Rivaroxaban

from Wikipedia, the free encyclopedia
Structural formula
Rivaroxaban structural formula
General
Non-proprietary name Rivaroxaban
other names
  • ( S ) -5-chloro- N - {2-oxo-3- [4- (3-oxomorpholin-4-yl) phenyl] -1,3-oxazolidin-5-ylmethyl} thiophene-2-carbamide ( IUPAC )
  • Rivaroxabanum (INN Latin )
Molecular formula C 19 H 18 ClN 3 O 5 S
External identifiers / databases
CAS number 366789-02-8
EC number 685-132-2
ECHA InfoCard 100.210.589
PubChem 9875401
DrugBank DB06228
Wikidata Q420262
Drug information
ATC code

B01 AX06

Drug class

anticoagulant

properties
Molar mass 435.88 g · mol -1
solubility

10 mg l −1 in water

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Rivaroxaban (trade name Xarelto ® ; manufacturer Bayer AG ) is a drug used to inhibit blood clotting (anticoagulation) . The substance is a direct factor Xa inhibitor and thus belongs to the group of direct oral anticoagulants (DOAC) , which are also known as new oral anticoagulants (NOAC) .

The substance is approved for the prophylaxis of venous thrombosis and embolism (venous thromboembolism, VTE) in patients with hip or knee replacement , for the prevention of ischemic strokes in patients with non-valvular atrial fibrillation and for the acute and long-term treatment of patients with deep vein thrombosis and pulmonary embolism . The drug is taken in the form of a tablet ( oral application) .

Pharmacological properties

It is a substance from the group of oxazolidinones . Rivaroxaban is absorbed enterally and is subject to first-pass metabolism of cytochrome P450 3A4 . The bioavailability is high (80–100%) with a peak concentration in serum after 2–4 hours and a half-life of 7–11 hours. In the plasma it is 95% bound to protein and around 30% is eliminated renally. Therefore, even with impaired kidney function ( GFR 30–80 ml / min.), It does not have an increased plasma level. As a direct inhibitor of factor Xa, rivaroxaban acts independently of antithrombin .

A clinical study has shown that doses of 15 mg or more should be taken with food in order to ensure optimal bioavailability of the drug.

Analytics

For the reliable qualitative and quantitative determination of rivaroxaban, after sufficient sample preparation z. B. the coupling of HPLC with mass spectrometry can be used by solid phase extraction .

Clinical studies

A phase III clinical study program with four studies, which was completed in 2008, investigated whether rivaroxaban offers advantages to patients after major orthopedic operations (e.g. patients who receive an artificial knee or hip joint). Result: Compared to standard therapy with low molecular weight heparin (here enoxaparin was tested), the risk for the combined endpoint of deep vein thrombosis , pulmonary embolism or death from thromboembolism is almost halved. The results were significant in all four studies, but are mainly achieved by reducing clinically irrelevant thromboses. In these studies, there were small differences in the incidence of side effects between comparator therapy and rivaroxaban; major bleedings occurred more often than with enoxaparin.

Further studies on the treatment of deep vein thrombosis and pulmonary embolism, on thrombosis prophylaxis in internal medicine patients, on the treatment of acute coronary syndrome and on stroke prophylaxis in the case of atrial fibrillation were carried out in 2007.

In the Rocket AF study, the results of which were presented at the annual meeting of the American Heart Association in 2010 , rivaroxaban was no less effective than warfarin (similar to Marcumar, which is better known in Germany ) in the prevention of strokes and peripheral embolisms. The rates of bleeding and other side effects were the same. There was less intracranial and fatal bleeding with rivaroxaban .

Both in the treatment of acute coronary syndrome and in the prophylaxis of venous thromboembolism VTE, moderate and severe bleeding was significantly more common with rivaroxaban compared to placebo (ATLAS study) or to low molecular weight heparin and placebo (MAGELLAN study).

If a revascularization , i.e. a restoration of the arterial blood flow, is carried out because of a peripheral arterial occlusive disease , there is a high risk of postoperative complications such as acute ischemia , amputation , myocardial infarction , apoplexy or death from a cardiovascular cause. In a randomized study it could be shown that complications occurred less frequently after 2 × 2.5 mg rivaroxaban and 100 mg aspirin daily than after aspirin alone. Revascularization was carried out endovascularly in 65%, for example by thrombectomy , and in 35% by open surgery.

Admission status

In 2008, rivaroxaban was approved by the European Commission under the trade name Xarelto ® for the prophylaxis of venous thromboembolism (VTE) in adult patients after elective hip or knee replacement surgery. The development was a cooperation between Bayer AG and Janssen Pharmaceutica (part of the US company Johnson & Johnson ). Bayer holds the distribution rights for all markets outside the USA.

At the beginning of 2011, the manufacturer submitted an application for approval to the European Medicines Agency (EMA) for the prevention of strokes in patients with non-valvular atrial fibrillation. In addition, approval for the treatment of acute deep vein thrombosis and the prevention of recurrent deep vein thrombosis and pulmonary embolism was applied for at the EMA. Bayer received approval for both indications in December 2011. The active ingredient is also approved for the treatment of pulmonary embolism even without evidence of thrombosis.

In July 2011, it was approved by the FDA in the USA and in November 2011 for the prevention of stroke in patients with non-valvular atrial fibrillation.

In May 2013, the European Commission granted approval for the use of rivaroxaban in combination with a standard therapy for antiplatelet aggregation as secondary prophylaxis after acute coronary syndrome .

Drug Prescription Report

In the drug prescription report 2009, rivaroxaban was given the rating A (= innovative structure with therapeutic relevance ). Of 29 drugs newly approved in 2008, 7 were rated A (= innovative structure with therapeutic relevance ), 6 were rated B (= improvement in pharmacodynamic or pharmacokinetic properties ), 15 were rated C (= analog preparation with no or only minor differences ) and one received the rating D (= insufficiently assured active principle or unclear therapeutic value ).

Evaluation and criticism

In an information from the Drugs Commission of the German Medical Association (AkdÄ) from 2013 it says: “With treatment times of up to three months, rivaroxaban is easier to handle because regular monitoring is not required, but the lack of controllability of the coagulation status can also be a disadvantage. For use from three months, the significantly higher therapy costs must be taken into account. "

In September 2013, the manufacturers of the new oral anticoagulants (NOAC for short: apixaban , dabigatran etexilate and rivaroxaban) pointed out in a joint information letter agreed with the competent pharmaceutical authorities that reports of adverse drug reactions (ADRs) from clinical studies and from practice have shown that even with the new oral anticoagulants there is a significant risk of severe bleeding events, including death. In order to minimize the risk of bleeding, the prescribing physicians must individually assess the risk of bleeding of the patient and observe the information on dosage and contraindications as well as warnings and precautionary measures. Common to all new oral anticoagulants are the following contraindications:

  • acute, clinically relevant bleeding
  • Lesions or clinical situations considered to be a significant risk factor for major bleeding
  • simultaneous use of other anticoagulants such as heparins or vitamin K antagonists (with a few exceptions).

Kidney dysfunction can also be a contraindication, but different recommendations apply to the three drugs.

The Federal Institute for Drugs and Medical Devices (BfArM) announced in September 2013 that an increasing number of suspected cases in connection with the anticoagulant had been registered. According to this, 968 cases of undesirable side effects with 72 deaths are said to have occurred in the first 8 months of 2013, compared to 750 suspicious transaction reports and 58 deaths in the whole of 2012. The Federal Institute, however, sees no reliable evidence for a "causal relationship between drug and side effect".

Advisors to the American regulatory authority Food and Drug Administration (FDA) came to the conclusion in March 2009 that Xarelto does not offer any additional therapeutic benefit compared to the long-established anticoagulant warfarin (better known in Germany is the related active ingredient Phenprocoumon, trade name Marcumar ). Xarelto cannot prevent strokes more frequently than the established and inexpensive means. In addition, no long-term studies on the side effects of Xarelto were available at the time. According to the FDA experts, the studies submitted by BAYER raise questions about the risk of heart attacks and bleeding in particular.

On March 24, 2019, Bayer and its partner company Janssen Pharmaceuticals accepted a settlement payment of $ 775 million (EUR 686 million) to achieve the settlement of around 25,000 lawsuits in the United States related to Xarelto. The plaintiffs held the anticoagulant responsible for bleeding and even death and accused Bayer of not providing sufficient information about dangers such as these. Bayer expects half of its costs to be paid for through product liability insurance.

Latest news in WHO Pharmaceuticals Newsletter No. 2/2019 from New Zealand also report increased bleeding tendencies and strokes when using Xarelto in the Medsafe news .

Contraindications

In the case of regional anesthesia procedures close to the spinal cord ( spinal anesthesia or epidural anesthesia ), rivaroxaban should be paused for 22–26 hours (corresponds to two half-lives) before application at low doses in patients with healthy kidneys. In the event of impaired renal function or high doses, rivaroxaban should be paused for 44–65 hours (corresponds to five to six half-lives). After insertion or removal of the catheter, the first indication of rivaroxab should be given after 4–5.5 hours at the earliest (corresponds to 8 hours of clot formation time minus the time between ingestion and maximum effect).

In October 2018, it was announced that rivaroxaban is not indicated for thromboprophylaxis in patients undergoing heart valve replacement (including TAVI).

Antagonization

An overdose of rivaroxaban can lead to bleeding complications due to its pharmacodynamic properties. Furthermore, an otherwise uncritical bleeding z. B. be life-threatening in the context of an emergency operation under a usual dose of rivaroxaband. A specific antidote that reverses the pharmacodynamic properties of rivaroxaban has not been available for a long time. A dialysis can rivaroxaban due to its high plasma protein binding is not removed from the body. In May 2018, the Xarelto antidote Andexanet alfa (AndexXa) was approved in the US, and on March 1, 2019, the EMA recommended approval of the antidote Ondexxya in the EU. In April 2019 it was approved by the European Commission for the European member states.

In an experiment, the administration of prothrombin concentrate PPSB normalized the thromboplastin time (TPZ, PT) that was prolonged by rivaroxaban . 50 units of PPSB per kilogram of body weight (e.g. 4000 units of PPSB for 80 kg) were used to neutralize the laboratory effects of a previous daily dose of 20 mg rivaroxaban. Another recommendation gives the dose for the treatment of intracerebral hemorrhage with rivaroxaban as 30 IU / kg PPSB.

A study published in the New England Journal of Medicine in December 2015 found that the anticoagulant activity of rivaroxaban could be reversed within minutes by infusion of andexanet alfa . Andexanet alfa side effects were reported to be minimal.

Effect control

As part of the application, regular laboratory control is not necessary because of the comparatively easily predictable effect. In patients with threatening bleeding or before emergency surgery, measuring the effects of rivaroxaban may be necessary in order to assess the further risk of bleeding or to plan the time for an intervention. The influence of rivaroxaban on standard coagulation tests depends on the time of administration and is unreliable. When the peak level of rivaroxaban in the blood is reached, the INR value can rise and the aPTT can be prolonged. However, based on these values, no conclusions can be drawn about the effectiveness. Normal values ​​in the standard coagulation tests do not rule out rivaroxaban action. A measurement of anti-factor Xa activity is best for measuring the effects of rivaroxaban. It should be noted, however, that the standard anti-factor Xa activity tests are calibrated for measuring heparin activity. An anti-factor X activity test calibrated for rivaroxaban is required for exact measurement of the rivaroxaban effect, which is usually only possible in specialized laboratories on special request.

Others

Xarelto is Bayer's top-selling drug: sales rose from 2.9 billion euros in 2016 to 3.6 billion euros in 2018. In 2019, however, Bayer will lose Xarelto customers to competitor Bristol-Myers Squibb .

Web links

  • www.xarelto.de - Official website for pharmaceuticals from Bayer HealthCare

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