Xarelto, 28 pcs., 15 mg, film-coated tablets
Pharmacokinetic interaction
Elimination of rivaroxaban occurs primarily through hepatic metabolism mediated by the cytochrome P450 system (CYP3A4, CYP2J2) and via renal excretion of unchanged drug using the P-gp/BCRP transporter systems.
Rivaroxaban does not suppress or induce the CYP3A4 isoenzyme and other important cytochrome isoforms.
Concomitant use of Xarelto and strong CYP3A4 and P-gp inhibitors may result in decreased renal and hepatic clearance and thus significantly increase systemic exposure.
The combined use of Xarelto® and the azole antifungal agent ketoconazole (at a dose of 400 mg 1 time per day), which is a strong inhibitor of CYP3A4 and P-gp, 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-administration of Xarelto® and the HIV protease inhibitor ritonavir (at a dose of 600 mg 2 times a day), which is a strong inhibitor of CYP3A4 and P-gp, led to an increase in the average steady-state 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 effect of the drug. In this regard, Xarelto® is not recommended for use by patients receiving systemic treatment with azole antifungals or HIV protease inhibitors (see “Contraindications”, subsection WITH CAUTION).
Clarithromycin (at a dose of 500 mg 2 times a day), a strong inhibitor of the CYP3A4 isoenzyme and a moderate inhibitor of P-gp, caused an increase in AUC values by 1.5 times and Cmax of rivaroxaban by 1.4 times. This increase is of the order of normal variability in AUC and Cmax and is considered clinically insignificant.
Erythromycin (at a dose of 500 mg 3 times a day), a moderate inhibitor of the CYP3A4 isoenzyme and P-gp, caused an increase in the AUC and Cmax values of rivaroxaban by 1.3 times. This increase is of the order of normal variability in AUC and Cmax and is considered clinically insignificant.
In patients with renal impairment (creatinine clearance <80–50 mL/min), erythromycin (500 mg three times daily) increased rivaroxaban AUC by 1.8-fold and Cmax by 1.6-fold compared with patients with normal renal function. who did not receive concomitant therapy. In patients with renal insufficiency (Cl creatinine 49–30 ml/min), erythromycin caused an increase in rivaroxaban AUC values by 2 times and Cmax by 1.6 times compared with patients with normal renal function who did not receive concomitant therapy (see “Contraindications” , subsection WITH CAUTION).
Fluconazole (at a dose of 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 of 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 coadministration.
Co-administration of Xarelto® and rifampicin, which is a strong inducer of CYP3A4 and P-gp, led to a decrease in the mean AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects.
Concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's wort) may also result in decreased plasma concentrations of rivaroxaban. The decrease in plasma concentrations of rivaroxaban was considered clinically insignificant. Strong CYP3A4 inducers should be used with caution.
Pharmacodynamic interaction
After simultaneous use of enoxaparin sodium (single dose 40 mg) and Xarelto® (single dose 10 mg), there was a summation of their effects on anti-Factor Xa activity, which was not accompanied by an additional summation effect on blood clotting tests (PT, APTT). Enoxaparin did not change the pharmacokinetics of rivaroxaban (see “Contraindications”, subsection CAUTIONS).
Due to the increased risk of bleeding, caution should be exercised when used together with any other anticoagulants (see "Contraindications", "CAUTIONS" and "Special Instructions").
No pharmacokinetic interaction was found between Xarelto® (at a dose of 15 mg) and clopidogrel (loading dose - 300 mg followed by a maintenance dose of 75 mg), but in a subgroup of patients a significant increase in bleeding time was found, which did not correlate with the degree of platelet aggregation and P content -selectin or GPIIb/IIIa receptor (see “Contraindications”, subsection WITH CAUTION).
After co-administration of Xarelto® (at a dose of 15 mg) and naproxen at a dose of 500 mg, no clinically significant increase in bleeding time was observed. However, a more pronounced pharmacodynamic response is possible in some individuals.
Caution should be exercised when using Xarelto® together with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors, since the use of these drugs usually increases the risk of bleeding.
Switching patients from warfarin (IHO 2 to 3) to Xarelto® (20 mg) or from Xarelto® (20 mg) to warfarin (MHO 2 to 3) increased PT/INR (Neoplastin®) more than expected would be expected by simple summation of the effects (individual MHO values can be as high as 12), whereas the effects on aPTT, factor Xa suppression, and endogenous thrombin potential were additive.
If it is necessary to study the pharmacodynamic effects of Xarelto® during the transition period, anti-Xa activity, PiCT and HepTest® can be used as necessary tests that are not affected by warfarin. Starting from the 4th day after stopping the use of warfarin, all test results (including PT, aPTT, inhibition of factor Xa activity and effects on EPT - endogenous thrombin potential) reflect only the effect of Xarelto® (see "Dosage and Administration" ).
If it is necessary to study the pharmacodynamic effects of warfarin during the transition period, measuring the INR value at Spromezhat can be used. rivaroxaban (24 hours after the previous dose of rivaroxaban), since rivaroxaban has minimal effect on this indicator during this period.
No pharmacokinetic interactions have been reported between warfarin and Xarelto®.
The drug interaction of Xarelto® with VKA phenindione has not been studied. It is recommended, whenever possible, to avoid transferring patients from Xarelto® therapy to VKA phenindione therapy and vice versa.
There is limited experience converting patients from VKA acenocoumarol therapy to Xarelto®.
If there is a need to transfer a patient from Xarelto® therapy to VKA therapy with phenindione or acenocoumarol, special care should be taken; daily monitoring of the pharmacodynamic effects of the drugs (MHO, PT) should be carried out immediately before taking the next dose of Xarelto®.
If there is a need to transfer a patient from VKA therapy with phenindione or acenocoumarol to Xarelto® therapy, special care should be taken; monitoring of the pharmacodynamic effect of the drugs is not required.
Incompatibility. Unknown.
No interaction detected
No pharmacokinetic interactions have been identified between rivaroxaban and midazolam (CYP3A4 substrate), digoxin (P-gp substrate) or atorvastatin (CYP3A4 and P-gp substrate).
Co-administration with the proton pump inhibitor omeprazole, the H2 receptor antagonist ranitidine, the antacid aluminum/magnesium hydroxide, naproxen, clopidogrel or enoxaparin does not affect the bioavailability and pharmacokinetics of rivaroxaban.
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed with the combined use of Xarelto® and acetylsalicylic acid at a dose of 500 mg.
Effect on laboratory parameters. Xarelto® affects blood clotting parameters (PT, APTT, HepTest®) due to its mechanism of action.
Rivaroxaban
After oral administration, rivaroxaban is absorbed quickly and almost completely. Cmax is reached 2-4 hours after taking the tablet. The bioavailability of rivaroxaban when taking 2.5 mg and 10 mg tablets is high (80-100%), regardless of food intake. Food intake does not affect AUC and Cmax when taking the drug at a dose of 10 mg. Riaroxaban tablets in dosages of 2.5 mg and 10 mg can be taken with food or on an empty stomach.
The pharmacokinetics of rivaroxaban is characterized by moderate interindividual variability, the coefficient of variability Cv% ranges from 30% to 40%.
Rivaroxaban has a high degree of binding to plasma proteins - approximately 92-95%, mainly rivaroxaban binds to serum albumin. The drug has an average Vd of approximately 50 liters.
Rivaroxaban is metabolized through isoenzymes CYP3A4, CYP2J2, as well as through mechanisms independent of the cytochrome system. The main sites of biotransformation are the oxidation of the morpholine group and the hydrolysis of amide bonds.
in vitro data
, rivaroxaban is a substrate for the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).
Unchanged rivaroxaban is the only active compound in plasma; no major or active circulating metabolites have been detected in plasma. Rivaroxaban, whose systemic clearance is approximately 10 L/h, can be classified as a drug with low clearance.
When rivaroxaban is eliminated from plasma, the terminal half-life is 5 to 9 hours in young patients and 11 to 13 hours in elderly patients.
Pharmacokinetics in special clinical situations
Age.
In elderly patients over 65 years of age, plasma concentrations of rivaroxaban are higher than in younger patients, with a mean AUC value approximately 1.5 times higher than in younger patients, mainly due to an apparent decrease in total and renal clearance.
Floor.
No clinically significant differences in pharmacokinetics were found in men and women.
Body mass.
Too little or too much body weight (less than 50 kg and more than 120 kg) has only a small effect on the plasma concentration of rivaroxaban (the difference is less than 25%).
Childhood.
Data on pharmacokinetics in children are not available.
Interethnic differences.
Clinically significant differences in pharmacokinetics and pharmacodynamics were not observed in patients of Caucasian, Negroid, Asian, or Hispanic, Japanese or Chinese ethnicity.
Liver dysfunction.
The effect of hepatic impairment on the pharmacokinetics of rivaroxaban was studied in patients classified according to the Child-Pugh classification (according to standard procedures in clinical trials). The Child-Pugh classification allows you to assess the prognosis of chronic liver diseases, mainly cirrhosis. In patients undergoing anticoagulant therapy, a particularly important critical point in liver dysfunction is the decrease in the synthesis of coagulation factors in the liver. Because. This indicator corresponds to only one of the five clinical/biochemical criteria that make up the Child-Pugh classification; the risk of bleeding does not clearly correlate with this classification. The question of treating such patients with anticoagulants should be decided regardless of the Child-Pugh class.
Rivaroxaban is contraindicated in patients with liver disease associated with coagulopathy causing a clinically significant risk of bleeding.
In patients with cirrhosis of the liver with mild liver failure (class A according to the Child-Pugh classification), the pharmacokinetics of rivaroxaban differed only slightly from the corresponding indicators in the control group of healthy volunteers (on average, there was an increase in AUC of rivaroxaban by 1.2 times). There were no significant differences in pharmacodynamic properties between groups.
In patients with cirrhosis and moderate hepatic impairment (Child-Pugh class B), the mean AUC of rivaroxaban was significantly increased (2.3-fold) compared with healthy volunteers due to significantly reduced drug clearance, indicating serious liver disease. The suppression of factor Xa activity was more pronounced (2.6 times) than in healthy volunteers. Prothrombin time was also 2.1 times higher than in healthy volunteers. By measuring prothrombin time, the extrinsic coagulation pathway is assessed, including coagulation factors VII, X, V, II and I, which are synthesized in the liver. Patients with moderate hepatic impairment are more sensitive to rivaroxaban, which is a consequence of a closer relationship between pharmacodynamic effects and pharmacokinetic parameters, especially between concentration and prothrombin time.
There are no data on the use of the drug in patients with class C hepatic impairment according to the Child-Pugh classification. Therefore, in patients with liver cirrhosis and impaired liver function B and C according to the Child-Pugh classification, rivaroxaban is contraindicated.
Renal dysfunction.
In patients with renal failure, an increase in rivaroxaban exposure was observed, inversely proportional to the degree of decrease in renal function, which was assessed by CC.
In patients with renal failure of mild (creatinine clearance 50-80 ml/min), moderate (creatinine clearance 30-49 ml/min) or severe (creatinine clearance 15-29 ml/min) severity, a 1.4-, 1.5- and 1.6-fold increase was observed rivaroxaban plasma concentrations (AUC), respectively, compared with healthy volunteers. The corresponding increase in pharmacodynamic effects was more pronounced.
In patients with mild, moderate and severe renal failure, the overall suppression of factor Xa activity increased by 1.5, 1.9 and 2 times compared with healthy volunteers; prothrombin time due to the action of factor Xa also increased by 1.3, 2.2 and 2.4 times, respectively.
Data on the use of rivaroxaban in patients with CC 15-29 ml/min are limited, and therefore caution should be exercised when using the drug in this category of patients. There are no data on the use of rivaroxaban in patients with creatinine clearance <15 ml/min, and therefore it is not recommended to use the drug in this category of patients.
