Xarelto, 15 mg 98 pcs

Interaction

Pharmacokinetic interactions

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 using the P-gp/Bcrp (P-glycoprotein/milk cancer resistance protein) transporter systems.

Inhibiting CYP

Rivaroxaban does not inhibit CYP 3A4 or any other major CYP isoforms.

Induction of CYP

Rivaroxaban does not induce CYP 3A4 or any other major CYP isoforms.

The effects on rivaroxaban

The concomitant use of rivaroxaban and potent CYP3A4 and P-glycoprotein isoenzyme inhibitors may lead to decreased renal and hepatic clearance of rivaroxaban and thereby significantly increase its systemic effects.

. Co-administration of rivaroxaban and the azole antifungal agent ketoconazole (400 mg once daily), a potent CYP3A4 and P-glycoprotein inhibitor, resulted in a 2.6-fold increase in mean equilibrium AUC of rivaroxaban and a 1.7-fold increase in mean Cmax of rivaroxaban, with a significant increase in pharmacodynamic effects of the drug.

. Co-administration of rivaroxaban and the HIV protease inhibitor ritonavir (600 mg twice daily), a potent CYP3A4 and P-glycoprotein inhibitor, resulted in a 2.5-fold increase in mean equilibrium AUC of rivaroxaban and a 1.6-fold increase in mean Cmax of rivaroxaban, with significant enhancement of the drug pharmacodynamic action. In this regard, rivaroxaban is not recommended for use in patients receiving systemic treatment with antifungal drugs of azole group or HIV protease inhibitors (see sections “Caution”, “Special Precautions”.

Clarithromycin (500 mg 2 times daily), a potent CYP3A4 isoenzyme inhibitor and moderate P-glycoprotein inhibitor, caused a 1.5-fold increase in AUC and 1.4-fold increase in Cmax values 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 to be clinically insignificant.

In patients with mild renal dysfunction (CLKR 50-80 ml/min), erythromycin (500 mg 3 times daily) caused a 1.8-fold increase in rivaroxaban AUC and 1.6-fold increase in Cmax compared with patients with normal renal function who were not receiving concomitant therapy. In patients with moderate renal impairment (CLKR 30-49 ml/min), erythromycin caused a 2.0-fold increase in the AUC of rivaroxaban and 1.6-fold increase in Cmax compared to patients with normal renal function who were not receiving concomitant therapy (see “Caution. Caution section).

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 Xarelto^® and rifampicin, which is a potent 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 potent CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital or preparations of St. John’s wort) may also lead to decreased plasma concentrations of rivaroxaban. Reduced plasma concentrations of rivaroxaban have been found to be clinically insignificant. Powerful CYP3A4 inducers should be used with caution.

Pharmacodynamic interactions

After concomitant use of enoxaparin sodium (single dose of 40 mg) and Xarelto^® (single dose of 10 mg), a summation effect was observed with respect to anti-factor Xa activity, without additional summation effects with respect to clotting tests (prothrombin time, ACTV). Enoxaparin sodium did not alter the pharmacokinetics of rivaroxaban (see section “Caution”).

Due to the increased risk of bleeding, caution should be exercised when co-administered with any other anticoagulants.

No pharmacokinetic interaction has been found between Xarelto^® (15 mg) and clopidogrel (loading dose of 300 mg followed by maintenance dose of 75 mg), but in a subgroup of patients a significant increase of bleeding time was found, which was not correlated with the degree of platelet aggregation and the content of P-selectin or GPIIb/IIIa-receptor (see “Caution”). Cautionary Note).

There was no clinically significant increase in bleeding time after co-administration of Xarelto^® (15 mg) and naproxen at a dose of 500 mg. However, a more pronounced pharmacodynamic response is possible in individuals.

W Caution should be exercised when Xarelto® is coadministered with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors, as use of these drugs generally increases the risk of bleeding. ® (20 mg) or from Xarelto^® (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/ INR (Neoplastin) to a greater extent than would be expected by simply summing the effects (individual INR values as high as 12), whereas the effects on AChTV, suppression of factor Xa activity, and endogenous thrombin potential were additive.

If the pharmacodynamic effects of Xarelto^® need to be investigated during the transition period, anti-Xa activity, PiCT and HepTest determination may be used as necessary tests that are not affected by warfarin. From day 4 after discontinuation of warfarin, all test results (including PV, ACTV, inhibition of factor Xa activity, and on EPT (endogenous thrombin potential)) reflect only the effects of Xarelto.

If the pharmacodynamic effects of warfarin need to be investigated during the transition period, the measurement of INR at Spro- mesto of rivaroxaban (24 hours after the previous administration of rivaroxaban) may be used, since rivaroxaban has minimal effect on this parameter during this period.

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

The drug interaction of Xarelto^® with the vitamin K antagonist (VKA) phenyndione has not been studied. It is recommended to avoid transferring patients from Xarelto^® therapy to AVK therapy with phenyndione and vice versa whenever possible.

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

If it becomes necessary to transfer a patient from Xarelto^® phenindion or acenocoumarol for AVC therapy, special care should be taken and daily monitoring of pharmacodynamic effects (INR, prothrombin time) of Xarelto® and AVC should be performed immediately prior to the next dose of Xarelto®.

If a patient needs to be switched from phenyndione or acenocoumarol AVC therapy to Xarelto^® therapy, special care must be taken and pharmacodynamic monitoring of the drugs is not required.

As with other anticoagulants, caution should be exercised when Xarelto^® is coadministered with selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs), as use of these drugs increases the risk of bleeding. Results of clinical trials have demonstrated a numerical increase in major and minor clinically significant bleeding in all treatment groups when these drugs are used together.

Foods and dairy products

The drug Xarelto^® 15 mg and 20 mg should be taken with meals (see section “Pharmacological properties”).

No interactions have been identified

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

The co-administration with the proton pump inhibitor omeprazole, the H2 receptor antagonist ranitidine, aluminum hydroxide/magnesium hydroxide antacids, naproxen, clopidogrel or enoxaparin has no effect on the bioavailability and pharmacokinetics of rivaroxaban.

No clinically significant pharmacokinetic or pharmacodynamic interactions have been observed when Xarelto^® and 500 mg acetylsalicylic acid are used together.

Impact on laboratory parameters

The drug Xarelto^® affects blood clotting parameters (PV, ACTV, HepTest^®) due to its mechanism of action (see “Pharmacological properties of Xarelto^®. Pharmacological properties/Pharmacodynamic effects) .

Special Instructions

The use of concomitant drugs

The use of rivaroxaban is not recommended in patients receiving concomitant systemic treatment with azole antifungals (e.g., ketoconazole) or HIV protease inhibitors (e.g., ritonavir). These drugs are potent inhibitors of CYP3A4 and P-glycoprotein. Thus, these drugs may increase plasma concentrations of rivaroxaban to clinically significant levels (2.6-fold on average), which may lead to an increased risk of bleeding (see sections Caution, Interaction with other medicinal products).

The azole antifungal drug fluconazole, a moderate CYP3A4 inhibitor, however, has a less pronounced effect on rivaroxaban exposure and can be used simultaneously with it (see section “Interaction with other medicinal products”).

Rivaroxaban should be used with caution in patients with moderate renal function impairment (QLcr 30-49 mL/min) receiving concomitant medications that may increase plasma concentrations of rivaroxaban (see sections. Sections

Cautions with Caution, Interaction with other medicinal products).

In patients with severe renal dysfunction (KlKr < 30 ml/min), plasma concentrations of rivaroxaban may be significantly elevated (1.6-fold on average), which may lead to an increased risk of bleeding. Therefore, due to the presence of the specified underlying disease, such patients have an increased risk of developing both bleeding and thrombosis. Due to limited clinical data, rivaroxaban should be used with caution in patients with a CLR of 15-29 mL/min.

There are no clinical data on the use of rivaroxaban in patients with severe renal impairment (CLKr < 15 ml/min). Therefore, the use of Xarelto^® is not recommended in these patients (see sections “Contraindications”, “Dosage and administration”, “Pharmacological properties”).

Patients with severe renal dysfunction (CLKR 15-29 ml/min), increased risk of bleeding, and patients receiving concomitant systemic treatment with azole antifungal agents or HIV protease inhibitors should be monitored closely for signs of bleeding after treatment initiation.

The risk of bleeding

As with other anticoagulants, patients taking Xarelto^® should be monitored closely for signs of bleeding.

In case of severe bleeding, Xarelto^® should be stopped.

In clinical studies, bleeding from mucous membranes (namely, bleeding from the nose, gums, gastrointestinal tract, genitourinary system, including abnormal vaginal or increased menstrual bleeding) and anemia were observed more frequently with long-term treatment with rivaroxaban compared to AVC treatment. Thus, in addition to appropriate clinical monitoring, a laboratory hemoglobin/hematocrit study may be relevant to detect hidden bleeding and to quantify the clinical significance of overt bleeding that would be deemed tolerable.

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

• patients with a congenital or acquired tendency to bleeding;
• patients with uncontrolled severe arterial hypertension;
Patients with acute peptic ulcer disease;
• Patients who have recently had peptic ulcer disease;
• Patients who have recently had peptic ulcer disease
• Patients with vascular retinopathy;
• Patients who have recently had intracranial or intracerebral hemorrhage;
• Patients with pathology of cerebral vessels or spinal cord;
• Patients who have recently had brain, spinal cord, or eye surgery;
• Patients with a history of bronchiectasis or pulmonary bleeding.

. Precautions should be taken if the patient is concomitantly taking medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet aggregation inhibitors, other antithrombotic drugs, or selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) (see “Interaction with NSAIDs”). Interactions with other medicinal products).

In patients at risk of peptic ulcer disease, appropriate prophylactic treatment may be indicated.

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

Therapy with rivaroxaban does not require routine monitoring of its exposure. However, the measurement of rivaroxaban concentrations using a calibrated test to quantify anti-Xa activity may be useful in exceptional cases where information on rivaroxaban exposure may be used to make clinically meaningful decisions, such as in cases of overdose or emergency surgical intervention.

Patients with artificial heart valves

Based on data from a randomized controlled clinical trial comparing therapy with Xarelto^®

Based on data from a randomized controlled clinical trial comparing Xarelto^{® and antiplatelet therapy, the use of Xarelto® is not recommended for thrombosis prevention in patients who have undergone recent transcatheter aortic valve replacement. The safety and efficacy of Xarelto® have not been studied in patients with any other artificial heart valves or in patients after other cardiac valve interventions, therefore, there is no evidence that Xarelto® can prevent thrombosis.sup>®} 20 mg (15 mg in patients with moderate to severe renal impairment at CLR 15-49 ml/min) provides adequate anticoagulant effect in these patient categories.

Patients at high risk of triple positive antiphospholipid syndrome The use of Xarelto^® is not recommended in patients with a history of thrombosis who have a history of resistant triple positive antiphospholipid syndrome (presence of lupus anticoagulant, antibodies to cardiolipin and antibodies to beta-2-glycoprotein I), since rivaroxaban therapy is associated with an increased rate of recurrent thrombotic events compared to therapy with vitamin K antagonists (VKA).

Patients with non-valvular atrial fibrillation undergoing PCI with stenting

There are data from an international clinical trial whose primary objective was to evaluate safety in patients with non-valvular atrial fibrillation undergoing PCI with stenting. Data on efficacy in this therapy are limited (see section “Dosage and administration”).

Patients with hemodynamically unstable pulmonary embolism (PATE) and patients requiring thrombolysis or thrombectomy

Patients with hemodynamically unstable pulmonary embolism (TPA) and patients requiring thrombolysis or thrombectomy

Rivaroxaban is not recommended. Rivaroxaban is not recommended as an alternative to unfractionated heparin in patients with hemodynamically unstable pulmonary embolism or in patients who may require thrombolysis or thrombectomy, as the safety and efficacy of Xarelto^® in these clinical situations has not been established.

Surgical procedures and interventions

If invasive procedures or surgical interventions are necessary, Xarelto^® should be stopped at least 24 hours before the intervention and on the advice of the physician.

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

The use of Xarelto^® should be restarted after an invasive procedure or surgical intervention, given appropriate clinical indications and adequate hemostasis (see section Pharmacological properties).

Spinal anesthesia

. When performing epidural/spinal anesthesia or spinal tap in 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 a permanent epidural catheter or concomitant therapy with drugs that affect hemostasis. Traumatic epidural or spinal puncture or repeated puncture may also increase the risk.

Patients should be monitored for signs and symptoms of neurologic disorders (e.g., numbness or weakness in the legs, bowel or bladder dysfunction). If neurologic disorders are detected, immediate diagnosis and treatment is necessary.

The physician should weigh the potential benefit against the relative risk before performing a spinal intervention in patients receiving anticoagulants or who are scheduled to receive anticoagulants for thrombosis prevention. There is no clinical experience with rivaroxaban at doses of 15 mg and 20 mg in these situations.

The exact time to achieve a sufficiently low anticoagulant effect in each patient is not known, however.

Based on general pharmacokinetic characteristics, the epidural catheter is inserted after at least twice the elimination half-life, i.e., no earlier than 18 hours after the last Xarelto^® dose for younger patients and no earlier than 26 hours for older patients. Xarelto^® should not be administered earlier than 6 hours after removal of the epidural catheter.

In case of traumatic puncture, administration of Xarelto^® should be delayed for 24 hours.

Skin reactions

In post-marketing observations, cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported. Xarelto^® should be discontinued if a severe skin rash first appears (e.g., if it spreads, intensifies and/or blisters form) or if there are other hypersensitivity symptoms associated with mucosal lesions.

Women of childbearing age

The drug Xarelto^® may only be used in women of childbearing age if effective contraceptive methods are used.

Longening of the corrected QT interval

There has been no effect of Xarelto^® on QT interval duration.

Safety data from preclinical studies

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

Impact on the ability to operate vehicles, machinery

In the background of taking the drug, fainting and dizziness have been observed, which may affect the ability to operate vehicles or other machinery (see section “Adverse effects”). Patients who experience such adverse reactions should not drive or operate vehicles or other mechanisms.

Synopsis

round biconvex, pink-brown, film-coated tablets; engraved by extrusion: on one side – a triangle with the dosage “15”, on the other – the brand name Bayer cross.

Contraindications

• high sensitivity to rivaroxaban or any excipients contained in the tablet;
• clinically significant active bleeding (e.g., intracranial hemorrhage, gastrointestinal bleeding);
• concomitant therapy with any other anticoagulants, such as unfractionated heparin, low-molecular-weight heparins (enoxaparin, dalteparin, etc.), and heparin derivatives (e.g., heparin, etc.).), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, apixaban, dabigatran, etc.), except in cases of transition or transition to heparin.), except when switching from or to rivaroxaban (see “Dosage and Administration”). Dosages)or when using unfractionated heparin in doses necessary to support a central venous or arterial catheter;
• Hepatic disease with coagulopathy that causes clinically significant bleeding risk (see section “Pharmacological properties and medicinal properties”). Pharmacological properties);
• pregnancy and breastfeeding (see Pregnancy and breastfeeding. Pregnancy and Breastfeeding);
• children and adolescents under 18 years of age (effectiveness and safety in patients in this age group has not been established);
• severe renal dysfunction (KlKr < 15 mL/min) (no clinical data on the use of rivaroxaban in this patient population are available);
• congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption (due to the presence of lactose).

WARNING

Precaution should be used:

• .When treating patients with an increased risk of bleeding (including congenital or acquired susceptibility to bleeding, uncontrolled severe arterial hypertension, acute gastric and duodenal ulcer disease, recent gastric and duodenal ulcer disease, vascular retinopathy, bronchiectasis, or history of pulmonary bleeding);
• When treating patients with moderate renal dysfunction (CKR 30-49 mL/min) who are concomitantly receiving drugs that increase plasma concentrations of rivarok-saban (see “Interaction with other drugs”).
• In treatment of patients with severe renal impairment (QRcf 15-29 ml/min) (see Interaction with other medicinal products;
• In treatment of patients with severe renal impairment (QRcf 15-29 ml/min).
• To treat patients with severe renal impairment (CKR 15-29 mL/min) (see Specific Information

).In patients receiving concomitant medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents, other antithrombotic agents or selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SSRIs).Sections “Interaction with other medicinal products”, “Cautions”).

• Patients with severe renal dysfunction (CLR 15-29 ml/min), increased risk of bleeding and patients receiving concomitant systemic treatment with azole antifungals or HIV protease inhibitors should be monitored closely after treatment initiation for timely detection of bleeding complications.

.

Side effects

The safety of Xarelto^® was evaluated in thirteen phase III studies involving 53,103 patients taking Xarelto^®.

The number of patients who participated in the study and took at least 1 dose of rivaroxaban, the total daily dose, and the maximum duration of treatment in the phase III clinical trials with Xarelto® are shown in Table 2 below:

Table 2.