Buy Xarelto pills 2.5 mg, 56 pcs
  • Buy Xarelto pills 2.5 mg, 56 pcs

Xarelto® [Rivaroxaban]

Bayer Pharma AG
588 Items
2019-09-19
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Clinical Pharmacology

Round biconvex pills film coated, light yellow color. On one side, an extrusion is applied with a triangle with the dosage designation “2.5”, on the other side, the Bayer logo in the form of a cross. In cross section, the core is white.

Absorption and bioavailability
Rivaroxaban is rapidly absorbed; The maximum concentration (Сmax) is reached in 2-4 hours after taking the pill.
After ingestion rivaroxaban is absorbed almost completely and its bioavailability when taking pills 2.5 mg and 10 mg high (80-100%), regardless of the meal. Meal does not affect the AUC (the area under the concentration-time curve) and Cmax when taking a dose of 10 mg. Xarelto® pills at a dosage of 2.5 mg and 10 mg can be taken both with food and on an empty stomach (see the section "Dosage and administration").
The pharmacokinetics of rivaroxaban is characterized by moderate interindividual variability, the coefficient of variability Cv% ranges from 30% to 40%.

Distribution
Rivaroxaban has a high degree of binding to plasma proteins, it is approximately 92 - 95%, mainly rivaroxaban is associated with serum albumin. The drug has an average volume of distribution, it is approximately 50 liters.

Metabolism and excretion
When ingestion of approximately 2/3 of the dose received, rivaroxaban is metabolized and half is excreted by the kidneys and the second half through the intestines. The remaining third of the dose received is eliminated through direct renal excretion unchanged, mainly due to active renal secretion.
Rivaroxaban is metabolized by isoenzymes of cytochrome P450 - 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 Bcrp (breast cancer resistance proteins) carrier proteins.
Unchanged rivaroxaban is the only active compound in the blood plasma; no major or active circulating metabolites are detected in the plasma. Rivaroxaban, whose systemic clearance is approximately 10 l / h, can be attributed to low clearance drugs. When removing rivaroxaban from plasma, the final half-life is from 5 to 9 hours in young patients and from 11 to 13 hours in elderly patients.

Sex / Elderly (over 65)
Older patients have higher plasma rivaroxaban concentrations than younger patients; the average AUC value is approximately 1.5 times higher than the corresponding values ​​in young patients, mainly due to the apparent decrease in total and renal clearance.
In men and women, no clinically significant differences in pharmacokinetics were found.

Body mass
Too small or large body weight (less than 50 kg and more than 120 kg) only slightly affects the concentration of rivaroxaban in the blood plasma (the difference is less than 25%).

Childhood
No data for this age category.

Inter-ethnic differences
There were no clinically significant differences in pharmacokinetics and pharmacodynamics in patients of Caucasian, Negroid, Asian races, as well as in representatives of Latin American, Japanese, or Chinese ethnicity.

Liver dysfunction
The effect of hepatic insufficiency on the pharmacokinetics of rivaroxaban was studied in patients distributed according to the Child-Pugh classification (according to standard procedures in clinical studies). Child-Pu's classification allows us to estimate the prognosis for a patient with chronic liver disease, mainly cirrhosis. For patients who are scheduled for anticoagulant therapy, the most important consequence of 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 quite clearly correlate with this classification. The question of the treatment of such patients with anticoagulants should be resolved regardless of the class of Child-Pugh classification.
Xarelto® is contraindicated in patients with liver disease that occurs with coagulopathy, causing a clinically significant risk of bleeding.
In patients with liver cirrhosis and mild hepatic insufficiency (Child-Pugh class A), 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 rivaroxaban AUC 1.2 times). There were no significant differences in pharmacodynamic properties between the groups.
In patients with cirrhosis and liver failure of moderate severity (Child-Pugh class B), the average AUC of rivaroxaban was significantly increased (2.3 times) compared with healthy volunteers due to significantly reduced clearance of the drug substance, which indicates serious liver disease . The suppression of the activity of factor Xa was more pronounced (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 susceptible to rivaroxaban, which is a consequence of the closer relationship of pharmacodynamic effects and pharmacokinetic parameters, especially between concentration and prothrombin time.
Data for patients with hepatic insufficiency of class C according to Child-Pugh classification are not available.
Therefore, in patients with cirrhosis of the liver and abnormal liver function B and C according to the Child-Pugh classification, rivaroxaban is contraindicated.

Renal dysfunction
In patients with renal insufficiency, an increase in rivaroxaban exposure was observed, inversely proportional to the degree of decline in renal function, which was assessed by creatinine clearance.
In patients with mild renal failure (creatinine clearance 50-80 ml / min), moderate (creatinine clearance 30-49 ml / min) or severe severity (creatinine clearance 15-29 ml / min) was observed 1.4, 1, 5- and 1.6-fold increase in plasma concentrations of rivaroxaban (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 general inhibition of the activity of factor Xa increased by 1.5, 1.9 and 2 times compared with healthy volunteers; the prothrombin time due to the action of factor Xa also lengthened by 1.3, 2.2, and 2.4 times, respectively.
Data on the use of Xarelto® in patients with creatinine clearance 15-29 ml / min is limited, therefore, caution should be exercised when using the drug in this category of patients. Data on the use of Xarelto® in patients with creatinine clearance

Indications

Prevention of death due to cardiovascular causes and myocardial infarction in patients after acute coronary syndrome (ACS), which occurred with an increase in cardiospecific biomarkers, in combination therapy with acetylsalicylic acid or with acetylsalicylic acid and thienopyridine - clopidogrel or tiklopidididididomom tidopididididomom tidopididididomom tidopididipidididom oridikipidididididom)

Composition

1 tablet film coated, contains:
active ingredient: rivaroxaban micronized 2.5 mg,
excipients: microcrystalline cellulose - 40.00 mg, croscarmellose sodium - 3.00 mg, hypromellose 5cP - 3.00 mg, lactose monohydrate - 35.70 mg, magnesium stearate - 0.60 mg, sodium lauryl sulfate - 0.20 mg ; shell: iron dye yellow oxide - 0.015 mg, hypromellose 15cP - 1,500 mg, macrogol 3350 - 0.500 mg, titanium dioxide - 0.485 mg.

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Xarelto® [Rivaroxaban]

Dosage and Administration

For the prevention of VTE in large orthopedic operations
It is recommended to appoint 1 tablet (10 mg) 1 time / day.
Duration of treatment: 5 weeks after major surgery on the hip joint; 2 weeks after major knee surgery.
Rivaroxaban can be taken regardless of the meal.
The initial dose should be taken 6-10 hours after surgery, provided hemostasis is achieved.
If the patient misses a dose, rivaroxaban should be taken immediately and the next day, continue with treatment at 1 tablet / day, as before.
Dose adjustment depending on the age of the patient (over 65 years), gender, body weight or ethnic group is not required.
With liver disease
Rivaroxaban is contraindicated in patients with liver diseases 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 hepatic insufficiency (class B on the Child-Pugh scale) indicate a significant increase in the pharmacological activity of the drug. For patients with severe hepatic impairment (Child-Pugh class C), clinical data are not available.
Kidney disease
When prescribing rivaroxaban to patients with mild renal failure (CC 80-50 ml / min) or medium (CC

Adverse reactions

From the hemopoietic system: often - anemia (including relevant laboratory parameters), rarely - thrombocythemia (including elevated platelet count).
Since the cardiovascular system: infrequently - tachycardia, arterial hypotension (including lowering blood pressure, hypotension during procedures).
From the digestive system: often - nausea, increased GGT activity, transaminases (including ALT, ACT). Infrequently - constipation, diarrhea, abdominal pain (including pain in the upper abdomen, feeling of discomfort in the stomach), dyspepsia (including epigastric discomfort), dry mouth, vomiting, increased lipase, amylase, LDH, alkaline phosphatase, concentration bilirubin. Rarely - liver dysfunction, increased concentration of conjugated bilirubin (with a concomitant increase in ALT activity or without it).
From the side of the central nervous system: infrequently - dizziness, headache, short-term loss of consciousness (including syncopal states).
From the urinary system: infrequently - renal failure (including an increase in the concentration of creatinine, an increase in the concentration of urea).
From the blood coagulation system: often - hemorrhages after the procedures (including postoperative anemia and bleeding from a wound). Infrequently - hemorrhage (including hematoma and rare cases of hemorrhage into the muscles), bleeding from the gastrointestinal tract (including bleeding from the gums, rectum, hemorrhage), hematuria (including microhematuria), hemorrhage from the genital tract (including menorrhagia), nasal bleeding.
On the part of the body as a whole: infrequently - local edema, feeling unwell (including fatigue, general weakness), fever, peripheral edema.
Allergic reactions: infrequently - itching (including rare cases of generalized itching), rash, urticaria (including rare cases of generalized urticaria). Rarely - allergic dermatitis.
Other: infrequently - posttraumatic hematomas, discharge from a wound, pain in the extremities.
In other clinical studies of rivaroxaban
Selected cases of hemorrhage in the adrenal glands and conjunctiva, and also bleeding from gastrointestinal ulcers with a fatal outcome are described.
In rare cases, there has been jaundice and hypersensitivity.
Infrequently - hemoptysis.
Single intracranial hemorrhages are described, especially in patients with arterial hypertension and / or taking concomitant anti-hemostatic drugs, which in isolated cases can be potentially life-threatening.

Contraindications

Clinically significant active bleeding, for example:
Intracranial bleeding.
Gastrointestinal bleeding.
Liver disease that occurs with coagulopathy, which causes a clinically significant risk of bleeding.
Pregnancy.
Lactation period (breastfeeding period).
Children and adolescents under 18 years of age (efficacy and safety for patients in this age group have not been established).
Hypersensitivity to rivaroxaban or any excipients contained in the tablet.
The use of rivaroxaban has not been studied in clinical trials for surgical interventions in patients with a fracture of the femur. Therefore, the use of rivaroxaban is not recommended for this category of patients.
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Drug interactions

Pharmacokinetic interactions
Rivaroxaban is eliminated mainly through metabolism in the liver mediated by the cytochrome P450 system (CYP3A4, CYP2J2), and also by renal excretion of unchanged drug substance using P-gp / Bcrp vector systems (P-glycoprotein / protein for resistance to breast cancer) .
Rivaroxaban does not inhibit and does not induce the CYP3A4 isoenzyme and other important cytochrome isoforms.
The simultaneous use of Xarelto® and the potent inhibitors of the CYP3A4 isoenzyme and P-glycoprotein can lead to a decrease in the renal and hepatic clearance of rivaroxaban and, thus, significantly increase its systemic effect.
The combined use of Xarelto® and the azole antifungal agent ketoconazole (400 mg 1 time per day), which is a potent inhibitor of CYP3A4 and P-glycoprotein, led to an increase in the equilibrium mean AUC of rivaroxaban 2.6 times and an increase in the mean Cmax rivaroxaban 1.7 times, which was accompanied by a significant increase in the pharmacodynamic effect of the drug.
Co-administration of Xarelto® and HIV protease inhibitor ritonavir (600 mg 2 times a day), which is a potent CYP3A4 inhibitor and P-glycoprotein, led to an increase in the equilibrium mean AUC of rivaroxaban 2.5 times and an increase in the mean Cmax of rivaroxaban 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 in patients receiving systemic treatment with antifungal drugs of the azole group or HIV protease inhibitors (see the section "With caution").
Clarithromycin (500 mg 2 times a day), a potent inhibitor of the CYP3A4 isoenzyme and a moderate inhibitor of P-glycoprotein, caused an increase in AUC values ​​of 1.5 times and Cmax of rivaroxaban 1.4 times. This increase has the order of the normal variability of AUC and Cmax and is considered clinically insignificant.
Erythromycin (500 mg 3 times a day), a moderate inhibitor of CYP3A4 isoenzyme and P-glycoprotein, caused an increase in AUC and Cmax of rivaroxaban 1.3 times. This increase has the order of the normal variability of AUC and Cmax and is considered clinically insignificant.
Fluconazole (400 mg once daily), a moderate inhibitor of the CYP3A4 isoenzyme, caused an increase in the mean AUC of rivaroxaban 1.4 times and an increase in the mean Cmax 1.3 times. This increase has the order of the normal variability of AUC and Cmax and is considered clinically insignificant.
The combined use of Xarelto® and rifampicin, which is a strong inducer of CYP3A4 and P-glycoprotein, led to a decrease in the average AUC of rivaroxaban by approximately 50% and a parallel decrease in its pharmacodynamic effects. The combined use of rivaroxaban with other strong inducers of CYP3A4 (for example, phenytoin, carbamazepine, phenobarbital, or Hypericum perforatum) can also lead to a decrease in plasma concentrations of rivaroxaban. The decrease in plasma concentrations of rivaroxaban was considered clinically insignificant. Strong inducers of CYP3A4 must be used with caution.
Pharmacodynamic interactions
After simultaneous use of enoxaparin sodium (single dose of 40 mg) and Xarelto® (single dose of 10 mg), a summing effect was observed with respect to anti-factor Xa activity, which was not accompanied by additional summation effects with respect to blood clotting tests (prothrombin time, APTT). Enoxaparin sodium did not alter the pharmacokinetics of rivaroxaban (see section "With caution").
No pharmacokinetic interaction was detected between Xarelto® (15 mg) and clopidogrel (loading dose of 300 mg followed by the maintenance dose of 75 mg), but a significant increase in bleeding time was found in the patient subgroup, which did not correlate with the degree of platelet aggregation and P-selectin or GPIIb content / IIIa receptor (see the section "With caution").
After combined use of Xarelto® (15 mg) and naproxen in a dose of 500 mg, there was no clinically significant increase in bleeding time. However, in individuals, a more pronounced pharmacodynamic response is possible.
The transition of patients from warfarin (INR from 2.0 to 3.0) to Xarelto® (20 mg) increased the prothrombin time / INR (Neoplastin) to a greater extent than could be expected with a simple summation of effects (individual INR values ​​can 12), while the effect on APTT, the suppression of the activity of factor Xa and the endogenous potential of thrombin was additive.
If necessary, study the pharmacodynamic effects of Xarelto® during the transition period, as necessary tests that are not affected by warfarin, you can use the determination of the activity of anti-Xa, PiCT and HepTest®. Starting from the 4th day after discontinuation of warfarin, all test results (including PT, APTT, inhibition of factor Xa activity and EPT (endogenous thrombin potential)) reflect only the effect of Xarelto® (see the section “Dosage and administration”) .
No pharmacokinetic interactions have been reported between warfarin and Xarelto®.
Incompatibility: unknown.
Impact on laboratory parameters
Xarelto® has an effect on blood clotting rates (PF, APTTV, HepTest®) due to its mechanism of action.

Special instructions

The use of rivaroxaban has not been studied in clinical trials for surgical interventions undertaken with hip fractures.

If an unexplained decrease in hemoglobin or blood pressure is necessary to find the source of bleeding.

During treatment with rivaroxaban, no prolongation of the QT interval was observed.

When performing spinal puncture and epidural / spinal anesthesia for patients receiving platelet aggregation inhibitors to prevent thromboembolic complications, there is a risk of developing epidural or spinal hematoma that can lead to prolonged paralysis. The risk of these events is further increased with the use of permanent catheters or the concomitant use of drugs that affect hemostasis. Injury when performing epidural or spinal puncture or re-puncture may also contribute to increased risk. Patients should be supervised to identify signs or symptoms of neurological disorders (for example, numbness or weakness of the legs, bowel or bladder dysfunction). If neurological disorders are detected, urgent diagnosis and treatment is necessary. The physician must compare the potential benefits and risks of spinal cord intervention to patients receiving anticoagulants or preparing to receive anticoagulants to prevent thrombosis. The epidural catheter is removed no earlier than 18 hours after the last dose of rivaroxaban is prescribed. Rivaroxaban should not be prescribed earlier than 6 hours after removal of the epidural catheter.In the case of traumatic puncture, the appointment of rivaroxaban should be postponed for 24 hours.

Safety data obtained from preclinical studies

With the exception of the effects associated with the enhancement of the pharmacological action (bleeding), the analysis of preclinical data obtained in studies on pharmacological safety revealed no specific danger to humans.

Influence on ability to drive motor transport and control mechanisms

Research on the effect of rivaroxaban on the ability to drive vehicles and work with potentially dangerous moving machinery has not been conducted.

In the postoperative period, rarely there were cases of fainting and dizziness. Patients who experience these adverse reactions should not drive or work with moving machinery.

Overdosage

Symptoms: An overdose of rivaroxaban can lead to hemorrhagic complications due to the pharmacodynamic properties of the drug. The specific antidote of rivaroxaban is unknown.
Treatment: in case of overdose, activated carbon can be used to reduce the absorption of rivaroxaban. Taking activated carbon for 8 hours after an overdose reduces the absorption of rivaroxaban.

  • Brand name: Xarelto
  • Active ingredient: Rivaroxaban
  • Manufacturer: Bayer Pharma AG
  • Country of Origin: Germany

Studies and clinical trials of Rivaroxaban (Click to expand)

  1. Utility of a physiologically–based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug–drug–disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice
  2. Rivaroxaban versus enoxaparin for thromboprophylaxis after total hip or knee arthroplasty: a meta-analysis of randomized controlled trials
  3. Rivaroxaban and dabigatran etexilate: two new oral anticoagulants for extended postoperative prevention of venous thromboembolism after elective total hip arthroplasty
  4. Rivaroxaban for venous thromboembolism prevention after total knee arthroplasty: RECORD3 findings
  5. Extended-duration rivaroxaban thromboprophylaxis in acutely ill medical patients: MAGELLAN study protocol
  6. Comparison of unfractionated heparin, low-molecular-weight heparin, low-dose and high-dose rivaroxaban in preventing thrombus formation on mechanical heart valves: results of an in vitro study
  7. Determination of rivaroxaban by different factor Xa specific chromogenic substrate assays: reduction of interassay variability
  8. Determination of rivaroxaban – a novel, oral, direct Factor Xa inhibitor – in human plasma by high-performance liquid chromatography–tandem mass spectrometry
  9. Rivaroxaban for thromboembolism prophylaxis after orthopaedic surgery
  10. Rivaroxaban for thromboembolism prophylaxis after orthopaedic surgery
  11. Rivaroxaban (BAY 59-7939) – an oral, direct Factor Xa inhibitor – has no clinically relevant interaction with naproxen
  12. Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects
  13. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor
  14. Rivaroxaban – an oral, direct Factor Xa inhibitor – has potential for the management of patients with heparin-induced thrombocytopenia
  15. The impact of elective knee/hip replacement surgery and thromboprophylaxis with rivaroxaban or dalteparin on thrombin generation
  16. Dabigatran and rivaroxaban for prevention of venous thromboembolism – systematic review and adjusted indirect comparison
  17. Rivaroxaban for the prevention and treatment of venous thromboembolism
  18. Pharmacodynamic and pharmacokinetic basics of rivaroxaban
  19. Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits
  20. Will oral rivaroxaban improve clinically relevant outcomes and thromboprophylaxis management in the orthopedic patient?
  21. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays
  22. The International Normalized Ratio calibrated for rivaroxaban has the potential to normalize prothrombin time results for rivaroxaban-treated patients: results of an in vitro study
  23. Detection of lupus anticoagulant in the presence of rivaroxaban using Taipan snake venom time

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