Xarelto pills 15mg, 28pcs

Composition

of 1 tab. contains rivaroxaban micronized 15 mg.

Auxiliary substances:

microcrystalline cellulose – 37.5 mg,

croscarmellose sodium-3 mg,

hypromellose 5cP-3 mg,

lactose monohydrate-25.4 mg,

magnesium stearate-600 mcg,

sodium lauryl sulfate-500 mcg.

Shell composition:

iron oxide red dye – 150 mcg,

hypromellose 15cP-1.5 mg,

macrogol 3350-500 mcg,

titanium dioxide-350 mcg.

Pharmacological action

Xarelto is a direct-acting anticoagulant. 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. 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. 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 undergoing major orthopedic surgery, the 5/95 percentiles for prothrombin time (Neoplastin) 2-4 hours after taking the pill (i. e. at the maximum effect) vary from 13 to 25 seconds. Rivaroxaban also dose-dependently increases APTT and HepTest score; however, these parameters are not recommended for evaluating the pharmacodynamic effects of rivaroxaban. Rivaroxaban also affects the activity of anti-Xa factor, but there are no standards for calibration. Monitoring of blood clotting parameters is not required during treatment with rivaroxaban. In healthy men and women over 50 years of age, QT prolongation was not observed under the influence of rivaroxaban.

Indications

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

Contraindications

• clinically significant active bleeding (e. g., intracranial bleeding, gastrointestinal bleeding);
• diseases of the liver, occurring with coagulopathy, which causes a clinically significant risk of bleeding;
• pregnancy;
• lactation (breastfeeding);
• childhood and adolescence to 18 years (efficacy and safety for patients in this age group have not been established);
• increased sensitivity to rivaroxaban or any of the auxiliary substances contained in the pill.

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

Hereditary lactose or galactose intolerance (for example, caused by lactase deficiency or glucose-galactose malabsorption), since the composition of this drug includes lactose.

Side effects

The safety of rivaroxaban 10 mg was evaluated in four phase III trials involving 6,097 patients who underwent major orthopedic surgery on the lower extremities (total knee or hip replacement) and received treatment lasting up to 39 days.

Adverse reactions are classified by frequency and organ systems, and should be interpreted according to the surgical situation.

Given the mechanism of action, the use of rivaroxaban may be associated with an increased risk of hidden or obvious bleeding from any organs and tissues, which can lead to post-hemorrhagic anemia. Signs, symptoms, and severity (including possible death) vary depending on the location, severity, or duration of bleeding and/or anemia. The risk of bleeding may increase in patients with uncontrolled arterial hypertension and / or when co-administered 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 volume or shock, for unexplained other reasons. In some cases, anemia can lead to symptoms of myocardial ischemia, such as chest pain and angina pectoris. Therefore, when assessing the condition of a patient receiving anticoagulants, the possibility of hemorrhage should be considered.

Summary data on the frequency of adverse reactions reported for Xarelto® are given in the table below. In frequency groups, undesirable 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 < 1/10 000) were identified. Adverse reactions that were identified only at the stage of post-marketing observational studies or for which it was impossible to make an estimate of the frequency are designated as “frequency unknown”.

All adverse reactions that occurred during treatment in patients participating in phase III clinical trials are listed below.

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

From the cardiovascular system: infrequently-tachycardia, hypotension (including a decrease in blood pressure, hypotension during procedures), hematoma (including rare cases of muscle hemorrhages), bleeding from the gastrointestinal tract (including bleeding from the gums, rectum, bloody vomiting), hemorrhage from the genitourinary tract, nosebleeds.

From the digestive system: often – nausea, increased levels of GGT, transaminases (including ALT, ACT); infrequently – constipation, diarrhea, abdominal pain (including upper abdominal pain, stomach discomfort), dyspepsia (including epigastric discomfort), dry mouth, vomiting, increased activity of lipase, amylase, increased bilirubin concentration, increased LDH, alkaline phosphatase activity; rarely – liver function disorders, increased concentration of LDH, alkaline phosphatase. conjugated bilirubin (with or without a concomitant increase in ALT activity).

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

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

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

From the musculoskeletal system: infrequently – pain in the extremities.

From 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 the procedures performed (including postoperative anemia and bleeding from the wound); infrequently-discharge from the wound.

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

According to other clinical studies, the occurrence of vascular pseudoaneurysms after percutaneous interventions is reported.

Other clinical studies and post-marketing observational studies have reported known bleeding complications, such as compartment syndrome. In addition, the development of acute renal failure and renal failure was reported, which were the result of bleeding, the intensity of which was sufficient to cause hypoperfusion.

Interaction

Pharmacokinetic interaction

Elimination of rivaroxaban is mainly carried out through 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 the azole antifungal agent 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 antifungal drugs of the azole group 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.

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 potent CYP3A4 inducers (e. g., phenytoin, carbamazepine, phenobarbital, or St. John’s wort) may also result in a decrease in rivaroxaban plasma concentrations. A decrease in rivaroxaban plasma concentrations was found to be clinically insignificant.

Strong inducers of CYP3A4 should be used with caution.

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 saturation effect is expected without further increasing the average rivaroxaban plasma content at hypertherapeutic doses of 50 mg or higher.

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.

Special instructions

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

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

No prolongation 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 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 concomitant use of medications that affect hemostasis. An injury during an epidural or spinal tap or repeated puncture may also contribute to an increased risk.

Patients should be monitored for signs or 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 benefits and risks before performing spinal surgery 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 is administered. Rivaroxaban should not be administered earlier than 6 hours after removal of the epidural catheter. In case of a traumatic puncture, the appointment 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), 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

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

Fainting and dizziness were infrequently reported in the postoperative period. Patients who experience these adverse reactions should not drive vehicles or work with moving machinery.

Storage conditions

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

Shelf life

3 years

Active ingredient

Rivaroxaban

Conditions of release from pharmacies

By prescription

Dosage form

Tablets