Rivaroxaban

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Rivaroxaban
Rivaroxaban structure.svg
Rivaroxaban ball-and-stick.png
Systematic (IUPAC) name
(S)-5-chloro-N-{[2-oxo-3-[4-(3-oxomorpholin-4-yl)
phenyl]oxazolidin-5-yl]methyl} thiophene-2-carboxamide
Clinical data
Trade names Xarelto
AHFS/Drugs.com Micromedex Detailed Consumer Information
Licence data EMA:Link, US FDA:link
Pregnancy cat. C (US)
Legal status POM (UK) -only (US)
Routes oral
Pharmacokinetic data
Bioavailability 80% to 100%; Cmax = 2–4 hours (10 mg oral)[1]
Metabolism CYP3A4 , CYP2J2 and CYP-independent mechanisms[1]
Half-life 10 mg oral 7–11 hours[1]
Excretion 2/3 metabolized in liver and 1/3 eliminated unchanged[1]
Identifiers
CAS number 366789-02-8 N
ATC code B01AF01
PubChem CID 6433119
DrugBank DB06228
ChemSpider 8051086 YesY
UNII 9NDF7JZ4M3 YesY
ChEBI CHEBI:68579 N
ChEMBL CHEMBL198362 YesY
PDB ligand ID RIV (PDBe, RCSB PDB)
Chemical data
Formula C19H18ClN3O5S 
Mol. mass 435.882 g/mol
 N (what is this?)  (verify)

Rivaroxaban (BAY 59-7939) is an oral anticoagulant invented and manufactured by Bayer; in a number of countries it is marketed as Xarelto.[1] In the United States, it is marketed by Janssen Pharmaceutica.[2] It is an orally active direct factor Xa inhibitor. Rivaroxaban is well absorbed from the gut and maximum inhibition of factor Xa occurs four hours after a dose. The effects lasts 8 to 12 hours, but factor Xa activity does not return to normal within 24 hours so once-daily dosing is possible.

There is currently no specific way to reverse the anticoagulant effect of rivaroxaban in the event of a major bleeding event, unlike warfarin.[3]

Medical uses[edit]

Rivaroxaban can be used to prevent strokes in those with atrial fibrillation due to causes other than heart valve disease, and at least one additional risk factor for stroke (congestive heart failure, hypertension, age, diabetes, and prior stroke)

Rivaroxaban can also be used to prevent the formation of blood clots in the veins (deep venous thrombosis) in adults who have had an operation to replace a hip or knee and for treatment and prevention of acute deep venous thrombosis in adults. It can not be used for prevention of venous thrombosis in hospitalized medically ill patients.[4]

Rivaroxaban is not indicated for prosthetic heart valves[5] or for mitral stenosis.

Rivaroxaban is not indicated as an add-on treatment for dual antiplatelet therapy in the secondary prevention of coronary incidents (double and triple therapy).[6][7] In Europe, however, a 2.5-mg twice-daily dose was approved by the European Commission after a recommendation by the European Medicines Agency (EMA) for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine.[8]

Non-valvular atrial fibrillation[edit]

A systematic review of novel anticoagulants concluded: new oral anticoagulants are a viable option for patients receiving long-term anticoagulation. As for all new oral anticoagulants treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment. There were no head-to-head comparisons of novel anticoagulants and limited data on harms.[9] The new oral anticoagulants seem no more effective than warfarin for prevention of nonhemorrhagic stroke and systemic embolic events in the overall non-valvular atrial fibrillation population, but are generally associated with a lower risk of intracranial bleeding than warfarin. The numbers of all strokes and systemic embolic events avoided per 1000 patients per year were highly dependent on the geographic region and quality of warfarin therapy, with no significant differences in European patients or in centres with TTR ≥65%. The absolute risk reduction in major bleedings was mainly observed in centres with TTR <65%. The absolute risk difference in all-cause death per 1000 patients treated per year was highly dependent on quality of warfarin therapy. No significant differences between the NOAC and warfarin were seen in centres with TTR ≥65%, while a significant absolute risk reduction was achieved in centres with TTR <65%. The absolute benefit of the new oral anticoagulants tends to be of a lesser magnitude in Europe than in other regions, which might be due to regional differences in quality of oral anticoagulation and overall management of associated risk factors for thrombosis. [10]

Venous thromboembolism[edit]

In a systematic review compared with vitamin K antagonists (warfarin) in treatment of acute venous thromboembolism, the novel oral anticoagulants had a similar risk of recurrence of acute venous thromboembolism and all cause mortality.[11] In a systematic review of three trials, novel anticoagulants (rivaroxaban and dabigatran) did not differ for mortality or venous thromboembolism related mortality from warfarin in prevention of venous thromboembolism.[9] In a more recent systematic review five studies were included about dabigatran, rivaroxaban, apixaban and edoxaban. NOACs have a comparable efficacy for recurrent VTE, fatal PE and overall mortality and are associated with a significantly lower risk of bleeding complications compared to warfarin, although the NNT to prevent one major bleeding is relatively high at 149.[12]

A synthesis of systematic reviews concludes: the new oral anticoagulants are effective for thromboprophylaxis after total hip replacement and total knee replacement. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding. So there is no evidence that new anticoagulants have a better harm-benefit balance than LMWH. New oral anticoagulants have not been compared with warfarin in this indication.[13]

In a systematic review comparing rivaroxaban, dabigatran and apixaban with enoxaparin after total hip or knee replacement, the higher efficacy of rivaroxiban was associated with a higher bleeding tendency, but the new anticoagulants did not differ significantly for efficacy and safety.[14] The use of once-daily enoxaparin regimen as control in clinical trials will lead to more favorable estimates of relative efficacy for the new oral anticoagulants than if enoxaparin 30 mg twice daily had been chosen as a comparator.[15]

Myocardial infarctions[edit]

In patients with a recent acute coronary syndrome, the addition of a new oral anticoagulant to antiplatelet therapy results in a modest reduction in cardiovascular events but a substantial increase in bleeding, most pronounced when new oral anticoagulants are combined with dual antiplatelet therapy. The use of anti-Xa or direct thrombin inhibitors is associated with a dramatic increase in major bleeding events (2- to 3-fold higher odds) , which might offset all ischemic benefits in patients receiving antiplatelet therapy after an ACS. There is no net clinical benefit, calculated as the sum of composite ischemic events and major bleeding events for different doses of new anticoagulants.[6][7] In people with the acute coronary syndrome, new oral anticoagulants increase risk for gastrointestinal bleeding and clinically relevant bleeding with 400 and 98% compared with standard care. Number needed to harm 26 and 27.[16]

Adverse effects[edit]

According to a systematic review, adverse effects of new anticoagulants (dabigatran, rivaroxaban and apixaban) compared with warfarin were lower for fatal bleeding and hemorrhagic stroke, numerically lower for major bleeding, numerically higher for gastrointestinal bleeding, and higher for discontinuation due to adverse events. Bleeding risks may be increased for persons older than 75 years or those receiving warfarin who have good control. There were limited data on harms. [9]

Bleeding risk[edit]

Rivaroxaban increases the risk of bleeding and can cause serious, potentially fatal bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding including aspirin and other anti-platelet agents (clopidogrel), other anticoagulants (warfarin and other new anticoagulants), heparin and LWMH, thrombolytic agents, SSRIs and SNRIs (both antidepressants), and NSAIDs (anti-inflammatory). Concommitant use of strong CYP3A4- and P-glycoprotein (P-gp)-inhibitors also increases the bleeding risk.

There is a 48% higher risk of gastrointestinal bleeding for rivaroxaban compared to standard care; but it is also a problem for dabigatran (58% higher), and maybe for all new anticoagulants. Combined in all studies of new anticoagulants there was a 45% higher risk; the lowest numerical risk increase was for apixaban and edoxaban.[17]

Bleeding risk of new anticoagulants depends more on clinical setting, than on type of anticoagulant. In patients undergoing hip surgery, patients with coronary syndrome and thromboprofylaxis of medically ill patients, they were linked with significantly higher risks of bleeding than the comparator agents. On the contrary in the settings of non valvular atrial fibrillation and extended treatment of venous thromboembolism there was no difference. Rivaroxaban was associated with significant reductions in major bleeding in the setting of acute venous thromboembolism and pulmonary embolism, but a four-times-higher risk of major bleeding in the setting of acute coronary syndrome and a nearly threefold higher risk of bleeding in the setting of acutely ill patients.[18]

Overdose[edit]

There is no established way to reverse the anticoagulant effect of rivaroxaban in cases of serious bleedings or accidents, which can be expected to persist for about 24 hours after the last dose (i.e., about two half-lives). Half-life is 5-9 hr and 11-13 hr for the elderly. A specific antidote is not available. Prothrombin complex concentrate immediately and completely reversed the anticoagulant effect in a study with 12 healthy subjects[19] but the clinical effectiveness of this treatment has yet to be proven.[20] If bleeding cannot be controlled, administration of a specific procoagulant reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is currently very limited clinical experience with the use of these products in individuals receiving rivaroxaban.[21]

Stopping rivaroxaban[edit]

There is increased risk of stroke with stopping of rivaroxaban. Stopping rivaroxaban in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. If rivaroxaban must be discontinued for a reason other than pathological bleeding, coverage with another anticoagulant should be considered. Rivaroxaban has a black-box warning in the U.S. regarding potential thrombosis that may occur if it is discontinued and not replaced by another anticoagulant.[22] Stopping rivaroxaban is potentially associated with a prothrombotic rebound effect.[23] Another possible explanation is poor INR control.

Other common adverse events[edit]

In 1 to 10% of patients: anaemia, wound secretion, pruritus, extremity pain, dizziness, headache, syncope, gastrointestinal pains, peripheral oedema, decreased general strength and energy.[24]

Drug interactions[edit]

For many potential interactions with drugs that are often used in AF patients no detailed information is available yet.[25]

Strong dual Inhibitors of CYP3A4 and P-gp (e.g., ketoconazole (Nizoral), itraconazole (Sporanox), ritonavir, or clarithromycin) increase the exposure to rivaroxaban and increase the risk of bleeding . Avoid them. Avoid concomitant use of P-gp and weak or moderate CYP3A4 inhibitors (eg, erythromycin, azithromycin, diltiazem, verapamil, quinidine, ranolazine, amiodarone, felodipine) in patients with renal impairment, unless the benefit outweighs the bleeding risk.

Strong dual inducers of CYP3A4 and P-gp decrease exposure to rivaroxaban and increase the risk of stroke. Avoid concomitant use of rivaroxaban with rifampicin (Rifadin), carbamazepine (Tegretol), phenytoin and St. John’s wort, because such drugs will decrease exposure to rivaroxaban.

Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID increases the risk of bleeding.

Long term safety[edit]

The safety (and efficacy) of rivaroxaban in the longer term (beyond two years) are uncertain.

Contraindications[edit]

Rivaroxaban must not be used in people who are actively bleeding, or who have liver disease which leads to problems with blood clotting and an increased risk of bleeding. The medicine must also not be used in people with conditions putting them at risk of major bleeding, such as an ulcer in the gut, or in people being treated with other anticoagulant medicines.

Rivaroxaban must not be used in women who are pregnant or breast-feeding due to lack of data and in patients below 18 years of age.

It is not recommended in people with severe renal impairment (creatinine clearance <15 ml/min).

It is not recommended in people receiving concomitant systemic treatment with strong concurrent CYP3A4- and P-gp-inhibitors, i.e. azole-antimycotics itraconazole (Sporanox) and ketoconazole (Nizoral) or HIV protease inhibitors as ritonavir (Norvir) and in people concomitantly treated with dronedarone (Multaq). It is also not indicated in people receiving concomitant treatment with strong CYP3A4 inducers, such as rifampicin, St Johns wort (Hypericum perforatum), and the anti epileptics carbamazepine (Tegretol), phenobarbital, and phenytoin, unless closely observation for signs and symptoms of thrombosis. [1]

It must not be used in people who are hypersensitive (allergic) to rivaroxaban or any of the other ingredients.[26]

Mechanism of action[edit]

Rivaroxaban is an oxazolidinone derivative optimized for inhibiting both free Factor Xa and Factor Xa bound in the prothrombinase complex.[27] It is a highly selective direct Factor Xa inhibitor with oral bioavailability and rapid onset of action. 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.[1]

Pharmacokinetics[edit]

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).[28] Clinical trial data have shown that it allows predictable anticoagulation with no need for dose adjustments and routine coagulation monitoring.[1] However, these trials have excluded patients with liver disease and end-stage renal disease; therefore, the safety of rivaroxaban in these populations is unknown. The bioavailability of rivaroxaban is high (80-100%) with a top concentration in the serum after 2−4 hours. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly. In the plasma it is 95% protein bound. Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the administered dose undergoes direct renal excretion as unchanged active substance in the urine. Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. In individuals with mild (creatinine clearance 50 - 80 ml/min), moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal impairment, rivaroxaban plasmaconcentrations were increased 1.4, 1.5 and 1.6 fold respectively.[29] Food intake has an impact on the absorption and bioavailability of rivaroxaban (area under the curve plasma concentrations increase by 39%), rivaroxaban should be taken together with food.[30]

Chemistry[edit]

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. 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. Studies found that neither rivaroxaban nor its metabolites have any antibiotic effect against Gram-positive bacteria. As for mitochondrial toxicity, in vitro studies found the risk to be low.[31]

Society and culture[edit]

Approval[edit]

In September 2008, Health Canada granted marketing authorization for rivaroxaban taken once daily for the prevention of venous thromboembolism (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery.[32] In September 2008, the European Commission granted marketing authorization of rivaroxaban for the same indication.[33]

In December 2011, rivaroxaban was approved by the European Commission for use in two new indications: prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (AF) with one or more risk factors, and for treatment of deep venous thromboembolism. It was also approved for prevention of recurrent deep venous thromboembolism and pulmonary embolism (PE) following an acute deep venous thromboembolism in adults.[34]

On July 1, 2011, the U.S. 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.[2] On November 4, 2011, the U.S. FDA approved rivaroxaban for stroke prophylaxis in patients with non-valvular atrial fibrillation. On November 2, 2012, the U.S. Food and Drug Administration (FDA) approved rivaroxaban for the treatment of patients with deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as long-term treatment to prevent recurrence.[35]

On May 24 2013 the European Commission has given its approval to rivaroxaban for secondary prevention in adult patients who have had biomarker-confirmed acute coronary syndrome (ACS). The indication is for 2.5-mg twice daily in combination with standard antiplatelet therapy.[36]

Pharmacovigilance[edit]

As in 2011, dabigatran and warfarin were the most frequently named suspect drugs in direct reports to the FDA in 2012. Rivaroxaban was ranked tenth. 582 deaths were associated with dabigatran, 151 with rivaroxaban and 56 with warfarin.[37]

In Germany the number of side-effect reports on Bayer's anticoagulant drug Xarelto appears to be increasing, and some doctors are growing wary of using the drug as a standard first-line treatment. For the first 8 months of 2013, 968 side-effect reports were filed with Germany's drug regulators, including 72 deaths. During all of 2012, the agency received 750 reports of adverse reactions, including 58 deaths.[38]

In the reports to the FDA embolic thrombotic events such as pulmonary embolism and deep vein thrombosis were much more likely to be reported in lower dose 10mg xarelto patients after hip and knee surgery, compared to atrial fibrillation patients with the 20 mg daily dose. This raises the concern whether the 10 mg dose is suboptimal for prevention of venous thromboembolism and pulmonary embolism.[39] The Netherlands Medicines Evaluation Board, based on reports from the Netherlands Pharmacovigilance Centre Lareb, reported that adverse effects were not described sufficiently in the product information for eight cases of pulmonary embolism. These reports may indicate a lack of efficacy of rivaroxaban. [40]

320 cases of serious hepato-biliar adverse events were reported by EMA during rivaroxaban treatment,[41] but in clinical trials there was no sign of serious drug-induced liver injury.[42]

Related drugs[edit]

A number of anticoagulants inhibit the activity of Factor Xa. Unfractionated heparin (UFH), low molecular weight heparin (LMWH), and fondaparinux inhibit the activity of factor Xa indirectly by binding to circulating antithrombin (AT III). These agents must be injected. Warfarin, phenprocoumon, and acenocoumarol are orally active vitamin K antagonists (VKA) which decrease hepatic synthesis of a number of coagulation factors, including Factor X. In recent years, a new series of oral, direct acting inhibitors of Factor Xa have entered clinical development. These include rivaroxaban, apixaban, betrixaban, LY517717, darexaban (YM150) and DU-176b edoxaban. Dabigatran is a direct thrombin inhibitor.[43]

References[edit]

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  23. ^ Discontinuation of Rivaroxaban Filling in the Gaps Matthew R. Reynolds, MD, MSc J Am Coll Cardiol. 2013;61(6):659-660. doi:10.1016/j.jacc.2012.09.056
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  25. ^ EHRA Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary Hein Heidbuchel , Peter Verhamme ,MarcoAlings ,Matthias Antz ,WernerHacke , Jonas Oldgren , Peter Sinnaeve ,A.JohnCamm , and Paulus Kirchhof http://www.iqanda-cme.com/assets/pdf/cmr_5075/EHRA-NOAC-Practical-ExecSumm-EHJ-2013.pdf
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  39. ^ QuarterWatch January 9, 2 01 3 — Data from 2012 Quarter 2QuarterWatch
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External links[edit]