical studies of rivaroxaban have described individual cases of hemorrhage in the adrenal gland and conjunctiva, and also bleeding from a gastrointestinal ulcer with a fatal outcome, in rare cases there was jaundice and hypersensitivity infrequently - hemoptysis. Single intracranial hemorrhages are described (especially in patients with arterial hypertension and / or taking concomitant medications that affect hemostasis / for example, NSAIDs, antiplatelet agents, or other antithrombotic drugs /), which in some cases can be potentially life-threatening.

Other clinical trials have reported the occurrence of vascular pseudo-aneurysm after percutaneous interventions.

According to other clinical studies and post-marketing observational studies, known bleeding complications such as compartment syndrome are reported. Moreover, The development of acute renal failure and renal failure, which was the result of bleeding, the intensity of which was sufficient to cause hypoperfusion, was recorded.

Drug interaction

Pharmacokinetic interaction

Elimination of rivaroxaban is mainly accomplished through metabolism in the liver mediated by the P450 cytochrome system (CYP3A4, CYP2J2), as well as by renal excretion of unchanged drug substance using P-trans gpc / breast cancer resistance protein).

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

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

The combined use of rivaroxaban and the azole antifungal ketoconazole (400 mg 1 time / day), which is a strong inhibitor of CYP3A4 and P-glycoprotein, led to 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 1.7 pharmacodynamic effects of the drug.

Co-administration of Xarelto® and the HIV protease inhibitor ritonavir (600 mg 2 times / day), a potent inhibitor of CYP3A4 and P-glycoprotein, led to an increase in the average equilibrium AUC of rivaroxaban by 2. 5 times and an increase in the average Cmax of rivaroxaban by 1.6 times, which was accompanied by a significant increase in the pharmacodynamic action of the drug. In this regard, Xarelto® is not recommended for use in patients receiving systemic treatment with antifungal drugs of the azole group or HIV protease inhibitors.

Clarithromycin (500 mg 2 times / day), a potent inhibitor of the CYP3A4 isoenzyme and a moderate inhibitor of P-glycoprotein, caused a 1.5-fold increase in AUC and a 1.4-fold increase in Cmax of rivaroxaban. This increase is in the order of normal variability of AUC and Cmax and is considered clinically insignificant.

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

Fluconazole (400 mg 1 time / day), a moderate inhibitor of the CYP3A4 isoenzyme, caused a 1.4-fold increase in the average AUC of rivaroxaban and a 1.3-fold increase in the average Cmax. This increase is in the order of normal variability of AUC and Cmax is considered clinically insignificant.

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

The combined use of Xarelto® and rifampicin, a potent inducer of CYP3A4 and P-glycoprotein, led to a decrease in the average AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects.

Co-administration of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or perforated hypericum preparations) can also lead to a decrease in plasma concentrations of rivaroxaban. A decrease in plasma concentrations of rivaroxaban is considered clinically insignificant.

Strong CYP3A4 inducers must be used with caution.

Overdose

Rare cases of overdose with up to 600 mg of rivaroxaban without bleeding or other adverse reactions have been reported. Due to the limited absorption, the effect of saturation is expected without further increasing the mean plasma rivaroxaban content at hypertensive doses of 50 mg or higher.

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

Storage conditions

The product should be stored out of the reach of children at a temperature not exceeding 30 ° C.

Shelf life

3 years.

Deystvuyushtee substance

Rivaroxaban

Terms and conditions

prescription

Dosage form

tablets

Appointment

Appointment

Adults doctor's prescription



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