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Siste oppdatering 08 april 2016
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Xarelto® in Practice Q&A

Answers to commonly asked questions about Xarelto®

Xarelto® is the first oral, once-daily direct Factor Xa inhibitor for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery. With the introduction of any new therapeutic option, there are often questions regarding its use in clinical practice. These answers to some commonly asked questions are designed to provide further guidance to the physician about the appropriate use of Xarelto®.

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Is there any evidence of liver toxicity with Xarelto®?

Based on the clinical evidence reported to date from over 18,000 patients who have been exposed to Xarelto®, no safety issues attributable to Xarelto® have been observed. This includes long-term exposure of approximately 7,000 patients treated with Xarelto® for at least 3 months, of which approximately 4,500 patients were treated with Xarelto® for 6 to 12 months or longer.64
In the RECORD1-3 studies the incidence of alanine transferase (ALT) elevation > 3 x upper limit of normal (ULN), which is a marker for potential liver damage, was low and comparable with enoxaparin. The incidence across the RECORD1-3 studies in the Xarelto® arm ranged from 1.6% to 2.0% and from 1.7% to 4.7% in the enoxaparin group.2, 3, 4

What is the cardiovascular profile of Xarelto®?

The RECORD programme is a large-scale program to actively assess and report the cardiovascular outcomes in hip and knee replacement surgery – all of which were adjudicated by an independent committee.
The independent panel of specialists found that the incidence of cardiovascular events across the RECORD1-3 studies was low and similar between Xarelto® and enoxaparin (up to 0.3% for Xarelto® and up to 0.5% for enoxaparin).2, 3, 4

Do I need to adjust the dose of Xarelto® in patients with renal impairment?

Xarelto® is eliminated via both the faecal and the renal pathway, with two thirds metabolised by the liver and one third of active drug eliminated unchanged via the kidneys. Xarelto® does not require any dose adjustments in patients with mild renal impairment (creatinine clearance 50-80 mL/min) or moderate renal impairment (creatinine clearance 30-49 mL/min), but should be used with caution in patients with severe renal impairment (creatinine clearance 15-29 mL/min) or moderate renal impairment (creatinine clearance 30-49 mL/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations.1
Xarelto® has not been studied in the patient population with a creatinine clearance < 15 mL/min and its use is not recommended in this patient population.

Can I treat all my patients with the 10 mg once daily dose regardless of age, weight, and gender?

In RECORD1-3 (RECORD2 compared 5 weeks of Xarelto® versus 2 weeks of enoxaparin) Xarelto® displayed comparable safety and superior efficacy to enoxaparin in a wide range of patients (18 to 93 years, 33 to 190 kg and both genders) after elective hip and knee replacement. Based on the outcome of the RECORD programme, a dose adjustment of Xarelto® is not required.1
Xarelto® has not been studied in patients under 18 or who are undergoing hip fracture surgery. Therefore, its use is not recommended in children or adolescents below 18 years of age or in patients undergoing hip fracture surgery.1

Why is no routine coagulation monitoring required?

Xarelto® has predictable pharmacokinetics, with little variation of plasma concentration with age, weight, or renal function following a fixed dose. With a fixed dose, a wide therapeutic window, few drug interactions, and predictable pharmacodynamics, no routine monitoring of coagulation parameters is required.1, 8
The pharmacodynamics of Xarelto® are predictable, as Factor Xa activity closely correlates with the plasma concentration. The prothrombin time (PT) varies in a linear dose-dependent fashion with plasma levels of Xarelto®.

How will clotting parameters change in a patient on Xarelto®?

Prothrombin time (PT) varies in a linear fashion, with plasma concentration with a correlation coefficient r = 0.98 when Neoplastin® is used for the assay.
In patients undergoing major orthopaedic surgery, the 5/95 percentiles for PT (Neoplastin®) 2–4 hours after tablet intake ranged from 13 to 25 seconds. The PT should be reported as seconds and not reported as the INR (international normalised ratio), because the INR is only calibrated and validated for coumarin and can not be used for any other anticoagulant.
The activated partial thromboplastin time (aPTT) and HepTest® are also prolonged dose-dependently; however, they are not recommended to assess the pharmacodynamic effect of Xarelto®.1, 8

Is there an antidote for Xarelto® in case the need arises? How should an overdose be treated?

Overdose following administration of Xarelto® may lead to haemorrhagic complications due to its pharmacodynamic properties. A specific antidote antagonising the pharmacodynamic effect of Xarelto® is not available. The use of activated charcoal to reduce absorption in case of Xarelto® overdose may be considered.
Should bleeding occur, management of the haemorrhage may include the following steps:
  • Delay of next Xarelto® administration or discontinuation of treatment as appropriate. Xarelto® has a mean terminal half-life between 7 and 11 hours
  • Appropriate symptomatic treatment, e.g. mechanical compression, surgical interventions, fluid replacement and haemodynamic support, blood product or component transfusion should be considered
If life-threatening bleeding cannot be controlled by the above measures, administration of recombinant Factor VIIa may be considered. However, there is currently no experience with the use of recombinant Factor VIIa in individuals receiving Xarelto®. The recommendation is based on limited non-clinical data. Re-dosing of recombinant Factor VIIa shall be considered and titrated, depending on improvement of bleeding.
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of Xarelto®. There is neither scientific rationale for benefit nor experience with the use of systemic haemostatics (eg, desmopressin, aprotinin, tranexamic acid, aminocaproic acid) in individuals receiving Xarelto®. Due to high plasma protein binding, Xarelto® is not expected to be dialysable.1

  • 64 - Bayer’s Novel Anticoagulant Rivaroxaban Submitted for Approval in the U.S. [press release] Available at http://www.viva.vita.bayerhealthcare.com/index.php?id=36&tx_ttnews[tt_news]=12625&cHash=97a2ea4a90
  • 2 - Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775.
  • 3 - Kakkar AK, Brenner B, Dahl OE, et al; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372(9632):31-39.
  • 4 - Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786.
  • 1 - Xarelto® (rivaroxaban) Summary of Product Characteristics as approved by the European Commission.
  • 8 - Kubitza D, Haas S. Novel factor Xa inhibitors for prevention and treatment of thromboembolic diseases. Expert Opin Investig Drugs. 2006;15(8):843-855.
Factor Xa
Pivotal component of blood clotting cascade. Stimulates the production of thrombin, the enzyme in the coagulation cascade that promotes the formation of blood clots.
Venous thromboembolism
A disease process beginning with a blood clot occurring within the venous system, including deep vein thrombosis and pulmonary embolism.
Efficacy
The ability of a drug to produce the desired effect.
Prothrombin
Inactive version of thrombin, the enzyme in the coagulation cascade that promotes the formation of blood clots. Factor Xa stimulates the conversion of prothrombin to thrombin.
Major orthopaedic surgery
Major operations on the bones or joints including total hip or knee replacement surgery.
International Normalized Ratio
A system for assessing the clotting tendency of blood in patients receiving anticoagulant therapy. For patients with atrial fibrillation, the recommended target INR range is between 2 and 3. If the INR is higher than 3, patients are at risk of serious bleeding. If the INR is less than 2, patients are at risk of a blood clotting event.

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Xarelto® demonstrated a comparable safety profile to enoxaparin in all four RECORD studies. 9

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