Xarelto, 10 mg 30 pcs

Rivaroxaban is a highly selective direct factor Xa inhibitor with high bioavailability when administered orally. Activation of factor X with the formation of factor Xa through the internal and external clotting pathways plays a central role in the coagulation cascade. Factor Xa is a component of the forming prothrombinase complex, the action of which leads to the conversion of prothrombin to thrombin. As a result, these reactions lead to the formation of fibrin thrombus and platelet activation by thrombin. One molecule of factor 2 Xa catalyzes the formation of more than 1,000 molecules of thrombin, which has been called the “thrombin burst”.

Indications

Active ingredient

Composition

How to take, the dosage

For the prevention of VTE in major orthopedic surgeries

Preventive therapy is indicated for oral administration of 10 mg once daily. The duration of treatment is determined by the type of orthopedic intervention.

The duration of treatment: 5 weeks after major hip surgery; 2 weeks after major knee surgery.

Rivaroxaban can be taken regardless of meals.

The initial dose should be taken 6-10 h after surgery if hemostasis is achieved.

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

Transfer patients from vitamin K antagonists (VKAs) to Xarelto

If MHO ≤ 3, AVK treatment should be discontinued and Xarelto should be started. When transferring patients from AVC to Xarelto, MHO values will falsely increase after taking Xarelto. Therefore, MHO values should not be used to monitor the anticoagulant effect of Xarelto.

Transition from Xarelto to vitamin K antagonists (VKAs)

There is a possibility of insufficient anticoagulant effect when patients are transferred from Xarelto to VKAs. During the transition period associated with transfer to another anticoagulant drug, it is necessary to ensure a continuous and sufficient anticoagulant effect. Keep in mind that Xarelto may contribute to an increase in MHO.

When converting a patient from Xarelto to AVC, both drugs should be given simultaneously until MHO reaches a value ≥ 2. The standard dose of AVC should be used for the first two days of the transition period, and the MHO value should guide thereafter. During coadministration of Xarelto and AVC, MHO should be determined no earlier than 24 h (after the previous but before the next dose of Xarelto). After withdrawal of Xarelto, MHO determination with sufficient reliability is possible 24 h after the last dose of the drug.

Transition from parenteral anticoagulants to Xarelto

. When transferring a patient from parenteral anticoagulants to Xarelto, Xarelto should be started 0-2 h before the intended administration of the next dose of parenteral drug (e.g. low molecular weight heparin) or during withdrawal of the long-term used parenteral drug (e.g. intravenous infusion of unfractionated heparin).

Transition from Xarelto to parenteral anticoagulants

The first dose of Xarelto should be stopped and the first dose of parenteral anticoagulant administered at the time the next dose of Xarelto should be taken.

The use in selected groups of patients

There is no need to adjust the dose according to the patient’s age (older than 65 years), sex, body weight or ethnicity.

In liver disease

Rivaroxaban is contraindicated in patients with liver disease accompanied by coagulopathy, which causes a clinically significant risk of bleeding. Patients with other liver diseases do not require dose changes. The 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. No clinical data are available for patients with severe hepatic impairment (Child-Pugh class C).

In the administration of rivaroxaban to patients with mild (CKR 80-50 ml/min) or moderate (CKR < 50-30 ml/min) renal impairment, no dose reduction is required.

In renal disease

Limited clinical data available in patients with severe renal impairment (CK < 30-15 ml/min) show a significant increase in rivaroxaban concentrations in these patients. Rivaroxaban should be used with caution to treat this category of patients.

The use of rivaroxaban is not recommended in patients with CK < 15 ml/min.

Interaction

Pharmacokinetic interaction

Excretion of rivaroxaban is primarily by metabolism in the liver mediated by the cytochrome P450 system (CYP3A4, CYP2J2) and also by renal excretion of unchanged drug substance using the P-gp/Bcrp (P-glycoprotein/milk cancer resistance protein) carrier systems.

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

The concomitant use of rivaroxaban and strong CYP3A4 and P-glycoprotein isoenzyme inhibitors may lead to decreased renal and hepatic clearance and thus significantly increase systemic exposure.

The co-administration of rivaroxaban and the azole antifungal agent ketoconazole (400 mg once daily), which is a strong inhibitor of CYP3A4 and P-glycoprotein, resulted in a 2.6-fold and increased the mean Cmax of rivaroxaban by 1.7-fold, which was accompanied by a significant increase in the pharmacodynamic action of the drug.

The co-administration of rivaroxaban and the HIV protease inhibitor ritonavir (600 mg 2 times/day), which is a strong CYP3A4 and P-glycoprotein inhibitor, resulted in a 2.5-fold and increased the mean Cmax of rivaroxaban by 1.6-fold, which was accompanied by a significant increase in the pharmacodynamic action of the drug. Therefore, rivaroxaban is not recommended for use in patients receiving systemic treatment with antifungal drugs of azole group or HIV protease inhibitors.

It is expected that other drugs that strongly inhibit only one of the excretion pathways of rivaroxaban – involving CYP3A4 CYP3A4 or P-glycoprotein – will increase the plasma concentration of rivaroxaban to less significant values.

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

Eritromycin (500 mg 3 times daily), 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 of the order of the normal variability of AUC and Cmax and is considered clinically insignificant.

In patients with renal impairment (CK ≤ 80-50 mL/min), erythromycin (500 mg 3 times/day) caused a 1.8-fold increase in AUC values of rivaroxaban and a 1.6-fold increase in Cmax compared with patients with normal renal function who were not receiving concomitant therapy. In patients with renal impairment (CKR 50-30 ml/min), erythromycin caused a 2.0-fold increase in AUC values of rivaroxaban and a 1.6-fold increase in Cmax compared to patients with normal renal function who were not receiving concomitant therapy.

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

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

The co-administration of rivaroxaban and rifampicin, which is a strong inducer of CYP3A4 and P-glycoprotein, resulted in a reduction of the mean AUC of rivaroxaban by approximately 50% and a concomitant reduction of its pharmacodynamic effects. Co-administration of rivaroxaban with other strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, or preparations of St. John’s wort) may also lead to decreased plasma concentrations of rivaroxaban. Decreased plasma concentrations of rivaroxaban have been found to be clinically insignificant.

Pharmacodynamic interaction

After concomitant administration of enoxaparin sodium (single dose of 40 mg) and rivaroxaban (single dose of 10 mg) there was a total effect on anti-Factor Xa activity with no additional total effects on clotting tests (prothrombin time, ACTV). Enoxaparin did not alter the pharmacokinetics of rivaroxaban.

There was no clinically significant prolongation of bleeding time after co-administration of rivaroxaban at a dose of 15 mg and naproxen at a dose of 500 mg. However, a more pronounced pharmacodynamic response is possible in individuals.

No pharmacokinetic interaction was found between rivaroxaban at a dose of 15 mg and clopidogrel (a shock dose of 300 mg followed by a maintenance dose of 75 mg), but a significant increase in bleeding time was found in some patients that was not correlated with platelet aggregation rate and P-selectin or GPIIb/IIIa-receptor content.

. Conversion of patients from warfarin (MHO 2 to 3) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (MHO 2 to 3) was accompanied by more than additive increases in prothrombin time/MNO (Neoplastin) (up to 12 in some cases), whereas the effects of changes in ACTV, suppression of factor Xa activity, and endogenous thrombin potential (EPT) were additive.

To assess the transient pharmacodynamic effects of Xarelto®, anti-Xa factor, PiCT, and HepTest® analysis may be performed if the parameters determined in their course were not affected by warfarin.

From day 4 after warfarin withdrawal, all assays (including PV, ACTV, suppression of factor Xa activity, and on EPT (endogenous thrombin potential)) exclusively reflected the effect of Xarelto®.

To assess the pharmacodynamic effects of warfarin during the transition period, MHO measured at the time of reaching Cmax of rivaroxaban (24 h after the dose of rivaroxaban) can be used, because at this time, the effect of rivaroxaban on the assay results is minimal.

Pharmacokinetic interaction between warfarin and rivaroxaban was not found.

The drug interaction of Xarelto® with phenyndione AVC has not been studied. It is recommended to avoid transferring patients from Xarelto® therapy to AVC therapy with phenyndione and vice versa whenever possible.

There is limited experience with transferring patients from AVC therapy with acenocoumarol to Xarelto®.

If it becomes necessary to transfer a patient from Xarelto® therapy to AVC therapy with phenindion or acenocoumarol, special care should be taken and daily monitoring of pharmacodynamic effects of the drugs (MHO, prothrombin time) should be performed immediately before the next dose of Xarelto®. If it is necessary to switch a patient from AVC therapy with phenindion or acenocoumarol to therapy with Xarelto®, special caution should be exercised, control of pharmacodynamic actions of the drugs is not required.

Compatible use with other drugs

No clinically significant pharmacokinetic or pharmacodynamic interactions have been noted with concomitant use of rivaroxaban with midazolam (CYP3A4 substrate), digoxin (P-glycoprotein substrate) or atorvastatin (CYP3A4 and P-glycoprotein substrate).

There have been no clinically significant interactions with food.

Incompatibilities

It is unknown.

Impact on laboratory parameters

The effect on coagulation parameters (PV, ACTV, HepTest®) is as expected considering the mechanism of action of Xarelto®.

Directions for use

Special Instructions

Antithrombotic drugs, including rivaroxaban, should be used with caution in the treatment of patients at increased risk of bleeding.

In patients with severe renal impairment (CK < 30 ml/min), plasma concentrations of rivaroxaban may be significantly elevated, which may lead to an increased risk of bleeding. Because of the underlying disease, these patients are at increased risk of both bleeding and thrombosis.

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

If there is an unexplained decrease in hemoglobin or BP, look for the source of bleeding.

There has been no observed prolongation of the QT interval during treatment with rivaroxaban.

When performing spinal tap and epidural/spinal anesthesia for patients receiving platelet aggregation inhibitors to prevent thromboembolic complications, there is a risk of epidural or spinal hematoma, which may lead to prolonged paralysis. The risk of these events is further increased by the use of permanent catheters or concomitant use of medications that affect hemostasis.

Injury while performing an epidural or spinal tap or repeated puncture may also contribute to the increased risk. Patients should be monitored for signs or symptoms of neurological abnormalities (e.g., numbness or weakness in the legs, bowel or bladder dysfunction).

If neurological disorders are detected, immediate diagnosis and treatment is necessary. The physician should weigh the potential benefit and risk before performing a spinal intervention in patients receiving anticoagulants or preparing to receive anticoagulants to prevent thrombosis. The epidural catheter should not be removed before 18 h after the last dose of rivaroxaban. Rivaroxaban should not be administered earlier than 6 h after removal of the epidural catheter. In case of traumatic puncture the administration of rivaroxaban should be postponed for 24 h.

If an invasive procedure or surgery is necessary, Xarelto should be discontinued at least 24 h before the intervention and on the basis of a physician’s report.

If the procedure cannot be postponed, the increased risk of bleeding should be evaluated against the need for an emergency intervention.

The administration of Xarelto should be resumed after an invasive procedure or surgery, provided appropriate clinical signs and adequate hemostasis are present.

The use in liver disorders

Rivaroxaban is contraindicated in patients with liver disease accompanied by coagulopathy, which causes a clinically significant risk of bleeding. Patients with other liver diseases do not require dose changes.

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. No clinical data are available for patients with severe hepatic impairment (Child-Pugh class C).

The use in renal dysfunction

There is no need to reduce the dose when prescribing rivaroxaban in patients with mild (IQ 80-50 ml/min) or moderate (IQ < 50-30 ml/min) renal impairment.

Limited clinical data available in patients with severe renal impairment (KC < 30-15 ml/min) show a significant increase in rivaroxaban concentrations in these patients. Rivaroxaban should be used with caution to treat this category of patients.

The use of rivaroxaban is not recommended in patients with CK < 15 ml/min.

Safety data from preclinical studies

With the exception of effects associated with enhanced pharmacologic action (bleeding), no specific hazards to humans were found in the analysis of preclinical data from pharmacologic safety studies.

Influence on driving and operating machinery

There have been no studies of the effect of rivaroxaban on the ability to drive or operate potentially dangerous moving machinery.

In the postoperative period, fainting and dizziness have been infrequently reported. Patients who experience these adverse reactions should not drive motor vehicles or operate moving machinery.

Synopsis

Contraindications

Side effects

The safety of Xarelto® has been evaluated in four phase III studies involving 6097 patients who underwent major orthopedic lower extremity surgery (total knee or hip replacement) and 3997 patients hospitalized for medical reasons, treated with Xarelto® 10 mg for up to 39 days and in three phase III studies of venous thromboembolism including 4566 patients receiving Xarelto® either 15 mg 2 times daily for 3 weeks followed by a dose of 20 mg once daily, or 20 mg once daily with a treatment duration up to 21 months.

In addition, two phase III studies involving 7,750 patients provided safety data on the drug in patients with non-valvular atrial fibrillation who received at least one dose of Xarelto® for up to 41 months and 10,225 patients with ACS who received at least one dose of 25 mg (2 times/day) or 5 mg (2 times/day) of Xarelto® in addition to therapy with acetylsalicylic acid or acetylsalicylic acid with clopidogrel or ticlopidine, for up to 31 months.

Because of the mechanism of action, use of Xarelto® may be accompanied by an increased risk of occult or overt bleeding from any organs and tissues, which may lead to post-hemorrhagic anemia. The risk of bleeding may increase in patients with uncontrolled arterial hypertension and/or when co-administered with drugs that affect hemostasis.

The signs, symptoms and severity (including possible death) vary depending on the location, intensity or duration of bleeding and/or anemia.

Hemorrhagic complications may manifest as weakness, pallor, dizziness, headache, shortness of breath, and limb enlargement or shock that cannot be explained by other causes. In some cases, symptoms of myocardial ischemia, such as chest pain and angina, have developed due to anemia.

Known complications secondary to severe bleeding, such as interfacial space syndrome and renal failure, have been reported while taking Xarelto®. Therefore, the possibility of bleeding should be considered when evaluating a patient receiving anticoagulants.

The frequency of adverse reactions reported for Xarelto® is summarized below. In groups divided by frequency, adverse effects are presented in decreasing order of severity as follows: very common (≥1/10); common (≥1/100 and < 1/10); infrequent (≥1/1000 and < 1/100); rare (≥1/10,000 and < 1/1000).

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

Hematopoietic system: frequently – anemia (including appropriate laboratory parameters); infrequently – thrombocythemia (including increased platelet count)*.

Cardiovascular system: frequently – significant decrease of BP, hematoma; infrequently – tachycardia.

An organ of vision: often – ocular hemorrhage (including conjunctival hemorrhage).

Gastrointestinal system: frequently – bleeding gums, gastrointestinal bleeding (including rectal bleeding), gastrointestinal pain, dyspepsia, nausea, constipation*, diarrhea, vomiting*; infrequently – dry mouth.

Hepatic disorders: infrequent – liver function abnormalities; rarely – jaundice.

Laborary parameters: frequently – increased liver transaminase activity; infrequent – increased bilirubin concentration, increased ALT activity*, increased LDH activity*, increased lipase activity*, increased amylase activity*, increased GGT activity*; rarely – increased concentration of conjugated bilirubin (with or without accompanying increase in ALT activity).

Nervous system disorders: frequently – dizziness, headache; infrequent – intracerebral and intracranial hemorrhage, transient fainting.

Urogenital system disorders: often – bleeding from the urogenital tract (including hematuria and menorrhagia**), renal failure (including increased concentration of creatinine, increased concentration of urea)*.

Respiratory system disorders: often – nasal bleeding, hemoptysis.

Skin and subcutaneous tissue disorders: frequently – itching (including infrequent cases of generalized itching), rash, ecchymoses, cutaneous and subcutaneous hemorrhages; infrequently – urticaria.

Immune system disorders: infrequent allergic reactions, allergic dermatitis.

Muscular system: often – pain in the extremities *; infrequent – hemarthrosis; rarely – bleeding into the muscles.

As to the body in general: often – fever*, peripheral edema, worsening of overall muscle strength and tone (including weakness, asthenia); infrequently – worsening of general well-being (including malaise); rarely – local edema*.

Others: frequent – hemorrhage after procedures (including postoperative anemia and wound bleeding), excessive hematoma at contusion; infrequent – discharge from the wound*; rare – vascular pseudoaneurysm***.

* – have been reported after major orthopedic surgery.

** -reported in VTE treatment as very frequent in women < 55 years of age.

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

In post-registration monitoring, the following adverse reactions have been reported that were temporally associated with the use of Xarelto®. It is not possible to estimate the incidence of these adverse reactions in post-registration monitoring.

Immune system disorders: angioedema, allergic edema. In RCT phase III such adverse effects were considered infrequent (>1/1000 to <1/100).

Hepatic disorders: cholestasis, hepatitis (including hepatocellular damage). In a phase III RCT, such adverse effects were considered rare (>1/10,000 to <1/1000).

Hematopoietic system: thrombocytopenia. In a phase III RCT, such adverse effects were considered infrequent (>1/1000 to < 1/100).

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

Relinary system disorders: frequency unknown – renal failure/acute renal failure due to bleeding leading to renal hypoperfusion.

Overdose

Rare cases of overdose up to 600 mg have been reported without complications in the form of bleeding or other adverse reactions. Due to limited absorption, saturation effects are expected without further increase in mean plasma levels of rivaroxaban at hypertherapeutic doses of 50 mg or higher.

The specific antidote for rivaroxaban is unknown. In case of overdose, activated charcoal may be used to reduce absorption of rivaroxaban. Given the intense binding to plasma proteins, rivaroxaban is not expected to be excreted by dialysis.

The treatment of bleeding

In the event of a bleeding complication, the next administration of the drug should be delayed or treatment should be withdrawn, as appropriate. The half-life of rivaroxaban is approximately 5-13 hours. Treatment should be selected individually according to the severity and localization of bleeding.

. If necessary, appropriate symptomatic treatment such as mechanical compression (e.g., in cases of severe nasal bleeding), surgical hemostasis with bleeding control procedures, fluid replacement and hemodynamic support, blood products (red blood cell mass or fresh frozen plasma, depending on concomitant anemia or coagulopathy) or platelets may be used.

If the above measures do not eliminate bleeding, a specific procoagulant such as prothrombin complex concentrate, activated prothrombin complex concentrate or recombinant factor VIIa (rf VIIa) may be prescribed. However, to date, experience with the use of these drugs in the treatment of patients receiving rivaroxaban is very limited.

Protamine sulfate and vitamin K are not expected to affect the anticoagulation activity of rivaroxaban. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in patients receiving 20 Xarelto®. There is no scientific rationale or experience with the systemic hemostatic drug desmopressin in patients receiving Xarelto®.

Pregnancy use

It is contraindicated in children under 18 years of age, pregnant and during lactation.

Pregnancy

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

The data obtained in experimental animals showed marked maternal toxicity of rivaroxaban associated with the pharmacological action of the drug (e.g., complications in the form of hemorrhage) and leading to reproductive toxicity.

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

Women with preserved fertility should use effective contraception during treatment with rivaroxaban.

Lactation

There are no data on the use of rivaroxaban for the treatment of women during lactation.

The data obtained in experimental animals show that rivaroxaban is excreted with breast milk. Rivaroxaban can be used only after withdrawal of breastfeeding.