Xarelto tablets 15 mg, 100 pcs. (Rivaroxaban)

Release form

Tablets, film-coated.

Packing

100 pcs.

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, prote penitents 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.

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 maternal organism, 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 to prevent thromboembolic complications, there is a risk of developing 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).

In the detection of neurological disorders, 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.

An 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, no specific danger to humans 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,

croscarmellose sodium,

hypromellose,

lactose monohydrate,

magnesium stearate,

sodium lauryl sulfate.

Shell composition:

dye iron oxide red,

hypromellose 15cP,

macrogol 3350,

titanium dioxide.

Dosage and administration

Inside, regardless of food intake.

In order to prevent VTE in large orthopedic operations, it is recommended to prescribe 1 tablet of 10 mg once a day. Duration of treatment:

- 5 weeks after major surgery on the hip joint

- 2 weeks after major surgery on the knee joint.

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 on the next day with 1 tablet per day, as before.

Side effects of

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 knee or hip prosthetics), which continued on to the hip joint) 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 can be manifested by weakness, pallor, dizziness, headache, shortness of breath, as well as an increase in the limb in volume or shock, unexplained 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 that were identified only during the post-marketing observational studies or for which it was not possible to estimate the frequency are indicated 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 concomitant increase in 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.

In other clinical studies of rivaroxaban, isolated cases of hemorrhage in the adrenal glands and conjunctiva have been described, and also bleeding from a gastrointestinal ulcer with fatal outcome in rare cases, jaundice and hypersensitivity have been infrequent - hemoptysis. Single intracranial bleeding is described (especially in patients with arterial hypertension and / or taking concomitant drugs that affect hemostasis / for example, NSAIDs, antiplatelet agents, or other antithrombotic agents /), 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. In addition, 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 interactions

Pharmacokinetic interactions

Rivaroxaban is excreted primarily through hepatic metabolism mediated by the cytochrome P450 system (CYP3A4, CYP2J2), and also by renal excretion of an unchanged drug substance using P-gp / Bcrp (P-glycoprotein / breast cancer resistance protein) systems.

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

The simultaneous use of Xarelto® and powerful 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 ketoconazole (400 mg once daily), a potent inhibitor of CYP3A4 and P-glycoprotein, led to a 2.6-fold increase in the average equilibrium AUC of rivaroxaban by a factor of 2.6 and a 1.7-fold increase in the average Cmax of rivaroxaban by 1.7 times , which was accompanied by a significant increase in the pharmacodynamic action of the drug.

Co-administration of Xarelto® and the HIV protease inhibitor ritonavir (600 mg 2 times a day), a potent inhibitor of CYP3A4 and P-glycoprotein, led to a 2.5-fold increase in the average equilibrium AUC of rivaroxaban and a 1.6-fold increase in the average Сmax of rivaroxaban 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 (see section "With caution").

Clarithromycin (500 mg 2 times a 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 a day), a moderate inhibitor of the CYP3A4 isoenzyme 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 once daily), 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 and is considered clinically insignificant.

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. The combined use of rivaroxaban with other strong CYP3A4 inducers (for example, 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 in blood plasma is recognized as clinically insignificant. Strong CYP3A4 inducers must be used with caution.

Pharmacodynamic interactions

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

No pharmacokinetic interaction between Xarelto® (15 mg) and clopidogrel (loading dose of 300 mg followed by a maintenance dose of 75 mg) was found, but a significant increase in bleeding time was found in the patient subgroup, which did not correlate with the degree of platelet aggregation and the content of P-selectin or GPIIb / IIIa receptor (see "Caution").

After the combined use of Xarelto® (15 mg) and naproxen at a dose of 500 mg, a clinically significant increase in bleeding time was not observed. However, in individuals, a more pronounced pharmacodynamic response is possible.

Switching patients from warfarin (INR from 2.0 to 3.0) to Xarelto® (20 mg) increased prothrombin time / INR (Neoplastin) more than would be expected with a simple summation of effects (individual INR values ​​may reach 12), while the effect on APTT, the suppression of factor Xa activity and the endogenous potential of thrombin were additive.

If you need to study the pharmacodynamic effects of Xarelto® during the transition period, you can use the definition of anti-Xa, PiCT and HepTest® activity as necessary tests that are not affected by warfarin. Starting from the 4th day after stopping the use of warfarin, all test results (including PV, APTT, inhibition of factor Xa activity and EPT (endogenous thrombin potential)) reflect only the effect of Xarelto® (see section Dosage and administration).

No pharmacokinetic interactions have been reported between warfarin and Xarelto®.

Incompatibility

Unknown.

Effect on laboratory parameters

Xarelto® has an effect on blood coagulation (PV, APTT, HepTest®) due to its mechanism of action.

Overdose

Symptoms: Rivaroxaban overdose can lead to hemorrhagic complications due to the pharmacodynamic properties of the drug. The specific antidote for rivaroxaban is unknown.

Treatments: Activated charcoal can be used in case of overdose to reduce the absorption of rivaroxaban. Activation of activated charcoal within 8 hours after overdose reduces the absorption of rivaroxaban.

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

dosage form

tablets

Appointment

Appointment

Adults doctor's prescription



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