Pharmacological properties Xarelto 10 mg:
Pharmacodynamics. Xarelto – a highly selective inhibitor of the direct factor Xa, which has a sufficient bioavailability when taken orally.
Activation of factor X to form factor Xa via its own path and the outer has a central role in the coagulation cascade.
Pharmacodynamic effects. Rivaroxaban has a dose-dependent effect on prothrombin time and closely correlated with the concentrations in plasma (r = 0,98), when used for analysis set Neoplastin. With other reagents the results will vary. Readings should be removed in seconds, as the INR (international normalized ratio) has been calibrated and provalidirovano for coumarins and can not be applied to other anticoagulants. Patients who conducted extensive orthopedic interventions 5/95-protsentiley for prothrombin (Neoplastin) 2-4 hours after taking the pill (that is, while the maximum effect) ranging from 13 to 25.
Rivaroxaban also dose-dependently increases the activated partial thromboplastin time (aPTT) and the result Heptest, but these options are not recommended for assessing pharmacodynamic effects of rivaroxaban. Rivaroxaban affect the activity of antifactor Xa, although there are no standards for calibration.
During treatment rivaroksabanom to monitor coagulation parameters is not necessary.
Clinical efficacy and safety
Prevention of venous thromboembolic events in patients who have conducted extensive orthopedic interventions on the lower extremities.
The clinical program is designed to demonstrate the efficacy of rivaroxaban, used for the prevention of venous thromboembolism (VTE), ie, proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have conducted extensive orthopedic surgery of the lower extremities. As part of the RECORD, including controlled randomized double-blind clinical trial phase 3, was studied over 9500 patients (7050 patients who underwent total hip arthroplasty, and 2531 patients who underwent total knee replacement).
Were compared rivaroxaban 10 mg once a day in which patients began to receive not less than 6 hours after surgery with enoxaparin 40 mg once a day, which started treatment within 12 hours before surgery.
In all three studies, third phase (see table) rivaroxaban significantly reduced the incidence of VTE extensive total score (all venograficheski detected or symptomatic cases of DVT, non-fatal pulmonary embolism) and common VTE (proximal DVT, non-fatal pulmonary embolism associated with VTE), which were given primary and major secondary efficacy endpoints. Moreover, in all three trials, the rates of symptomatic VTE (DVT, non-fatal pulmonary embolism associated with VTE) in the treatment group rivaroksabanom was lower than in the enoxaparin treatment group.
The frequency of heavy bleeding, which is the main safety endpoint was comparable among patients who received rivaroxaban 10 mg and enoxaparin 40 mg.
Table
The results of the efficacy and safety
in clinical trials, phase 3
| Treatment, dosage, duration | rivaroxaban | enoxaparin | р |
| protocol1 | |||
| The study population | 4541 patient — total hip arthroplasty | ||
| all VTE | 18 (1,1%) | 58 (3,7%) | <0,001 |
| The frequency of major VTE | 4 (0,2%) | 33 (2%) | <0,001 |
| symptomatic VTE | 6 (0,4%) | 11 (0,7%) | |
| large hemorrhage | 6 (0,3%) | 2 (0,1%) | |
| protocol 2 | |||
| The study population | 2509 patients — total hip arthroplasty | ||
| all VTE | 17 (2%) | 81 (9,3%) | <0,001 |
| The frequency of major VTE | 6 (0,6%) | 49 (5,1%) | <0,001 |
| symptomatic VTE | 3 (0,4%) | 15 (1,7%) | |
| large hemorrhage | 1 (0,1%) | 1 (0,1%) | |
| protocol 3 | |||
| The study population | 2531 patient — total knee replacement | ||
| all VTE | 79 (9,6%) | 166 (18,9%) | <0,001 |
| The frequency of major VTE | 9 (1%) | 24 (2,6%) | 0,01 |
| symptomatic VTE | 8 (1%) | 24 (2,6%) | |
| large hemorrhage | 7 (0,6%) | 6 (0,5%) | |
The analysis combined the results of research third phase confirmed the receipt of individual research data that showed a greater reduction in the incidence of VTE, major VTE and symptomatic VTE in the treatment group rivaroksabanom 10 mg 1 time per day, compared with enoxaparin treatment of 40 mg 1 time day.
Pharmacokinetics. Absorption and bioavailability. The absolute bioavailability of rivaroxaban after administration of high doses of 10 mg and is 80-100%.
Rivaroxaban is rapidly absorbed and the maximum concentration is reached 2-4 hours after taking the pill.
Pill rivaroxaban 10 mg during a meal does not affect the AUC and Cmax of rivaroxaban. Rivaroxaban 10 mg can be taken irrespective of food intake.
The pharmacokinetics of rivaroxaban is characterized by moderate variability, individual variability (coefficient of variation) of 30-40%, excluding the day of and day after surgery, when volatility is high (70%).
Distribution. In humans, most of rivaroxaban (92-95%) associated with plasma proteins, the major binding component is serum albumin. Average volume of distribution is approximately 50 liters.
Metabolism and excretion from the body. Rivaroxaban appears mainly in the form of metabolites (about ⅔ the dose), and half of them are excreted by the kidneys and the other half – in the feces. Third the dose undergoes direct renal excretion in the urine as unchanged active substance, it is estimated mainly by active renal secretion.
Rivaroxaban exercise metabolism isoenzymes CYP 3A4, CYP 2J2, as well as enzymes that are independent of cytochrome P450. The main participant in the biotransformation is a morpholino group, exposed to oxidative degradation, and amide groups are exposed to hydrolysis.
According to the in vitro data, rivaroxaban is a substrate for protein – transporter P-gp (P-glycoprotein) and BCR-P (protein resistance to breast cancer).
Unchanged rivaroxaban is the most important compound in human plasma, the active circulating metabolites in plasma were not identified. Rivaroxaban, the systemic clearance of approximately 10 l / h could be attributed to drugs with low clearance. In the breeding of rivaroxaban plasma terminal half-life of 9.5 hours in young patients and 11-13 hours in elderly patients.
Sex / old age (65 years). In elderly patients the concentration of rivaroxaban plasma levels higher than those of younger patients, the mean AUC is approximately 1.5 times higher than the corresponding values in young patients, mainly due to reduced general and renal clearance.
Men and women have clinically relevant pharmacokinetic differences have been identified.
Too small or large body mass ( 120 kg) only marginally affect the concentrations of rivaroxaban in the blood plasma (the discrepancy is
Childhood. The data for this age group are not available.
Inter-ethnic characteristics. Clinically relevant differences of pharmacokinetics and pharmacodynamics in patients Caucasian, African American, Hispanic, Asian ethnicity were observed.
Patients with liver failure
Effect of hepatic dysfunction on the pharmacokinetics of rivaroxaban was investigated in subjects who were divided into categories according to Child-Pugh classification, a standard procedure in clinical development. The primary goal of Child-Pugh classification is to assess the prognosis of chronic liver disease, mainly cirrhosis. Patients who are assigned to anticoagulation, critical aspect of the liver is reduced synthesis of normal clotting factors in the liver. Since this point is covered by only one of five clinical / biochemical determinations in the system of classification of Child-Pugh, the risk of bleeding, patients may not clearly correlate with this classification scheme. With this in mind, the decision to treat patients with anticoagulants should be taken independently of Child-Pugh classification.
Rivaroxaban is contraindicated in patients with liver disease, accompanied by coagulopathy, which is the cause of clinically relevant bleeding risk.
In patients with liver cirrhosis with hepatic impairment is mild (class A to Child-Pugh), the pharmacokinetics of rivaroxaban is only slightly different from the corresponding (average increase in AUC of rivaroxaban 1.2 times) indicators in the control group of healthy volunteers.
In patients with liver cirrhosis with liver failure secondary to the severity (Grade B in Child-Pugh), the mean AUC of rivaroxaban was significantly increased (2.3 times) compared to healthy volunteers due to a significant reduction in the clearance of the drug. AUC unbound substances increased by 2.6 times. No data on patients with severe hepatic impairment.
Inhibition of factor Xa was more pronounced (difference of 2.6 times) than in healthy volunteers. Prothrombin time as well (2.1 times) higher than in healthy volunteers. Patients with moderate hepatic impairment were more sensitive to rivaroksabanu, resulting in a steeper curve pharmacokinetic and pharmacodynamic relationship between concentration and prothrombin time.
Data on patients with liver failure class C Child-Pugh absent.
Renal failure
Showed an increase in the exposure of rivaroxaban, which inversely correlated with decreased renal function (creatinine clearance was determined, respectively – QC).
In patients with mild (creatinine clearance In individuals with mild, moderate or severe renal impairment overall inhibition of factor Xa was 1.5, 1.9 and 2.0 times respectively compared with healthy volunteers, the prothrombin time increased to 1.3, 2.2, and 2.4 times, respectively. Data on patients with creatinine clearanceNot recommended for use on patients with creatinine clearance
INDICATIONS Xarelto 10 mg:
prevention of VTE in patients undergoing extensive orthopedic surgery of the lower extremities.
APPLICATION Xarelto 10 mg:
for the prevention of VTE in orthopedic extensive interventions recommended to administer 1 tablet of 10 mg 1 time per day.
Duration of treatment depends on the type of orthopedic surgery. After interventions for hip replacement therapy should be continued for 5 weeks. After knee replacement should continue taking the drug for 2 weeks.
The method and frequency of
Take 1 tablet Ksarelto 10 mg 1 time per day regardless of meals. The first dose should be taken after 6-10 h after surgery, with effective hemostasis.
In the case of missing pills, patients should immediately take the rivaroxaban and the next day to continue the treatment of 1 tablet per day, as well as to skip taking the pill.
CONTRAINDICATIONS Xarelto 10 mg:
Hypersensitivity to any components or rivaroksabanu drug;
active clinically significant bleeding (eg intracranial, gastrointestinal);
liver disease, accompanied by coagulopathy, which increases the risk of clinically relevant bleeding;
during pregnancy.
SIDE EFFECTS Xarelto 10 mg:
safety of rivaroxaban 10 mg was evaluated in three studies, third phase, involving 4571 patients who underwent extensive orthopedic intervention on the lower limbs (complete replacement knee or hip joint) and who were treated for up to 39 days. Adverse reactions are classified by frequency and by organs and systems, they must be weighed against the surgical situation.
Classification based on frequency of adverse reactions included the following categories:
common – ≥ 1% – Undistributed – ≥ 0,1% – Rare – ≥ 0,01% – rare – Given the pharmacological mechanism of action, the application of rivaroxaban may be associated with an increased risk of latent or overt bleeding from any organ or tissue that can lead to posthemorrhagic anemia. Signs, symptoms and severity (including the possibility of death) will differ depending on the location and severity or duration of bleeding. The risk of bleeding may be increased in certain patient groups, such as patients with uncontrolled severe hypertension and / or patients taking drugs that affect hemostasis (see PRECAUTIONS). Hemorrhagic complications may manifest weakness, asthenia, pallor, dizziness, headache, or swelling of unknown etiology. Therefore, in assessing the patient receiving anticoagulants, should assess the likelihood of bleeding.
The following are adverse reactions that have arisen during the period of treatment, patients and researchers registered in the three studies, third phase, classified by organs and systems (Meddra) and frequency.
On the part of the circulatory and lymphatic systems: common (≥ 1% – Cardio-vascular system: common (≥ 1% – Gastrointestinal disorders: Common (≥ 1% – System disorders and conditions associated with the place of the drug: non-proliferation (≥ 0,1% – Hepatobiliary disorders: Rare (≥ 0,01% – Violations by the immune system: Rare (≥ 0,01% – The nervous system: non-proliferation (≥ 0,1% – On the part of the musculoskeletal system: non-proliferation (≥ 0,1% – Skin and subcutaneous tissue: non-proliferation (≥ 0,1% – The kidneys and urinary tract: non-proliferation (≥ 0,1% -These laboratory studies: common (≥ 1% -
SPECIAL INSTRUCTIONS Xarelto 10 mg:
patients with renal failure
Must be used with caution in rivaroxaban in patients with renal insufficiency moderately (CC – 30-49 ml / min), which is carried out concomitant therapy drugs that increase the concentration of rivaroxaban in the blood plasma.
In patients with renal impairment rivaroxaban concentration in blood plasma can be significantly increased, which could lead to an increased risk of bleeding.
Therefore, given the limited clinical data on patients with renal insufficiency (creatinine clearance Patients with severe renal insufficiency or an increased risk of bleeding, patients receiving concomitant therapy with systemic azole antifungals, or a group of HIV protease inhibitors, after initiation of treatment should be under strict surveillance for timely detection of hemorrhagic complications. Such monitoring may include regular physical examination of the patient, careful monitoring of discharge from the surgical wound drainage and periodic determination of hemoglobin levels.
Surgery for hip fractures
Rivaroxaban has not been studied in clinical trials in patients who underwent surgery for fractures of the hip.
The risk of bleeding
Antithrombotics, including rivaroxaban, should be used with caution in patients with increased risk of bleeding, including if any:
congenital or acquired diseases that lead to bleeding;
uncontrolled hypertension, severe;
peptic ulcer gastrointestinal tract in the acute stage;
recently transferred peptic ulcer gastrointestinal tract;
Vascular retinopathy;
recently transferred intracranial or intracerebral hemorrhage;
intraspinal or intracerebral vascular pathology;
recently transferred neurosurgery (surgery on the brain, spinal cord) or ophthalmic surgery.
Be careful when appointing rivaroxaban in patients receiving drugs that affect hemostasis such as NSAIDs, platelet aggregation inhibitors or other antithrombotic agents (see Interactions).
When unexplained decrease in hemoglobin or blood pressure to exclude hemorrhage.
Spinal (epidural / spinal) anesthesia
When the spinal cord (epidural / spinal) puncture in patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of epidural or spinal hematoma which can result in prolonged paralysis.
The risk of these complications increases with the use of permanent epidural catheters or concomitant use of drugs affecting hemostasis. Injury when performing epidural or spinal puncture or repeated puncture may also increase the risk of complications.
Patients should be monitored for signs or symptoms of neurological disorders (such as numbness or weakness of the legs, dysfunction of the bowel or bladder). In identifying the neurological symptoms should be an immediate diagnosis and appropriate therapy.
Physician should weigh the potential benefits and risks before the spinal intervention in patients receiving anticoagulants or who are preparing to receive anticoagulants to prevent thrombosis.
Epidural catheter was removed not earlier than 18 hours after the appointment of the last dose of rivaroxaban.
Rivaroxaban should not be administered earlier than 6 h after removal of the epidural catheter.
In the case of traumatic puncture of rivaroxaban appointment should be postponed for 24 hours
Women of reproductive age
Data on the use of rivaroxaban for the treatment of women during pregnancy.
In experiments on rats and rabbits demonstrated severe toxicity of rivaroxaban for the mother’s body and placental changes associated with the pharmacological action of the drug (such as hemorrhagic complications as hemorrhage). The primary teratogenic effect of the drug is not revealed. The data obtained from studies conducted in experimental animals have shown that rivaroxaban crosses the placenta. In connection with these women during pregnancy is contraindicated rivaroxaban.
Women of childbearing age should use effective contraception during treatment rivaroksabanom.
Data on the use of rivaroxaban in women during lactation are not available. In studies on rats revealed that rivaroxaban excreted in breast milk. Taking this into account, rivaroxaban can be applied only after the cessation of breastfeeding.
Clinical data regarding the drug in children are missing.
Ability to influence the reaction rate on driving or operating other machinery. Reports on the impact of rivaroxaban on ability to drive vehicles or work with other mechanisms available.
INTERACTION Xarelto 10 mg:
Pharmacokinetic interactions
Excretion of rivaroxaban is mainly through hepatic metabolism mediated by cytochrome P450 (CYP 3A4, CYP 2J2) and renal excretion of unchanged drug, with the participation of transport systems P-gp/BCRP.
Inhibition of cytochrome
Rivaroxaban does not inhibit CYP 3A4 isoenzyme, and other important isoform of cytochrome.
Induction of cytochrome
Rivaroxaban does not induce the CYP 3A4 isoenzyme, and other important isoform of cytochrome.
Compounds that affect the pharmacokinetics of rivaroxaban
The simultaneous use of rivaroxaban and strong inhibitors of CYP 3A4 isoenzyme and P-gp may lead to reduced renal and hepatic clearance and thus significantly increase the systemic effects of the drug.
The combined use of rivaroxaban and the antifungal drug ketoconazole azole (400 mg once a day), which is a potent inhibitor of CYP 3A4 and P-gp, resulting in a 2.6-fold increase in the mean equilibrium AUC of rivaroxaban and 1.7-fold increase in mean C max of rivaroxaban that is accompanied by a significant increase in pharmacodynamic effects of the drug.
A combination of rivaroxaban and the appointment of an inhibitor of HIV protease ritonavir (600 mg 2 times a day), which is a potent inhibitor of CYP 3A4 and P-gp, resulting in a 2.5-fold increase in the mean equilibrium AUC of rivaroxaban and 1.6-fold increase in mean C max of rivaroxaban that is accompanied by a significant increase in pharmacodynamic effects of the drug. In this connection should be used with caution in rivaroxaban in patients while receiving systemic azole antifungals, or HIV protease inhibitors.
Clarithromycin (500 mg 2 times a day), a potent inhibitor of CYP 3A4 inhibitor, and the average intensity P-gp, caused a 1.5-fold increase in the average AUC and 1.4-fold increase in C max of rivaroxaban. This increase in AUC and Cmax increase varies from the norm and is considered to be clinically irrelevant.
Erythromycin (500 mg 3 times a day), moderately inhibits CYP 3A4 isoenzyme and P-gp, caused a 1.3-fold increase in the average equilibrium values of AUC and C max of rivaroxaban. This increase in AUC and Cmax increase varies from the norm and is considered to be clinically irrelevant.
Simultaneous with the appointment of rivaroxaban and rifampicin, a potent inducer of CYP 3A4 and P-gp, resulting in approximately 50% decrease in the mean AUC of rivaroxaban and the parallel reduction of its pharmacodynamic effects. The combined use of rivaroxaban with other strong inducers of CYP 3A4 (eg phenytoin, carbamazepine, phenobarbital or Hypericum means based on) can also lead to lower concentrations of rivaroxaban in the blood plasma. Reducing the concentration of rivaroxaban in the blood plasma is considered clinically nerelevatnym.
Pharmacodynamic interactions
After the combined use of enoxaparin (40 mg single dose) and rivaroxaban (10 mg single dose) was observed an additive effect relative to antifactor Xa activity that is not accompanied by additional effects on indicators of blood coagulation (prothrombin time, aPTT). Enoxaparin pharmacokinetics of rivaroxaban did not change (see Pharmacological properties).
There were no pharmacokinetic interaction between rivaroksabanom and clopidogrel (loading dose of 300 mg with the following appointment of a maintenance dose of 75 mg), but in the subgroup of patients identified relevant increase in bleeding time, which did not correlate with the level of platelet aggregation and P-selectin or GPIIb / IIIa-receptor.
After co-administration of rivaroxaban and naproxen 500 mg of clinically relevant prolongation of bleeding time were observed. However, individuals can more pronounced pharmacodynamic response.
Interaction with food: Rivaroxaban 10 mg can be taken with meals or by itself.
Effect on lab tests: effects on indices of coagulation (prothrombin time, aPTT, Hep-Test) corresponds to that expected in view of the mechanism of action of rivaroxaban.
OVERDOSAGE Xarelto 10 mg
Rivaroxaban overdose can lead to bleeding complications due to its pharmacodynamic properties.
No specific antidote. In case of overdose, to reduce the absorption of rivaroxaban may be used activated carbon. The use of activated charcoal in the period up to 8 hours after an overdose can reduce the absorption of rivaroxaban.
Given the high binding to plasma proteins, we can expect that rivaroxaban does not excreted from the body by dialysis.
If there is bleeding for his removal can be conducted the following activities: to defer the appointment of the next dose of rivaroxaban or stop treatment, depending on the situation (the half-life of rivaroxaban is about 5-13 h) to conduct a proper symptomatic treatment (eg mechanical compression should be considered in case of severe bleeding as necessary to provide surgical intervention, carried out the restoration of water and electrolyte balance and haemodynamic support, blood transfusion or blood components).
If the above steps do not lead to the elimination of bleeding, may be assigned to one of the following procoagulants:
activated prothrombin complex concentrate;
prothrombin complex concentrates;
recombinant factor VIIa (rf VIIa).
However, to date, experience with these drugs in overdose rivaroxaban is missing.
It is assumed that protamine sulfate and vitamin K will not affect the anticoagulant activity of rivaroxaban. The scientific rationale for and experience with systemic hemostatic drugs (for example dezmopressina, aprotinin, tranexamic acid, aminocaproic acid) to prevent an overdose of rivaroxaban absent.
