Xarelto film-coated pills 2.5 mg N28
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Active ingredients
Rivaroxaban
Release form
Pills
Composition
Micronized Rivaroxaban 2.5 mg. Auxiliary substances: microcrystalline cellulose - 40 mg, croscarmellose sodium - 3 mg, hypromellose 5cP - 3 mg, lactose monohydrate - 27.9 mg, magnesium stearate - 600 μg, sodium lauryl sulfate - 500 μg. The composition of the shell: iron dye red oxide - 15 mcg, hypromellose 15cP - 1.5 mg, macrogol 3350 - 500 mcg, titanium dioxide - 485 mcg.
Pharmacological effect
Mechanism of action: Rivaroxaban is a highly selective direct inhibitor of factor Xa, which has high bioavailability when administered. Activation of factor X to form factor Xa through the internal and external coagulation paths plays a central role in the coagulation cascade. Pharmacodynamic effects: In humans, a dose-dependent inhibition of factor Xa was observed. Rivaroxaban has a dose-dependent effect on prothrombin time and closely correlates with plasma concentrations (r = 0.98) if the Neoplastin kit is used for analysis ;. When using other reagents, the results will differ. The prothrombin time should be measured in seconds, since the MHO is calibrated and certified only for coumarin derivatives and cannot be used for other anticoagulants. In patients undergoing large orthopedic surgeries, the 5/95 percentile for the prothrombin time (Neoplastin;) 2-4 hours after taking the tablet (i.e. at the maximum effect) varies from 13 to 25 seconds. Also, rivaroxaban dose-dependently increases the APTT and the result of HepTest; however, these parameters are not recommended for evaluating the pharmacodynamic effects of rivaroxaban. During treatment with rivaroxaban, monitoring of blood clotting parameters is not required. However, if there is a clinical rationale for this (for example, in case of overdose of the drug or, if necessary, emergency surgical intervention), rivaroxaban concentration can be measured using a calibrated quantitative anti-factor Xa test (for example, STA-Liquid Anti-Xa, manufacturer Diagnostics Stago CAC France or similar). In healthy men and women older than 50 years, a prolongation of the QT interval under the influence of rivaroxaban was not observed.
Pharmacokinetics
Absorption: The absolute bioavailability of rivaroxaban after administration in a dose of 10 mg is high (80-100%). Rivaroxaban is rapidly absorbed, Cmax is reached 2-4 hours after taking the pill. When receiving rivaroxaban in a dose of 10 mg with food, no changes in AUC and Cmax were observed.Rivaroxaban in a dose of 10 mg can be administered with meals or regardless of the meal. The pharmacokinetics of rivaroxaban is characterized by moderate individual variability, individual variability (variation coefficient) ranges from 30% to 40%, except for the day of surgery and the next day, when the variability in exposure is high (70%). The absorption of rivaroxaban depends on the place of release in the gastrointestinal tract. A 29% and 56% decrease in AUC and Cmax, respectively, compared to taking the whole tablet, was observed when rivaroxaban granulate was released in the distal small intestine or ascending colon. The introduction of rivaroxaban in the gastrointestinal tract distal to the stomach should be avoided, since this may entail a decrease in the absorption and, accordingly, the drug exposure. The study evaluated the bioavailability (AUC and Cmax) of 20 mg of rivaroxaban taken orally as a crushed tablet mixed with applesauce or suspended in water, as well as administered through a stomach tube followed by a liquid diet, compared to taking the whole tablet. The results demonstrated a predictable dose-dependent pharmacokinetic profile of rivaroxaban, while the bioavailability at the above indicated administration corresponded to that when receiving rivaroxaban in lower doses. Distribution: In humans, a large part of rivaroxaban (92-95%) binds to plasma proteins, with serum albumin as the main binding component. Vd is moderate; Vss is about 50 liters. Metabolism: When ingested, approximately 2/3 of the prescribed dose of rivaroxaban is metabolized and subsequently excreted in equal parts with urine and feces. The remaining 1/3 dose is eliminated by direct renal excretion unchanged, mainly due to active renal secretion. Rivaroxaban is metabolized by 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. According to in vitro data, rivaroxaban is a substrate for P-gp (P-glycoprotein) and Vrpr (breast cancer resistance protein) carrier proteins.Unchanged rivaroxaban is the only active compound in human plasma, and no significant or active circulating metabolites are found in plasma. Withdrawal: When removing rivaroxaban from plasma, the final T1 / 2 is 5 to 9 hours in young patients. Rivaroxaban, the systemic clearance of which is approximately 10 l / h, can be attributed to drugs with a low level of clearance. Pharmacokinetics in special clinical situations: Older patients over 65 years old have a higher concentration of rivaroxaban in plasma than in young patients, the average AUC is about 1.5 times higher than in young patients, mainly due to the apparent decrease in total and renal clearance. When removing rivaroxaban from plasma, the final T1 / 2 in elderly patients ranges from 11 to 13 hours. In men and women, clinically significant differences in pharmacokinetics were not found. Too small or large body weight (less than 50 kg and more than 120 kg) only slightly affects the concentration of rivaroxaban in plasma (the difference is less than 25%). Data on the pharmacokinetics in children are not available. No clinically significant differences in pharmacokinetics and pharmacodynamics were observed in patients of Caucasoid, African American, Latin American, Japanese or Chinese ethnicity. The effect of hepatic insufficiency on the pharmacokinetics of rivaroxaban was studied in patients divided into classes according to the Child-Pugh classification (according to standard procedures in clinical studies). Child-Pu's classification allows to evaluate the prognosis of chronic liver diseases, mainly cirrhosis. In patients who are scheduled to undergo anticoagulant therapy, a particularly important critical point in the impaired liver function is a decrease in the synthesis of coagulation factors in the liver. Since this indicator corresponds to only one of the five clinical / biochemical criteria that constitute the Child-Pugh classification; the risk of bleeding does not clearly correlate with this classification. The question of the treatment of such patients with anticoagulants should be decided independently of the class according to the Child-Pugh classification.Rivaroxaban is contraindicated in patients with liver diseases that occur with coagulopathy, causing a clinically significant risk of bleeding. In patients with cirrhosis of the liver with mild hepatic insufficiency (class A according to Child-Pugh classification), the pharmacokinetics of rivaroxaban differed only slightly (on average, there was an increase in rivaroxaban AUC by a factor of 1.2) from the corresponding indicators in the control group of healthy subjects. There were no significant differences in pharmacodynamic properties between the groups. In patients with cirrhosis of the liver and liver failure of moderate severity (class B according to Child-Pugh classification), the average AUC of rivaroxaban was significantly increased (by a factor of 2.3) compared with healthy volunteers due to significantly reduced clearance of the drug substance indicating serious liver disease. The suppression of the activity of factor Xa was more pronounced (by 2.6 times) than in healthy volunteers. The prothrombin time is also 2.1 times higher than in healthy volunteers. Using the measurement of prothrombin time, an external coagulation pathway is estimated, including coagulation factors VII, X, V, II and I, which are synthesized in the liver. Patients with moderate hepatic insufficiency 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. Data for patients with hepatic insufficiency of class C according to the Child-Pu classification are not available. In patients with renal failure, an increase in plasma rivaroxaban concentration was observed, inversely proportional to the decrease in renal function, as assessed by CC. In patients with mild renal failure (CK 80–50 ml / min), moderate (CK 50–30 ml / min) or severe (CK 30–15 ml / min), a 1.4-, 1.5-, and 1.6-fold increase was observed. concentrations of rivaroxaban in plasma (AUC), respectively, compared with healthy volunteers. The corresponding increase in pharmacodynamic effects was more pronounced. In patients with mild, moderate and severe renal insufficiency, the overall suppression of factor Xa activity increased 1.5, 1.9 and 2 times compared with healthy volunteers, the prothrombin time due to the action of factor Xa also increased 1.3, 2.2 and 2.4 times, respectively.Data on the use of rivaroxaban in patients with CK 30-15 ml / min is limited, and therefore care should be taken when using the drug for this category of patients. Data on the use of rivaroxaban in patients with CK less than 15 ml / min are missing, and therefore it is not recommended to use the drug in this category of patients.
Indications
- prevention of venous thromboembolism (VTE) in patients undergoing large orthopedic operations on the lower limbs.
Contraindications
- hypersensitivity to rivaroxaban or any excipients contained in a tablet — clinically significant active bleeding (for example, intracranial bleeding, gastrointestinal bleeding) —a damage or pathological condition associated with an increased risk of major bleeding, including existing or recent gastrointestinal ulcers, the presence of malignant neoplasms with a high risk of bleeding, recent injuries to the brain or spinal cord, recent surgical interventions on the brain, spinal cord or eyes, recent intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous venous malformations, vascular aneurysm or large anomalies of the vascular structure of the brain or spinal cord — concomitant therapy with any other anticoagulum ntami, for example, unfractionated heparin (UFH), low molecular weight heparins (including enoxaparin, dalteparin), heparin derivatives (including fondaparinux), oral anticoagulants (including warfarin, apixaban, dabigatran), except when the patient is transferred from therapy or to therapy with Xarelto; or when UFH is prescribed in low doses to maintain the patency of the central venous or arterial catheter — liver diseases occurring with coagulopathy, which causes clinically significant risk of bleeding, including patients with cirrhosis of classes B and C according to the Child-Pugh classification — pregnancy — lactation period (breastfeeding period) - children and adolescents under 18 years of age (efficacy and safety for patients of this age group have not been established) - renal severe failure with CC is less than 15 ml / min (there are no clinical data on the use of rivaroxaban in patients of this category) - hereditary intolerance to lactose or galactose (for example, congenital lactic deficiency basics or glucose-galactose malabsorption),since lactose is part of the drug. The drug should be used with caution: - in the treatment of patients with an increased risk of bleeding (including congenital or acquired tendency to bleeding, uncontrolled severe arterial hypertension, gastric ulcer and duodenal ulcer in the acute stage , recent gastric and duodenal ulcers, vascular retinopathy, recent intracranial or intracerebral hemorrhage, with pathologists vessels of the spinal cord or brain, after recent surgery on the brain, spinal cord and eyes, bronchiectasis or pulmonary hemorrhage in history) —in treating patients with moderately severe renal failure (CK 50–30 ml / min) receiving simultaneously plasma concentration of rivaroxaban — when treating patients with severe renal insufficiency (CK 30–15 ml / min), caution should be exercised because, due to the underlying disease, such patients are prone to for risk of both bleeding and thrombosis — rivaroxaban is not recommended for use in patients receiving systemic treatment with antifungal drugs of the azole group (for example, ketoconazole) or HIV protease inhibitors (for example, ritonavir). These drugs are strong inhibitors of the CYP3A4 isoenzyme and P-glycoprotein. As a result, these drugs can increase the concentration of rivaroxaban in plasma to a clinically significant level (an average of 2.6 times), which increases the risk of bleeding. Fluconazole (an antifungal drug of the azoles group), a moderate CYP3A4 inhibitor, has a less pronounced effect on the removal of rivaroxaban and can be used with it simultaneously — patients with severe renal insufficiency (CK 30–15 ml / min) or an increased risk of bleeding and patients receiving concomitant systemic treatment with antifungal drugs of the azoles group or HIV protease inhibitors, after the start of treatment should be closely monitored for the timely detection of complications in the form of blood echeny.Such monitoring may include regular physical examination of patients, careful observation of the surgical wound drainage and periodic changes in hemoglobin levels. Any decrease in hemoglobin or blood pressure, for which there is no explanation, is a reason to look for a bleeding site — in patients receiving drugs that affect hemostasis (for example, NSAIDs, antiplatelet agents or other antithrombotic agents) - in patients at risk of acute gastric ulcer and duodenal ulcer intestine may be justified by the appointment of prophylactic anti-ulcer treatment.
Dosage and administration
The drug is taken orally, regardless of the meal. If the patient is unable to swallow the pill whole, Xarelto pill; can be crushed and mixed with water or liquid food, such as applesauce, just before ingestion. Crushed tablet Xarelto; You can enter through the gastric tube. The position of the probe in the gastrointestinal tract must be further coordinated with the doctor before taking Xarelto ;. The crushed tablet should be administered through a stomach tube in a small amount of water, after which a small amount of water must be introduced in order to wash off the remnants of the preparation from the probe walls. Prevention of VTE with large orthopedic operations It is recommended to prescribe 10 mg (1 tab.) 1 time / day. The initial dose should be taken 6-10 hours after surgery, provided hemostasis is achieved. Duration of treatment: 5 weeks - after major surgery on the hip joint, 2 weeks - after major surgery on the knee joint. Actions in case of skipping a dose. In case of skipping a dose, the patient should immediately take the drug and the next day continue with the regular dose of 10 mg (1 tab.) / Day, as before. Separate groups of patients Dose adjustment depending on the patient's age (over 65 years), gender, body weight or ethnicity is not required. Rivaroxaban is contraindicated in patients with liver disease, accompanied by coagulopathy, which causes a clinically significant risk of bleeding. Patients with other liver diseases are not required to change the dose. The limited clinical data available in patients with moderate-degree liver failure (class B according to the Child-Pugh classification) indicate a significant increase in the pharmacological activity of the drug. For patients with severe hepatic impairment (Child-Pugh class C), there are no clinical data.When prescribing rivaroxaban in patients with mild renal insufficiency (CK 80-50 ml / min) or moderate severity (CK 50-30 ml / min), no dose reduction is required. The limited clinical data available in patients with renal insufficiency (CK 30–15 ml / min) show a significant increase in rivaroxaban concentrations in these patients. For the treatment of this category of patients rivaroxaban should be used with caution. The use of rivaroxaban is not recommended in patients with CK less than 15 ml / min. Transfer of patients from vitamin K (AVK) antagonists to Xarelto; When transferring patients from AVK to Xarelto ;, after taking Xarelto; MHO values will be falsely elevated. Therefore, the indicator MHO should not be used to control the anticoagulant effect of Xarelto ;. Transfer of patients from Xarelto; on AVK There is a possibility of insufficient anticoagulant effect when switching from Xarelto; on avk. In this regard, it is necessary to provide a continuous sufficient anticoagulant effect during a similar transition. It should be noted that Xarelto; may contribute to improving MHO. When transferring a patient from Xarelto; on AVK, both drugs should be given simultaneously, until the MHO reaches ≥2. During the first two days of the transitional period, a standard dose of AVK should be used, and subsequently, be guided by the value of INR. During simultaneous use of Xarelto; and AVK MHO should be determined not earlier than 24 hours after the previous dose, but before taking the next dose of Xarelto ;. After discontinuation of Xarelto; the value of MHO can be reliably determined 24 hours after the last dose. Transfer of patients from parenteral anticoagulants to Xarelto; For patients receiving parenteral anticoagulants, use Xarelto; It should be started 0-2 hours before the next scheduled parenteral administration of the drug (for example, low molecular weight heparin) or at the time of termination of the continuous parenteral administration of the drug (for example, intravenous administration of unfractionated heparin). Transfer of patients from Xarelto; for parenteral anticoagulants Xarelto should be discontinued; and inject the first dose of the parenteral anticoagulant during the intended administration of the next dose of Xarelto;