Xarelto, 20 mg 98 pcs
€272.40 €236.08
Pharmacotherapeutic group: direct factor Xa inhibitors.
ATX code: B01AF01.
Pharmacological properties
Pharmacodynamics
The mechanism of action
p> Rivaroxaban is a highly selective direct factor Xa inhibitor with high bioavailability when taken orally.
The activation of factor X to form 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 into thrombin. As a result, these reactions lead to the formation of fibrin thrombus and platelet activation by thrombin. One molecule of factor Xa catalyzes the formation of over 1000 molecules of thrombin, which has been called the “thrombin burst. The reaction rate of prothrombinase-bound factor Xa increases 300,000 times that of free factor Xa, providing a dramatic jump in thrombin levels. Selective factor Xa inhibitors can stop the thrombin burst. Thus, rivaroxaban affects the results of some specific or general laboratory tests used to evaluate clotting systems.
Pharmacodynamic effects
In humans, there is a dose-dependent inhibition of factor Xa activity. Rivaroxaban has a dose-dependent effect on prothrombin time and correlates well with plasma concentrations (r=0.98) if the Neoplastin kit is used for the assay. Results will differ if other reagents are used. Prothrombin time should be measured in seconds because the INR (international normalized ratio) is calibrated and certified only for coumarin derivatives and cannot be used for other anticoagulants.
In patients with non-valvular atrial fibrillation taking rivaroxaban for prevention of stroke and systemic thromboembolism, the 5/95 percentile for prothrombin time (Neoplastin) 1-4 hours after taking the tablet (ie.i.e., at maximum effect) range from 14 to 40 seconds in patients taking 20 mg once daily and from 10 to 50 seconds in patients with moderate renal impairment taking 15 mg once daily.
In patients receiving rivaroxaban for the treatment and prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (TELA), 5/95 percentiles for prothrombin time (Neoplastin) 2 to 4 hours after taking the tablet (ie.i.e., at maximum effect) range from 17 to 32 seconds in patients taking 15 mg twice daily and from 15 to 30 seconds in patients taking 20 mg once daily.
Rivaroxaban also dose-dependently increases activated partial thromboplastin time (APT) and the HepTest® result; however, these parameters are not recommended for evaluating the pharmacodynamic effects of rivaroxaban. Also, if clinically warranted, rivaroxaban concentrations may be measured using a calibrated quantitative anti-factor Xa test.
Monitoring of clotting parameters is not required during treatment with Xarelto®.
In healthy men and women over 50 years of age, no prolongation of the electrocardiogram QT interval was observed under the influence of rivaroxaban.
Pharmacokinetics
Intake and bioavailability
Rivaroxaban is rapidly absorbed; maximum concentration (Cmax) is reached 2 to 4 hours after tablet administration.
The absolute bioavailability of rivaroxaban after a dose of 10 mg is high (80-100%) regardless of food intake. No change in AUC (area under the curve “concentration – time”) and Cmax (maximum concentration) was observed when rivaroxaban 10 mg was taken with food.
Due to the reduced degree of absorption, a bioavailability of 66% was observed when 20 mg was taken on an empty stomach. When Xarelto® 20 mg was taken with meals, there was a 39% increase in mean AUC compared to fasting intake, showing almost complete absorption and high bioavailability. Xarelto® 20 mg, 15 mg should be taken with meals.
The pharmacokinetics of rivaroxaban are characterized by moderate individual variability; individual variability (coefficient of variation) is 30% to 40%.
The absorption of rivaroxaban depends on the site of release in the gastrointestinal tract (GIT). A 29% and 56% reduction in AUC and Cmax, respectively, compared to whole tablet administration was observed when rivaroxaban pellet was administered to the proximal small intestine. Exposure to the drug is also reduced when administered into the distal small intestine or the ascending colon. Administration of rivaroxaban in the gastrointestinal tract distal to the stomach should be avoided as it may reduce absorption and therefore exposure to the drug.
The bioavailability (AUC and Cmax) of rivaroxaban 20 mg when taken as a whole tablet is comparable to the bioavailability of the drug taken orally as a crushed tablet (mixed with apple puree or suspended in water) and the bioavailability of the drug when administered via gastric tube followed by liquid food. Given the predictable dose-dependent pharmacokinetic profile of rivaroxaban, the results of this bioavailability study are also applicable to lower doses.
Distribution
In humans, most of rivaroxaban (92-95%) is bound to plasma proteins, with serum albumin being the major binding component. The volume of distribution is moderate, Vss is approximately 50 liters.
Metabolism and excretion
On oral administration, approximately 2/3 of the administered dose of rivaroxaban is metabolized and subsequently excreted in equal amounts in the urine and through the intestine. The remaining 1/3 of the dose is excreted via direct renal excretion unchanged primarily through active renal secretion.
Rivaroxaban is metabolized by CYP3A4, CYP2J2 isoenzymes as well as by mechanisms independent of the cytochrome system. The main sites of biotransformation are oxidation of the morpholine group and hydrolysis of the amide bonds. According to in vitro data, rivaroxaban is a substrate for P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein) transporter proteins. Unchanged rivaroxaban is the only active compound in human plasma; no major or active circulating metabolites have been detected in plasma. Rivaroxaban, which has a systemic clearance of approximately 10 L/h, may be classified as a low clearance drug. In the plasma excretion of rivaroxaban, the final elimination half-life is 5 to 9 hours in young patients and 11 to 13 hours in elderly patients.
Gender/Elderly (>65 years)
The plasma concentrations of rivaroxaban are higher in elderly patients than in younger patients; the average AUC is approximately 1.5 times greater than in younger patients, primarily due to the apparent decrease in total and renal clearance (see section “Dosage and administration”).
There are no clinically significant differences in pharmacokinetics between men and women (see section “Dosage and administration”).
Body weight
High or low body weight (less than 50 kg and greater than 120 kg) only slightly affects the plasma concentration of rivaroxaban (less than 25% difference) (see section “Administration and Dosages”).
Child and adolescent age (from birth to 18 years)
There are no data for this age group (see section on Dosage and administration).
Interethnic differences
There were no clinically significant differences in pharmacokinetics and pharmacodynamics in patients of Caucasian, African American, Hispanic, Japanese, or Chinese ethnicity (see section on Dosage and administration).
Patients with hepatic impairment
The effect of hepatic impairment on the pharmacokinetics of rivaroxaban has been studied in patients allocated according to the Child-Pugh classification (according to standard procedures in clinical trials). The Child-Pugh classification provides an assessment of the prognosis of chronic liver disease, mainly cirrhosis. In patients scheduled for anticoagulant therapy, the most important consequence of impaired liver function is reduced synthesis of blood clotting factors in the liver. Because this figure corresponds to only one of the five clinical/biochemical criteria that make up the Child-Pugh classification, the risk of bleeding does not correlate clearly with this classification. Treatment of such patients with anticoagulants should be decided regardless of the Child-Pugh classification.
Rivaroxaban is contraindicated in patients with liver disease presenting with coagulopathy that is clinically significant bleeding risk.
In patients with cirrhosis and mild hepatic impairment (Child-Pugh class A) the pharmacokinetics of rivaroxaban did not significantly differ from those of control group of healthy subjects (on the average there was 1.2-fold increase of AUC of rivaroxaban). There were no significant differences in pharmacodynamic properties between the 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 to healthy volunteers due to significantly decreased clearance of the drug substance, indicating serious liver disease. Suppression of factor Xa activity was more pronounced (2.6-fold) than in healthy volunteers. Prothrombin time was also 2.1 times that of healthy volunteers. Prothrombin time measurement assesses the external coagulation pathway, which includes clotting 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.
There are no data for patients with Child-Pugh class C hepatic impairment (see sections “Dosage and administration” and “Contraindications”).
Patients with impaired renal function
In patients with impaired renal function, there was an increase in the area under the concentration-time curve of rivaroxaban inversely proportional to the degree of decrease in renal function, as assessed by creatinine clearance.
. Patients with mild renal impairment (creatinine clearance 50-80 mL/min), moderate renal impairment (CLKR 30-49 mL/min), and severe renal impairment (CLKR 15-29 mL/min) showed 1.4-, 1.5-, and 1.6-fold increases in rivaroxaban plasma concentrations (AUC) compared to healthy volunteers, respectively(see Dosage and Administration, Caution, and Special Precautions).
The corresponding increase in pharmacodynamic effects was more pronounced. In patients with CLKR 50-80 ml/min, CLKR 30-49 ml/min, and CLKR 15-29 ml/min, total suppression of factor Xa activity was increased 1.5, 1.9, and 2-fold compared with healthy volunteers; prothrombin time due to factor Xa activity was also increased 1.3, 2.2, and 2.4-fold, respectively.
The data on the use of Xarelto® in patients with CLR 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 Xarelto® in patients with CLR < 15 ml/min, therefore it is not recommended to use the drug in this category of patients.
Due to the underlying disease, patients with severe renal dysfunction are at high risk of bleeding and thrombosis.
Patients with acute deep vein thrombosis (DVT)
. In patients receiving rivaroxaban at a dose of 20 mg once daily for treatment of acute deep vein thrombosis (DVT), the geometric mean value of maximum concentration 2-4 hours after drug administration was 215 mcg/L (22-535 mcg/L); the geometric mean value of the minimum concentration 24 hours after the drug intake was 32 mcg/L (6-239 mcg/L). Prediction interval = 90%
Ratio of pharmacokinetic parameters and pharmacodynamic effects The ratio of pharmacokinetic parameters and pharmacodynamic effects (PK/PD) between the plasma concentration of rivaroxaban and the pharmacodynamic endpoints was assessed with the administration of rivaroxaban at doses of 5 to 30 mg twice daily <
(Factor Xa inhibition, prothrombin time, activated partial thromboplastin time (APTV) and HepTest® results).
The relationship between rivaroxaban concentration and factor Xa activity is best demonstrated using the Emax model.
The linear slope model demonstrates the relationship between rivaroxaban concentration and prothrombin time value. The slope angle varied significantly depending on the reagents used to determine the prothrombin time. Using the Neoplastin kit, the baseline prothrombin time was about 13 s with a slope of about 3-4 s (100 µg/L). The results of the FK/FD ratio analysis in the phase II and III studies were similar to those of healthy patients.
Indications
- prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation;
- treatment of deep vein thrombosis and pulmonary embolism and prevention of recurrent DVT and TELA.
Active ingredient
Rivaroxaban
Composition
One film-coated tablet contains:
active ingredient:
Rivaroxaban micronized – 20,00 mg,
excipients:
microcrystalline cellulose – 35.00 mg,
croscarmellose sodium – 3.00 mg,
Hypromellose 5cP(hydroxypropyl methylcellulose 2910) – 3.00 mg,
How to take, the dosage
Ingestion.
The drug Xarelto® 15 mg and 20 mg should be taken with food.
If the patient is unable to swallow the tablet whole, the Xarelto® tablet may be crushed and mixed with water or a liquid food such as apple puree immediately before intake. After taking a crushed tablet of Xarelto® 15 mg or 20 mg, a meal should be taken immediately.
The crushed tablet of Xarelto® may be administered through a gastric tube. The position of the tube in the gastrointestinal tract must be further agreed with the physician before taking Xarelto®. The crushed tablet should be inserted through the gastric tube in a small amount of water, after which a small amount of water should be injected to wash out the drug residues from the walls of the tube. After intake of crushed Xarelto ® 15 mg or 20 mg tablet, enteral nutrition should be immediately administered (see section “Pharmacological properties”).
Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation
The recommended dose is 20 mg once daily.
For patients with impaired renal function (CLKR 30-49ml/min ), the recommended dose is 15 mg once daily.
The recommended maximum daily dose is 20 mg.
Long-term treatment: Therapy with Xarelto® should be considered long-term treatment for as long as the benefits of treatment outweigh the risk of possible complications (see Caution and Special Precautions).
Actions for Missed Dose
If another dose is missed, the patient must take a tablet of Xarelto immediately® and continue the next day’s regular dosing according to the recommended regimen.
The dose taken should not be doubled to make up for a previously missed dose.
Treatment of DVT and TELA and prevention of recurrence of DVT and TELA
. The recommended starting dose in the treatment of acute DVT or TELA is 15 mg twice daily for the first 3 weeks, with a subsequent transition to a dose of 20 mg once daily for further treatment and prevention of recurrence of DVT and TELA.
After at least 6 months of treatment of deep vein thrombosis or pulmonary embolism, the recommended dose of Xarelto® is 10 mg* once daily or 20 mg once daily, depending on the individual risk ratio for recurrence of DVT or TELA to bleeding risk.
Table 1.
Period | Acceptance pattern | Total daily dose | |||||
Treatment and prevention | 1 to 21 days | 15 mg twice daily |
|||||
After 22 days | 20 mg once every day | 20 mg |
TBV recurrence or TELA | |||||||
Preventing recurrence of DVT and TELA | After at least 6 months of treatment for DVT or TELA | 10 mg* once daily or 20 mg once daily | 10 mg or 20 mg |
Therapeutic area | Number /p> patients* | | width=”132″> The maximum duration of treatmentMaximum treatment duration | ||
Prevention of venous thromboembolism (VTE) in patients who have undergone elective hip or knee replacement surgery |
6,097 |
Prevention of venous thromboembolism in medically hospitalized patients | 3,997 | 10 mg | 39 days | ||||
Treatment of DVT, TELA and prevention of recurrence of DVT, TELA | 6,790 | Day 1 – 21: 30 mg From day 22: 20 mg After at least 6 months of therapy: 10 mg or 20 mg | 21 months | ||||
Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation of unclogged origin | width= 196, Prevention of stroke and systemic thromboembolism in patients with atrial fibrillation of unclogged origin./p> | 7,750 | 20 mg | 41 months | |||
Prevention of atherotic complications in patients after acute coronary syndrome (ACS) | 10,225 | 5 mg or 10 mg, respectively, in combination with acetylsalicylic acid or acetylsalicylic acid with clopidogrel or ticlopidine /p> | 31 months | ||||
Prevention of stroke, myocardial infarction, and death due to cardiovascular causes, as well as for the prevention of acute limb ischemia and overall mortality in patients with coronary heart disease (CHD) or ASD | Windows therapies | 18244 | 5 mg in combination with acetylsalicylic acid 100 mg or 10 mg in monotherapy | 47 months |
* Patients who have received at least one dose of rivaroxaban.
Frequency of bleeding and anemia in patients treated with Xarelto® phase III clinical trials:
Table 3.
Indication for use <./p> | Number of patients | ||||
Any bleeding /td> | Anemia | ||||
Prevention of venous thromboembolism (VTE) in patients who have undergone elective replacement surgery | 6.8% | 5.9% |
hip or knee | |||||
Prevention of venous thromboembolism in medically hospitalized patients | width=”208″> Prevention of venous thromboembolism in medically hospitalized patients | 12.6% | 2.1% | ||
Treatment of DVT, TELA and pro- phylaxis of recurrence of DVT, TELA | 23% | 1.6% | |||
Prevention of stroke and systemic thromboembolism in patients with non-valvular atrial fibrillation | 28 events per 100 patient-years | 2.5 events per 100 patient-years | |||
Prevention of atherothrombotic complications in patients after acute coronary syndrome (ACS) | 22 events per 100 patient-years | 1.4 events per 100 patient-years | |||
Prevention of stroke, myocardial infarction and death from cardiovascular causes, as well as prevention of acute limb ischemia and overall mortality in patients with CHD or AFS/p> | 6.7 events per 100 patient-years | 0.15 events per 100 patient-years* |
* When collection data about undesirable
In the use of Xarelto®, known complications secondary to severe bleeding, such as increased subfacial pressure syndrome (compartment syndrome) and renal failure due to hypoperfusion, have also been reported. Thus, the possibility of bleeding should be considered in the evaluation of any patient receiving anticoagulants.
The incidence of NCDs (adverse drug reactions) with Xarelto® is shown in the table below. Within each frequency group, adverse events are presented in decreasing order of severity.
The frequency of occurrence is defined as:
very common (≥1/10),
often: (≥1/100 to < 1/10), infrequent: (≥1/1,000 to < 1/100), rare: (≥1/10,000 to < 1/1,000),
Table 4: All treatment-emergent adverse drug reactions reported in patients in phase III clinical trials (cumulative data from RECORD 1-4, ROCKET AF, J-ROCKET, MAGELLAN, ATLAS
and EINSTEIN (DVT/PE/Extension CHOICE) and COMPASS*)
System-organ class (MedDRA –< Medical Vocabulary Version 20.0) | Frequently | Frequently | Rarely /td> | ||
Disorders of the blood and lymphatic system | Anemia (including relevant laboratory parameters) | Trombocytosis (including elevated platelets)A | |||
Immune system disorders | Allergic reaction, allergic dermatitis |
Nervous system disorders | Dizziness, headache | Intracerebral and intracranial hemorrhages, fainting |
|||
Visual disturbances /p> | Bleeding in the eye (including hemorrhage in conjunctival hemorrhage) | ||||
Disorders from the heart side /p> | Tachycardia |
||||
vascular disorders | Significant decrease in arterial pressure, hematoma | ||||
Disorders of the respiratory system, thoracic organs, and mediastinum | Nasal bleeding, hemoptysis /p> | ||||
Gastrointestinal tract disorders /p> | Gingival bleeding, gastrointestinal bleeding (including rectal bleeding), abdominal pain, dyspepsia, nausea, constipationA, diarrhea, vomitingA | Dry mouth | |||
Disorders of the liver and biliary tract |
Disorders of liver function | td width=”147″> Jaundice |
Skin and subcutaneous tissue disorders | Skin itching (including infrequent cases of generalized itching), skin rash, ecchymosis, skin and subcutaneous hemorrhages | Urticaria | |||
Disorders of the skeletal-muscular and connective tissue ./td> | Pain in the extremitiesA | Hemarthrosis | Muscle hemorrhage | ||
Renal and urinary tract disorders | Bleeding from the urogenital tract (including hematuria and menorrhagia sup>B), renal dysfunction (including increased creatinine concentration, increased urea concentration)A | ||||
General disorders and disorders at the site of administration | Fever sup>A, peripheral edema, decreased overall muscle strength and tone (including weakness, asthenia) | Deterioration in general well-being (including malaise) | Local edema sup>A |
Laboratory and instrumental findings | Elevated activity “hepatic” transaminases | Increased bilirubin concentration, increased alkaline phosphataseA activity, increased LDHA activity, increased lipaseA activity, increased amylaseA activity, increased GGTA activity | Increased concentration of conjugated bilirubin (with or without concomitant increase in ALT activity) | ||
Injuries, intoxications and complications of manipulation |
Wound secretionA | Vascular pseudoaneurysmC |
A were observed predominantly after major orthopedic lower extremity surgery
B observed in the treatment of VTE as very frequent in women aged < 55 years
C observed as infrequent in the prevention of complications in ACS (after percutaneous interventions).
* A prespecified selective approach to the collection of data on adverse events was applied. Because the incidence of adverse drug reactions did not increase and because no new adverse drug reactions were identified, data from the COMPASS study were not included for the frequency calculation in this table.
The following adverse reactions were reported during post-registration monitoring and had a temporary association with Xarelto® administration. It is not possible to estimate the incidence of these adverse reactions in post-treatment monitoring.
immune system disorders: angioneurotic edema, allergic edema. In a phase III RCT, such adverse events were considered infrequent (>1/1000 to <1/100).
Hepatic and biliary tract disorders: cholestasis, hepatitis (including hepatocellular damage). In a phase III RCT, such adverse events were considered rare (>1/10000 to <1/1000).
Disorders of the circulatory and lymphatic system: thrombocytopenia. In a phase III RCT, such adverse events were considered infrequent (
>1/1000 to <1/100).
Overdose
Rare cases of overdose have been reported when taking rivaroxaban up to 600 mg without the development of bleeding or other adverse reactions. Due to limited absorption, a low-level plateau of drug concentration is expected with no further increase in its average plasma concentration when using doses higher than therapeutic, equal to 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.
Treatment of bleeding
If a patient receiving rivaroxaban has a bleeding complication, the next administration of the drug should be delayed or, if necessary, treatment with this drug should be discontinued. The half-life of rivaroxaban is approximately 5 to 13 hours. Treatment should be individualized depending on the severity and localization of bleeding. If necessary, appropriate symptomatic treatment such as mechanical compression (e.g., in severe nasal bleeding), surgical hemostasis with assessment of its effectiveness, infusion therapy and hemodynamic support, use of blood products (red blood cell mass or fresh frozen plasma, depending on whether anemia or coagulopathy occurred) or platelets may be used.
If the above measures do not eliminate bleeding, specific procoagulant drugs such as prothrombin complex concentrate, activated prothrombin complex factor concentrate or recombinant factor VIIa may be prescribed. However, there is currently limited experience with these drugs in patients receiving Xarelto®.
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 Xarelto®. There is no scientific evidence or experience with the systemic hemostatic drug desmopressin in patients receiving Xarelto®.
Pregnancy use
Pregnancy
The safety and efficacy of rivaroxaban in pregnant women have not been established. The data obtained on experimental animals showed a pronounced maternal toxicity of rivaroxaban associated with the pharmacological action of the drug (e.g., complications in the form of hemorrhages) and leading to reproductive toxicity. No primary teratogenic potential has been identified.
Because of the possible risk of bleeding and the ability to penetrate the placenta, rivaroxaban is contraindicated in pregnancy (see section Contraindications.
Women who are fertile should use effective contraception during treatment with Xarelto®.
Breastfeeding
There are no data on the use of rivaroxaban to treat women during breastfeeding. Data obtained in experimental animals show that rivaroxaban is excreted with breast milk. Xarelto® may only be used after withdrawal of breastfeeding (see section “Contraindications”.
Fertility
Studies have shown that rivaroxaban has no effect on male or female fertility in rats. There have been no studies of the effect of rivaroxaban on fertility in humans.
Weight | 0.037 kg |
---|---|
Shelf life | 3 years. Do not use after the expiration date |
Conditions of storage | At a temperature not higher than 30 ° C. Keep out of reach of children. |
Manufacturer | Bayer AG, Germany |
Medication form | pills |
Brand | Bayer AG |
Other forms…
Related products
Buy Xarelto, 20 mg 98 pcs with delivery to USA, UK, Europe and over 120 other countries.