Rivaroxaban

Last updated

Rivaroxaban
Rivaroxaban2DCSD.svg
Rivaroxaban xtal 2005.png
Clinical data
Trade names Xarelto, others
Other namesBAY 59-7939
AHFS/Drugs.com Monograph
MedlinePlus a611049
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 80–100%; Cmax = 2–4 hours (10 mg oral) [3]
Metabolism CYP3A4, CYP2J2 and CYP-independent mechanisms [3]
Elimination half-life 5–9 hours in healthy subjects aged 20 to 45 [3] [7]
Excretion 2/3 metabolized in liver and 1/3 eliminated unchanged [3]
Identifiers
  • (S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)
    phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.210.589 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H18ClN3O5S
Molar mass 435.88 g·mol−1
3D model (JSmol)
  • O=C1COCCN1c2ccc(cc2)N3C[C@@H](OC3=O)CNC(=O)c4ccc(s4)Cl
  • InChI=1S/C19H18ClN3O5S/c20-16-6-5-15(29-16)18(25)21-9-14-10-23(19(26)28-14)13-3-1-12(2-4-13)22-7-8-27-11-17(22)24/h1-6,14H,7-11H2,(H,21,25)/t14-/m0/s1 Yes check.svgY
  • Key:KGFYHTZWPPHNLQ-AWEZNQCLSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication (blood thinner) used to treat and prevent blood clots. [8] Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. [8] It is taken by mouth. [8]

Contents

Common side effects include bleeding. [8] Other serious side effects may include spinal hematoma and anaphylaxis. [8] It is unclear if use in pregnancy and breastfeeding is safe. [1] Compared to warfarin it has fewer interactions with other medications. [9] It works by blocking the activity of the clotting protein factor Xa. [8]

Rivaroxaban was patented in 2007 and approved for medical use in the United States in 2011. [10] In the United States, it will not be available as a generic medication until 2024. [11] [12] It is on the World Health Organization's List of Essential Medicines. [13] In 2021, it was the 86th most commonly prescribed medication in the United States, with more than 8 million prescriptions. [14] [15]

Medical uses

In those with non-valvular atrial fibrillation, it appears to be as effective as warfarin in preventing ischemic strokes and embolic events. [16] [17] Rivaroxaban is associated with lower rates of serious and fatal bleeding events than warfarin, though rivaroxaban is associated with higher rates of bleeding in the gastrointestinal tract. [18]

In July 2012, the UK's National Institute for Health and Clinical Excellence recommended rivaroxaban to prevent and treat venous thromboembolism. [19]

Contraindications

Because of the difficulty associated with managing bleeding, rivaroxaban should be discontinued at least 24 hours before surgery, then restarted as soon as adequate hemostasis is established. [20]

Dosing recommendations do not recommend administering rivaroxaban with drugs known to be strong combined CYP3A4/P-glycoprotein inhibitors because this results in significantly higher plasma concentrations of rivaroxaban. [5] [21]

Adverse effects

The most serious adverse effect is bleeding, including severe internal bleeding. [22] [23] [24] Rivaroxaban is associated with lower rates of serious and fatal bleeding events than warfarin but is associated with higher rates of bleeding in the gastrointestinal tract. [18]

As of 2015, post-marketing assessments showed liver toxicity, and further studies are needed to quantify this risk. [25] [26] In 2015, rivaroxaban accounted for the highest number of reported cases of serious injury among regularly monitored medications to the FDA's Adverse Events Reporting System (AERS). [27]

Reversal agent

In October 2014, Portola Pharmaceuticals completed Phase I and II clinical trials for andexanet alfa as an antidote for Factor Xa inhibitors with few adverse effects, and started Phase III trials. [28] [29] Andexanet alfa was approved by the U.S. Food and Drug Administration in May 2018, under the trade name AndexXa. [30] [31]

Mechanism of action

Rivaroxaban inhibits both free and bound Factor Xa in the prothrombinase complex. [32] It is a selective direct factor Xa inhibitor with an onset of action of 2.5 to 4 hours. [33] Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated Factor II), and no effects on platelets have been demonstrated. [3] It allows predictable anticoagulation and dose adjustments and routine coagulation monitoring; [3] dietary restrictions are not needed. [34]

Unfractionated heparin (UFH), low molecular weight heparin (LMWH), and fondaparinux also inhibit the activity of factor Xa, indirectly, by binding to circulating antithrombin (AT III) and must be injected, whereas the orally active warfarin, phenprocoumon, and acenocoumarol are vitamin K antagonists (VKA), decreasing a number of coagulation factors, including factor X. [35]

Rivaroxaban has predictable pharmacokinetics across a wide spectrum of patients (age, gender, weight, race) and has a flat dose response across an eightfold dose range (5–40 mg). [36] The oral bioavailability is dose-dependent. [5] Doses of rivaroxaban under 10 mg can be taken with or without food, as it displayed high bioavailability independent of whether food was consumed or not. [37] If rivaroxaban is given at oral doses of 15 mg or 20 mg, it needs to be taken with food to aid in drug absorption and achieve appropriate bioavailability (≥ 80%). [37]

Chemistry

Chemical structures of linezolid (top) and rivaroxaban (bottom). The shared structure is shown in blue. Linezolid-rivaroxaban comparison.svg
Chemical structures of linezolid (top) and rivaroxaban (bottom). The shared structure is shown in blue.

Rivaroxaban bears a striking structural similarity to the antibiotic linezolid: both drugs share the same oxazolidinone-derived core structure. [38] Accordingly, rivaroxaban was studied for any possible antimicrobial effects and for the possibility of mitochondrial toxicity, which is a known complication of long-term linezolid use. [39] Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria.[ citation needed ] As for mitochondrial toxicity, in vitro studies published before 2008 found the risk to be low. [38]

History

Rivaroxaban was initially developed by Bayer. [40] In the United States, it is marketed by Janssen Pharmaceuticals (a part of Johnson & Johnson). [40] It was the first available direct factor Xa inhibitor which is taken by mouth. [41]

Society and culture

Economics

Using rivaroxaban rather than warfarin costs 70 times more, according to Express Scripts Holding Co, the largest U.S. pharmacy benefits manager. [34] As of 2016, Bayer claimed that the drug was licensed in 130 countries and that more than 23 million patients had been treated. [42]

In September 2008, Health Canada granted marketing authorization for rivaroxaban to prevent venous thromboembolism (VTE) in people who have undergone elective total hip replacement or total knee replacement surgery. [43]

In the same month, the European Commission also granted marketing authorization of rivaroxaban to prevent venous thromboembolism in adults undergoing elective hip and knee replacement. [44] [6]

In July 2011, the US Food and Drug Administration (FDA) approved rivaroxaban for prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in adults undergoing hip and knee replacement surgery. [45]

In November 2011, the US FDA approved rivaroxaban for stroke prevention in people with non-valvular atrial fibrillation. [46]

On March 25, 2019, over 25,000 lawsuits over rivaroxaban in the US were settled for $775 million to get paid out to those affected. Plaintiffs accused the drugmakers of not warning about the bleeding risks, claiming their injuries could have been prevented had doctors and patients been provided adequate information. [47]

Research

Researchers at the Duke Clinical Research Institute have been accused of withholding clinical data used to evaluate rivaroxaban. [48] Duke tested rivaroxaban in a clinical trial known as the ROCKET AF trial. [49] The clinical trial, published 2011 in the New England Journal of Medicine [50] and headed by Robert Califf, then Commissioner of the FDA, [51] [50] found rivaroxaban to be more effective than warfarin in reducing the likelihood of ischemic strokes in patients with atrial fibrillation. [50] The validity of the study was called into question in 2014, when pharmaceutical sponsors Bayer and Johnson & Johnson revealed that the INRatio blood monitoring devices used were not functioning properly, [48] [49] A subsequent analysis by the Duke team published in February 2016 found that this had no significant effect on efficacy and safety in the trial. [52]

Under-representation of racial minorities in clinical trials has been noted. Compared to warfarin, efficacy and safety was found to be similar across racial subgroups. [50]

Related Research Articles

<span class="mw-page-title-main">Anticoagulant</span> Class of drugs

An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood.

<span class="mw-page-title-main">Warfarin</span> Medication

Warfarin is an anticoagulant used as a medication under several brand names including Coumadin. While the drug is described as a "blood thinner", it does not reduce viscosity but rather inhibits coagulation. Accordingly, it is commonly used to prevent blood clots in the circulatory system such as deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who have atrial fibrillation, valvular heart disease, or artificial heart valves. Less commonly, it is used following ST-segment elevation myocardial infarction and orthopedic surgery. It is usually taken by mouth, but may also be administered intravenously.

Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and treatment of venous thromboembolism and in the treatment of myocardial infarction.

<span class="mw-page-title-main">Prothrombin time</span> Assay for evaluating the extrinsic pathway & common pathway of coagulation

The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the extrinsic pathway and common pathway of coagulation. This blood test is also called protime INR and PT/INR. They are used to determine the clotting tendency of blood, in such things as the measure of warfarin dosage, liver damage, and vitamin K status. PT measures the following coagulation factors: I (fibrinogen), II (prothrombin), V (proaccelerin), VII (proconvertin), and X.

<span class="mw-page-title-main">Ximelagatran</span> Anticoagulant

Ximelagatran is an anticoagulant that has been investigated extensively as a replacement for warfarin that would overcome the problematic dietary, drug interaction, and monitoring issues associated with warfarin therapy. In 2006, its manufacturer AstraZeneca announced that it would withdraw pending applications for marketing approval after reports of hepatotoxicity during trials, and discontinue its distribution in countries where the drug had been approved.

<span class="mw-page-title-main">Enoxaparin sodium</span> Anticoagulant medication (blood thinner)

Enoxaparin sodium, sold under the brand name Lovenox among others, is an anticoagulant medication. It is used to treat and prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) including during pregnancy and following certain types of surgery. It is also used in those with acute coronary syndrome (ACS) and heart attacks. It is given by injection just under the skin or into a vein. It is also used during hemodialysis.

<span class="mw-page-title-main">Phenprocoumon</span> Drug

Phenprocoumon is a long-acting blood thinner drug to be taken by mouth, and a coumarin derivative. It acts as a vitamin K antagonist and inhibits blood clotting (coagulation) by blocking synthesis of coagulation factors II, VII, IX and X. It is used for the prophylaxis and treatment of thromboembolic disorders such as heart attacks and pulmonary (lung) embolism. The most common adverse effect is bleeding. The drug interacts with a large number of other medications, including aspirin and St John's Wort. It is the standard coumarin used in Germany, Austria, and other European countries.

<span class="mw-page-title-main">Dabigatran</span> Anticoagulant medication

Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation. Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests. In a meta analysis of 7 different studies, there was no benefit of dabigatran over warfarin in preventing ischemic stroke; however, dabigatran were associated with a lower hazard for intracranial bleeding compared with warfarin, but also had a higher risk of gastrointestinal bleeding relative to warfarin. It is taken by mouth.

<span class="mw-page-title-main">VKORC1</span> Protein-coding gene in the species Homo sapiens

The human gene VKORC1 encodes for the enzyme, Vitamin K epOxide Reductase Complex (VKORC) subunit 1. This enzymatic protein complex is responsible for reducing vitamin K 2,3-epoxide to its active form, which is important for effective clotting (coagulation). In humans, mutations in this gene can be associated with deficiencies in vitamin-K-dependent clotting factors.

Direct factor Xa inhibitors (xabans) are anticoagulants, used to both treat and prevent blood clots in veins, and prevent stroke and embolism in people with atrial fibrillation (AF).

<span class="mw-page-title-main">Vitamin K antagonist</span>

Vitamin K antagonists (VKA) are a group of substances that reduce blood clotting by reducing the action of vitamin K. The term "vitamin K antagonist" is technically a misnomer, as the drugs do not directly antagonize the action of vitamin K in the pharmacological sense, but rather the recycling of vitamin K. Vitamin K antagonists (VKAs) have been the mainstay of anticoagulation therapy for more than 50 years.

The management of atrial fibrillation (AF) is focused on preventing temporary circulatory instability, stroke and other ischemic events. Control of heart rate and rhythm are principally used to achieve the former, while anticoagulation may be employed to decrease the risk of stroke. Within the context of stroke, the discipline may be referred to as stroke prevention in atrial fibrillation (SPAF). In emergencies, when circulatory collapse is imminent due to uncontrolled rapid heart rate, immediate cardioversion may be indicated.

<span class="mw-page-title-main">Edoxaban</span> Anticoagulant drug

Edoxaban, sold under the brand name Lixiana among others, is an anticoagulant medication and a direct factor Xa inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Betrixaban</span> Chemical compound

Betrixaban is an oral anticoagulant drug which acts as a direct factor Xa inhibitor. Betrixaban is FDA approved for venous thrombosis prevention in adults hospitalized for an acute illness who are at risk for thromboembolic complications. Compared to other directly acting oral anticoagulants betrixaban has relatively low renal excretion and is not metabolized by CYP3A4.

<span class="mw-page-title-main">Apixaban</span> Anticoagulant medication

Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor xa. Specifically, it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests or dietary restrictions. It is taken by mouth.

<span class="mw-page-title-main">Darexaban</span> Chemical compound

Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma. It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation and possibly ischemic events in acute coronary syndrome. It is used in form of the maleate. The development of darexaban was discontinued in September 2011.

Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant hirudin was made possible which opened the door to this new group of drugs. Before the use of DTIs the therapy and prophylaxis for anticoagulation had stayed the same for over 50 years with the use of heparin derivatives and warfarin which have some well known disadvantages. DTIs are still under development, but the research focus has shifted towards factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.

Andexanet alfa, sold under the brand name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding. It has not been found to be useful for other factor Xa inhibitors. It is given by injection into a vein.

The SAMe-TT2R2 score is a clinical prediction rule to predict the quality of vitamin K antagonist anticoagulation therapy as measured by time in therapeutic INR range (TTR) (VKA e.g. warfarin). It has been suggested that it can aid in the medical decision making between VKAs and new oral anticoagulant/non-VKA oral anticoagulant (NOAC e.g. dabigatran, rivaroxaban, apixaban or edoxaban) in patients with atrial fibrillation (AF). This score can be used with patients with ≥1 additional stroke risk factors using the CHA2DS2-VASc score, where oral anticoagulation is recommended or should be considered.

Four drugs from the class of direct Xa inhibitors are marketed worldwide. Rivaroxaban (Xarelto) was the first approved FXa inhibitor to become commercially available in Europe and Canada in 2008. The second one was apixaban (Eliquis), approved in Europe in 2011 and in the United States in 2012. The third one edoxaban was approved in Japan in 2011 and in Europe and the US in 2015. Betrixaban (Bevyxxa) was approved in the US in 2017.

References

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  2. ↑ Xarelto (Bayer Australia Ltd)
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  45. ↑ "FDA Approves Xarelto (rivaroxaban tablets) to Help Prevent Deep Vein Thrombosis in Patients Undergoing Knee or Hip Replacement Surgery" (Press release). Janssen Pharmaceutica. July 1, 2011. Archived from the original on November 5, 2011. Retrieved July 1, 2011.
  46. ↑ "FDA approves Xarelto to prevent stroke in people with common type of abnormal heart rhythm". US Food and Drug Association. November 4, 2011. Retrieved April 27, 2016.
  47. ↑ "Bayer, Johnson & Johnson settle more than 25,000 lawsuits over blood thinner Xarelto for $775 million". The Washington Post . Retrieved April 7, 2019.
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  49. 1 2 Patel V. "Duke clinical trial under scrutiny in drug case". The Chronicle. Duke Student Publishing Company.
  50. 1 2 3 4 Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. (September 2011). "Rivaroxaban versus warfarin in nonvalvular atrial fibrillation". The New England Journal of Medicine. 365 (10): 883–91. doi:10.1056/NEJMoa1009638. PMC   3860773 . PMID   21830957.
  51. ↑ "Meet Robert M. Califf, M.D., Commissioner of Food and Drugs". U.S. Food and Drug Administration. Archived from the original on May 15, 2016. Retrieved May 3, 2016.
  52. ↑ Patel MR, Hellkamp AS, Fox KA (February 2016). "Point-of-Care Warfarin Monitoring in the ROCKET AF Trial". The New England Journal of Medicine. 374 (8): 785–8. doi: 10.1056/NEJMc1515842 . hdl: 20.500.11820/69b742f0-5b6d-4f54-93a5-98a1da909653 . PMID   26839968.
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